incidental findings in genetic research

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Attachment F - Recommendations on Reporting Incidental Findings

Sachrp recommendations approved may 26, 2017 sharing study data and results: return of incidental findings, introduction.

There is currently significant attention to the distribution of study data and results, both to the subjects who participated in the research and to the public at large.  SACHRP has determined that there are four aspects of returning research results to subjects and releasing the results publicly, with overlap of the concepts along a spectrum:  

• Return of incidental findings to subjects
• Return of individual study results to subjects
• Return of general study results to subjects
• Public release of study data

SACHRP has issued four previous recommendations on this matter.  SACHRP partially addressed the issue of public release of data in December of 2013 by providing commentary in response to the June 4, 2013, Food and Drug Administration (FDA) Request for Comment relating to the availability of masked and de-identified non-summary safety and efficacy data.  While this commentary was focused on the issues presented in the FDA request for comment, it also addressed some of the broader issues associated with the public release of study data.  On March 25, 2015 SACHRP released a recommendation on the return of general study results to research subjects.  SACHRP next released a recommendation on September 28, 2015 on recent changes to HIPAA and CLIA regulations that potentially affect the return of individual research laboratory results.  SACHRP then released a recommendation on the return of individual study results to research subjects on May 19, 2016.  This final recommendation addresses the return of incidental findings to research subjects.  While there is overlap among the concepts, as shown above in the linear Venn diagram, SACHRP believes that each topic is best addressed individually for clarity.

Definition of Incidental Findings

In contrast to the return of general or individual study results to subjects, incidental findings are discoveries of individual-level findings that are unrelated to the goals of the study.  Examples include finding an indication of lung cancer in an X-ray done to look for tuberculosis for research exclusion criteria, finding a brain aneurysm during an MRI conducted for brain mapping purposes, or the discovery of a genetic marker unrelated to the goals of the study.  While most incidental findings will be discovered during clinical research, be medical in nature and have potential effect on the subject’s health, such as those just mentioned, incidental findings can occur in social behavioral and other fields of research as well, and can have implications that are not directly related to medical care.  There will be some findings that could be considered to be both an individual finding and an incidental finding, as noted in the Venn diagram above.

Definition of “Return”

It is also important to define what is meant by “return” of incidental findings.  There are several relevant issues.  First, there are many ways that results can be returned, such as discussion between the subject and their investigator or healthcare provider, postal mail, or emailing.  However, given that incidental findings will often have clinical relevance, their return to the subject should be similar to the return of clinical information in a standard clinical care setting, with the more important and complicated information being delivered personally. 

SACRHP considers “return of incidental findings” to subjects to include return of the findings to the subjects directly, to the Legally Authorized Representative (LAR) of adult subjects who lack competence, or to the parents or guardians of pediatric subjects.  The incidental findings might also be provided to the subject’s health care provider.

Another issue in considering return of incidental findings is the identity of the individuals who decide whether to return the incidental findings and, if the decision is made to return them, who will do so. The return of incidental findings is generally more a clinical issue than a research issue;  therefore the decision whether to return incidental findings could include the subject’s treating physician, the investigator and research staff, the IRB, the hospital ethics committee, or a genetic counselor or other relevant specialist.  Because there is great variability in the types of research and research settings where potentially returnable incidental findings might be uncovered, including behavioral research, there is no single preferred model for making decisions about whether to return incidental findings.  It is, however, preferable for medical concerns that an individual with a clinical relationship with the subject deliver or be involved with the delivery of information about the incidental finding.  This might be the researcher or other research team member who has a clinical relationship with the subject; however, when the researcher is not a clinician or does not have a clinical relationship with the subject, other choices may be more appropriate, such as a genetic counsellor.

For certain types of research, such as genome sequencing, it may be appropriate to return “individual” incidental findings to family members of the proband (i.e., the person serving as the starting point for genetic study of the family) as well as the proband.  However, this is a complicated ethical and legal area, and careful consideration should be given to such situations.  These considerations will be heavily fact dependent.

Finally, SACHRP notes that as the amount of time grows between the subject’s participation and the identification of the incidental finding, it becomes more administratively difficult to find the subject and to contact the investigator or another appropriate individual to return the finding.

Ethical Foundation

The provision of incidental findings to research subjects is primarily supported by the principle of beneficence.  The usual construct of an incidental finding is a directly actionable (clinically or otherwise) finding that needs to be provided to the subject in a timely manner.  However, beneficence also provides a directive to avoid harm to subjects, and to the extent that the return of incidental findings to subjects could lead to harm or discomfort, whether physical, psychological, financial, reputational or social, particularly with no offset of direct benefit, there must be consideration of whether it is appropriate to return such findings.  

In some studies, it may be impossible to provide incidental findings because the subjects are de-identified or anonymous, for example, certain tissue banking activities, research conducted under a waiver of consent, exempt studies, and cluster randomized studies.  

Validity and Actionability of Incidental Findings with Utility

When considering whether or not to return incidental findings that have potential implications for a subject’s physical or mental health, the more likely the findings are to be validated and actionable, the more justification there is for providing them.  “Actionable” can be either clinically actionable or personally actionable.  At the other end of the spectrum, those findings that are not validated and not actionable carry the least justification for return.  One way to visualize this approach is as follows:

Box 1 – Individual incidental findings that are validated and actionable.  

These would include incidental findings discovered when reviewing results of many standard clinical tests done in the context of research, such as pregnancy tests, liver function tests, EKGs, MRIs, and chest X-rays.  There is a strong presumption of disclosure for these incidental findings.  From a regulatory perspective, particularly in the medical field, “validated” will usually mean that the test or diagnosis is conducted using devices or assays that have regulatory approval from the Food and Drug Administration (FDA) or certification under CLIA from the Centers for Medicare and Medicaid Services (CMS).  

Box 2 – Incidental findings that are not validated but could be actionable.  

The decision to return incidental findings in this category will be fact dependent.  When possible, these non-validated results should be followed up with validated testing to help provide certainty, but in some situations there will not be approved or validated tests available.

Box 3 – Incidental findings that are validated but not actionable.  

An example here is a validated genetic diagnosis of Male Pattern Baldness.  SACHRP encourages consideration of disclosure in these situations, with consideration given to personal as well as clinical actionability.  Again, the decision to return incidental findings in this category is fact-dependent.  There is the possibility that the findings in question will become clinically actionable at a later date, either soon or long after the original study has concluded.  SACHRP notes that as the amount of time grows between the subject’s participation and the realization that the result is actionable, it becomes more administratively difficult to find the subject and to contact the investigator or another appropriate individual to return the finding. 

Box 4 - Results that are neither validated nor clinically actionable.  

These can include experimental results in basic science studies, such as a genetic variant that is not known to be associated with the disease of interest or any other disease.  There is not a strong presumption to make disclosure the default position for these types of purely experimental results. 

When the likelihood of identifying some incidental findings is high in a particular study (for instance, in whole genome sequencing), it may be appropriate to ask the subjects in advance if they wish to receive such information, and considerations around return of particular incidental findings may change if they become actionable in the future.

Regulatory Status

Hhs and fda human subject protection regulations.

The HHS and FDA regulations (45 CFR 46 and 21 CFR 50 and 56, respectively) are silent regarding the return of incidental findings to research subjects, and neither directly require nor disallow this activity.  However, FDA in ICH E6 Good Clinical Practice has stated that “The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.”   Similarly, FDA in the guidance document “Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects,”  says that;

The investigator should also inform a subject when medical care is needed for conditions or illnesses unrelated to the study intervention or the disease or condition under study when such condition or illness is readily apparent or identified through the screening procedures and eligibility criteria for the study. For example, if the investigator determines that the subject has had an exacerbation of an existing condition unrelated to the investigational product or the disease or condition under study, the investigator should inform the subject. The subject should also be advised to seek appropriate care from the physician who was treating the illness prior to the study, if there is one, or assist the subject in obtaining needed medical care.

Note that these guidance documents apply to clinical investigations as defined by the FDA, a distinct type of research.

The Health Insurance Portability and Accountability Act of 1996 (HIPAA) 

The Health Insurance Portability and Accountability Act of 1996 (HIPAA) (45 CFR 164) requires, among other things, that patients have access to their Protected Health Information (PHI) upon request.  There are certain exceptions, including some for research.  Subjects in research studies can obtain incidental findings from the research if they are part of the subjects’ “designated record set,” but those results may be withheld while the research is being conducted in order to protect the blinding and other research activities performed to reduce bias in the conduct of the research, as long as subjects have been informed of the access restrictions in place during the trial.  However, concerns for issues such as unblinding are less likely to arise with return of incidental findings, and this should be factored into any decision of whether to return incidental findings.

In responding to a request for access, a covered entity is not required to create new information, such as explanatory materials or analyses, that does not already exist in the designated record set.  However, individuals have a right under HIPAA to access PHI about themselves in human readable form.  Regardless of whether there are plans to return incidental findings, there may be an independent legal right under HIPAA for research participants upon request to have access to results in their designated record set.  There are laws to consider in determining whether research information can or must be provided to subjects. 

More information on this issue is available at http://www.hhs.gov/hipaa/for-professionals/privacy/guidance/access/index.html. 

The Clinical Laboratory Improvement Amendments of 1988 (CLIA)

The Clinical Laboratory Improvement Amendments of 1988 (CLIA) (42 CFR 493) is intended to ensure that laboratory results used in patient care are accurate.  CLIA contains an exception for research laboratories to return certain research results at 42 CFR 493.3(b)(2), by stating that the rules do not apply to “Research laboratories that test human specimens but do not report patient specific results for the diagnosis, prevention or treatment of any disease or impairment of, or the assessment of the health of individual patients.”  However, if individually identifiable research results are reported from the laboratory to another entity and the results are available to be used for clinical care for individual patients, then this exception does not apply.

SACHRP has separately issued a recommendation regarding HIPAA and CLIA and the return of individual results from research laboratories, and the inconsistency in the content and application of those regulations.  These considerations may arise with respect to return of incidental findings as well.  See the SACHRP recommendation issued on September 28, 2015.

Administrative Considerations

Inclusion of plans for incidental findings in the protocol and consent form.

Due to the definition and nature of incidental findings, it will not be common to include plans in research protocols for their return.  Likewise, it will not be common to address their return in consent forms.  However, there may be certain research protocols that involve processes such that the likelihood of identifying incidental findings justifies their discussion in the protocol and consent form.  Examples might include protocols involving imaging, genetic testing, or testing for infectious diseases.

Standard Process for Incidental Findings across Protocols

Some institutions, IRBs, and sponsors may find it useful to have standard procedures for incidental findings that can be applied across protocols.  Such procedures may consider the potential for disagreement about what is “actionable” and identify suggestions for determinations of actionability, especially when confirmatory testing or clinical input is needed. Because the likelihood of identifying potentially actionable incidental findings varies across studies, such procedures should be designed to be applied flexibly to different circumstances. They need not --but may -- involve the IRB, as incidental findings generally are clinical issues rather than research issues.  As noted on a protocol level basis, a standard process may make more sense in institutional settings where incidental findings are likely, such as imaging, genetic testing, or testing for infectious disease, when conducted for research purposes. For most research, it may be more than sufficient for the IRB to ask investigators to consider whether any potentially actionable incidental findings might arise and how the investigators would proceed if such a finding were identified, and to be available for consultation if questions arise.

Single IRBs

Single IRBs for multi-site research are becoming more common, a trend which will continue under the NIH policy and the Final Rule.  For a single IRB, the return of incidental findings can be considered on a protocol-specific basis, or can be considered as an issue of local research context.  As noted above, institutions might have standard processes for handling incidental findings.

The Final Rule and Provisions Regarding Return of Results

The Final Rule has new provisions regarding return of results at .104(d)(8), .116(b)(8), and .116(d)(6).  For each of these provisions it is uncertain whether either protocol specific or standard processes for providing incidental findings might constitute a plan to return individual research results within the meaning of these sections.  One clue is that the preamble cites the SACHRP recommendation on return of individual research results.

.104(d)(8) states: (8) Secondary research for which broad consent is required: Research involving the use of identifiable private information or identifiable biospecimens for secondary research use, if the following criteria are met:

(iii) An IRB conducts a limited IRB review and makes the determination required by §_.111(a)(7) and makes the determination that the research to be conducted is within the scope of the broad consent referenced in paragraph (d)(8)(i) of this section; and (iv) The investigator does not include returning individual research results to subjects as part of the study plan. This provision does not prevent an investigator from abiding by any legal requirements to return individual research results.

.116(b)(8) states: (8) A statement regarding whether clinically relevant research results, including individual research results, will be disclosed to subjects,

.116(d)(6) states: (6) Unless it is known that clinically relevant research results, including individual research results, will be disclosed to the subject in all circumstances, a statement that such results may not be disclosed to the subject;

Because incidental findings are more a clinical than a research issue, SACHRP recommends that the agencies specifically acknowledge that incidental findings are not individual research results. This will ensure flexibility in the consideration of whether and how to return incidental findings, and will make clear that IRBs and institutions are not out of compliance if they do not address returning incidental findings. The Final Rule’s provisions about return of individual research results assume a structured and organized approach to return of individual research results that does not apply to incidental findings. It may be administratively efficient, and helpful to some principal investigators, to include IRBs and research offices in the decision of whether or not and if so, how to return incidental findings, but it is not required.  

Related Letters

What should be done with unsettling ‘incidental findings’ in gene screens?

“Incidental findings” is the innocent sounding term for inadvertent but frequently unsettling discoveries made while looking for something else. They happen, for example, when genome sequencing for specific conditions reveals additional genetic variation. This variation is often of unknown significance for health and other kinds of well-being. So, how should it be handled?

Incidental findings that reveal a high risk for cancer or some other serious circumstance can be life saving. But mostly incidental findings are painful and sometimes confusing. At this still-early stage of genetic knowledge, it’s often impossible to know just what effect a particular genetic variant will have, or if it will have any effect at all.

Yet incidental findings are already an inevitable consequence of genetic tests. They are only going to get more frequent as the cost of DNA sequencing drops and direct-to-consumer testing expands. (For an exploration of many of the issues surrounding disclosure of incidental findings, see GLP’s Katherine Wendelsdorf’s article “ Personal gene maps: Is there such a thing as too much information about our DNA? ”)

Two years ago, the American College of Medical Genetics and Genomics (ACMG) held forth on the question of what to do about incidental findings. The group recommended that every time a lab conducts DNA sequencing that a doc has ordered, the lab should also test for several dozen specific genes associated with other disorders. The recommendations included BRCA1 and BRCA2 variants that are well known to increase the risk for breast and ovarian cancer, but they also covered less common gene variants, for example those that raise risk for rarer tumors such as those characteristic of Li-Fraumeni syndrome.

The ACMG argued that labs should not only do these analyses, they should report the incidental findings to anyone who ordered the tests, usually a physician. It would be up to the doc to decide whether to share this news with the patient. But ACMG also argued for disclosure to a patient when the variant is clearly linked to a disease, especially when steps can be taken to reduce the risk. The recommendations were controversial in part because they advocated disclosure even when the patient is a child or doesn’t want the information.

Enter the Presidential Commission for the Study of Bioethical Issues

In December 2013, an official government body with the impressive title of the Presidential Commission for the Study of Bioethical Issues issued its own recommendations about how to handle incidental findings. Its new report covered a variety of medical testing, including imaging studies, but put a major emphasis on genetic tests. The Commission’s recommendations differ substantially from ACMG’s. They also apply more broadly, covering not just clinical testing but also research projects and direct-to-consumer genetic testing by private companies.

The Commission’s central message is embodied in the report’s title: “Anticipate and Communicate.” Medical professionals who order such tests should expect the unexpected. Patients should be told before testing that variation unrelated to the condition being tested for might be found. Patients should decide in advance whether or not they want to be told about any such discoveries.

UK clinical geneticist Caroline Wright defends the right of patients not to know. But she also points out the reality that, whether the decision is for or against disclosure of incidentals, it’s a decision nearly always made in the absence of adequate information or evidence. She says, “[T]he level of genomic knowledge required to make an informed choice about what information to receive—or indeed not to receive—is enormous.”

Who’s your daddy?

One of the most common incidental findings in genetics has nothing to do with disease. It’s that a patient’s “father” is not her or his biological father at all. Back in the last century when I was a grad student in a genetics clinic, it was said that about 10 percent of purported fathers were not. What the Commission report calls “misattributed paternity” today is estimated to range from just one percent to as much as 20 percent of genetics patients, but I see that one in 10 remains the rule of thumb. That’s quite a significant proportion of the folks undergoing genetic tests.

The ACMG recommendations do not take up nonpaternity at all. The Commission report does discuss it a bit, using it as an example of how disclosing an incidental finding for which no preventive or positive action can be taken “has the potential to cause anxiety and distress with no corresponding medical benefit.”

The implication is that they’re against it. It’s not correct, though, to say there’s never a medical benefit. I recall two such cases from my clinic days. In each case, the father was suffering from a heritable condition and his children were at potential risk. Genetic testing, however, revealed that the patients had not fathered their apparent children, although neither they nor the children knew that.

Sticky. The docs handled the cases with superb nonchalance, however. They happily told the families not to worry, that the tests had revealed the children were not at risk. They simply skipped explaining the reason why.

I don’t know whether docs could get away with that tactful omission today; it’s an issue for the bioethicists (and maybe for policy makers and lawyers.) Today there would also be a greater risk that the families would press for details—or might even be so well informed about genetics, or such sophisticated Googlers, that they would realize the explanation was fishy.

With the possible exception of misattributed paternity, the government report mostly did not get down into the weeds of recommending disclosure of specific gene variations as the ACMG report did. It was grounded in long-established principles of bioethics such as justice, fairness and intellectual freedom and responsibility. The Commission’s recommendations were for the most part bland and unexceptional, not likely to excite controversy the way its predecessor did.

Although the report stayed away from specifics, it urged professional groups to develop lists of likely incidental findings from particular tests and also guidelines for handling them. As a practical matter, that’s likely to mean that for an unknown period of time both medical professionals and direct-to-consumer gene sequencers will be making up policies on incidental findings as they go along.

Making it up as they go along

Maybe that ad hoc approach won’t turn out so badly. Figuring out how to handle incidental genetic findings as they occur in the real world seems sensible and even forward thinking. Misattributed paternity aside, it’s not even clear how often incidental findings will actually be found. Some of the experts think accidental discoveries of significance are a certainty , especially if the test involves whole exomes or genomes. Hence, the sense of urgency in figuring out how to handle them.

But are incidentals really so frequent? Some think not. One of them is Wright.  She argues:

“Assessing someone’s genome for a hereditary genetic predisposition to breast cancer, for example, is unlikely to incidentally throw up the fact that they also have a dominant neurodegenerative disease – the mutations are in different locations and will not both be extracted by a computational search for either one of them. Simply stumbling upon clinically actionable IFs [incidental findings] in a whole genome sequence is highly unlikely.”

Eventually, I suppose, we will find out just who is right.

Tabitha M. Powledge is a long-time science journalist. She writes On Science Blogs for the PLOS Blogs Network. New posts on Fridays.

Additional Resource:

• Medics should plan ahead for incidental findings , Nature

1 thought on “What should be done with unsettling ‘incidental findings’ in gene screens?”

I am one of those people for who these accidental discoveries have provided a shock but will ultimately like survive because of them. I discovered I have BRCA1 and 2 mutations. I have zero family history of breast cancer and was considered low risk. Testing also incidentally explained why I have a long term history of depression and no success in getting antidepressant. Yes some of the stuff I found out was a huge shock but taken in the context of it being risk not absolutely fated, I think it is overwhelming useful. I only went this route because I was confronted with a two year wait for testing for a disorder for which I had a 1/1 symptomatic match and one, for which, I ultimately tested positive.

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A new genetic variant linked with obesity has been discovered, which could help explain weight gain for hundreds of thousands of people worldwide.

The researchers believe their findings may unlock new obesity treatments and are hoping to run a trial to see if a widely available, low-cost thyroid medication might be of value.

The genetic variant is a 17-nucleotide deletion that affects the small integral membrane protein (SMIM)1 and underlies a particular blood group known as Vel.

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“SMIM1 was only discovered a decade ago, as a long-sought blood group protein on red blood cells, but its other function has remained unknown until now,” explained researcher Jill Storry, PhD, from Lund University.

“It’s very exciting to find that it has a more general role in human metabolism.”

Fellow investigator Ole Pedersen, PhD, from the University of Copenhagen, added: “The whole team is very much looking forward to seeing how this new knowledge can be translated into practical solutions for people with this genetic make-up.”

Obesity rates have nearly tripled worldwide in the past 50 years and by 2030 it is estimated that a billion people will have obesity. While this is due to an imbalance between energy intake and expenditure, it is caused by genetic variants in a small minority of people.

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The investigators also compared fresh blood samples from people with different genotypes and confirmed their findings using four other cohorts.

The research suggested at least 200,000 people have the variant worldwide and it is present in one in 5000 British people, with a higher frequency in Scandinavian countries.

The SMIM1 −/−  genotype was associated with women carrying an extra 4.6 kg and men carrying an extra 2.4 kg.

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A Framework to Ethically Approach Incidental Findings in Genetic Research

Affiliations.

• 1 Department of Clinical Immunology, Sudan Medical Specialization Board, Khartoum, Sudan.
• 2 On behalf of the IFCC Task Force on Ethics (TF-E).
• PMID: 33376470
• PMCID: PMC7745305

With the advancement of science in the area of genetics and genomics, special ethical considerations should be taken in addition to the general ethical framework followed in research. Genetic research can reveal information about the susceptibility of an individual to disease and hence about his/her future health. Such information may be of interest and benefit to research participants, especially if preventive strategies exist. It may also expose them to other risks or anxieties when incidental findings that were not the primary scope of the study are found. Ethical guidelines acknowledge the duty of researchers to disclose incidental findings (IFs) to participants. In this review, we recommend four steps approach that researchers can use to disclose incidental findings: plan for IFs, discuss IFs in informed consent, identify and disclose IFs. Verification and identification of IFs should follow a categorical stratification based on the importance of the findings and the presence of a beneficial intervention to the participants.

Keywords: genetic research; genomics; incidental findings; research ethics; unsolicited findings.

Copyright © 2020 International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). All rights reserved.

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A framework to ethically address incidental findings in genetic research

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Germline and somatic genetic testing, in both clinical and research contexts, may identify secondary findings and incidental findings as a part of the test performed. Secondary findings are purposely analyzed as part of the test, but unrelated to the primary testing indication. Incidental findings are detected unexpectedly during the analysis, and also unrelated to the primary testing indication. Both of these types of variants may be disclosed as a part of the return-of-results process.

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June 21, 2024

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Study uncovers hidden DNA mechanisms of rare genetic diseases

by Pacific Northwest Research Institute

Researchers at the Pacific Northwest Research Institute (PNRI) and collaborating institutions have made a discovery that could significantly advance our understanding of genomic disorders. Their latest study, published in the journal Cell Genomics , reveals how specific DNA rearrangements called inverted triplications contribute to the development of various genetic diseases.

Genomic disorders occur when there are changes or mutations in DNA that disrupt normal biological functions. These can lead to a range of health issues, including developmental delays and neurological problems. One type of complex DNA mutation involves a structure known as a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP). This study delves into how these complex rearrangements form and their impact on human health.

The research team, led by PNRI Assistant Investigator Cláudia Carvalho, Ph.D., collaborated with her lab colleagues, study lead author Christopher Grochowski, Ph.D., from the James R. Lupski Lab at Baylor College of Medicine, and other scientists to analyze the DNA of 24 individuals with inverted triplications.

They discovered that these rearrangements are caused by segments of DNA switching templates during the repair process. Normally, DNA repair mechanisms use the undamaged complementary strand as a template to accurately repair the damaged DNA. However, sometimes during repair, the repair machinery may inadvertently switch to a different but similar sequence elsewhere in the genome.

These switches occur within pairs of inverted repeats—sections of DNA that are mirror images of each other. Inverted repeats can confuse the repair machinery, leading to the use of the wrong template, which can disrupt normal gene function and contribute to genetic disorders.

• Structural diversity: The study found that these inverted triplications generate a surprising variety of structural variations in the genome, which can lead to different health outcomes.
• Gene dosage impact: These rearrangements can alter the number of copies of certain genes, known as gene dosage. The correct number of gene copies is crucial for normal human development and function. Changes in gene dosage can cause diseases like MECP2 duplication syndrome, a rare neurodevelopmental disorder.
• Mapping breakpoints: By using advanced DNA sequencing techniques, the researchers identified the precise locations where these DNA segments switch templates leading to an altered number of genes including MECP2.

Dr. Carvalho and Baylor scientists first observed this pathogenic genomic structure in 2011 while studying MECP2duplication syndrome. Only recently, with the advent of long-read sequencing technology, has it become possible to investigate in detail how it forms in the genome.

"This study sheds light on the intricate mechanisms driving genetic rearrangements and their profound impact on rare diseases," said Dr. Carvalho, PNRI's lead scientist on the study. "By unraveling these complex DNA structures, we open new avenues for understanding the genetic causes of rare diseases and developing targeted treatments to improve patient outcomes."

These findings are being applied in a follow-up study led by Baylor's Davut Pehlivan, M.D., investigating how complex genomic structures influence the clinical features of MECP2 duplication syndrome and their impact on targeted therapeutic approaches.

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• Expert Review
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• Published: 11 June 2024

Genetics of child aggression, a systematic review

• Emiko Koyama 1 , 2 ,
• Tuana Kant 1 ,
• Atsushi Takata   ORCID: orcid.org/0000-0002-0928-4586 2 ,
• James L. Kennedy   ORCID: orcid.org/0000-0002-8733-3806 1 , 3 , 4 &
• Clement C. Zai   ORCID: orcid.org/0000-0003-0496-7262 1 , 3 , 4 , 5 , 6  

Translational Psychiatry volume  14 , Article number:  252 ( 2024 ) Cite this article

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• Psychiatric disorders

Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood aggression is attributed to genetic factors, the biological mechanism and the interplay between genes and environment that results in aggression remains elusive. The purpose of this systematic review is to provide an overview of studies examining the genetics of childhood aggression irrespective of psychiatric diagnosis. PubMed, PsycINFO, and MEDLINE databases were searched using predefined search terms for aggression, genes and the specific age group. From the 652 initially yielded studies, eighty-seven studies were systematically extracted for full-text review and for further quality assessment analyses. Findings show that (i) investigation of candidate genes, especially of MAOA (17 studies), DRD4 (13 studies), and COMT (12 studies) continue to dominate the field, although studies using other research designs and methods including genome-wide association and epigenetic studies are increasing, (ii) the published articles tend to be moderate in sizes, with variable methods of assessing aggressive behavior and inconsistent categorizations of tandem repeat variants, resulting in inconclusive findings of genetic main effects, gene-gene, and gene-environment interactions, (iii) the majority of studies are conducted on European, male-only or male-female mixed, participants. To our knowledge, this is the first study to systematically review the effects of genes on youth aggression. To understand the genetic underpinnings of childhood aggression, more research is required with larger, more diverse sample sets, consistent and reliable assessments and standardized definition of the aggression phenotypes. The search for the biological mechanisms underlying child aggression will also benefit from more varied research methods, including epigenetic studies, transcriptomic studies, gene system and genome-wide studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, and studies examining causal mechanisms.

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Introduction.

Childhood aggression is the most common reason for psychiatric referrals in children, comprising 64% of all referrals [ 1 ]. Youth are responsible for up to 200,000 homicides every year [ 2 ], and over 1000 children need emergency care for youth aggressive and physical assault-related injuries daily in the United States [ 3 ]. Aggression can be defined as behaviors that intend to create physical or emotional harm on another individual [ 4 ]. From an evolutionary standpoint, aggression has been seen as an advantageous adaptive strategy in obtaining and defending food and mates. Therefore, certain levels of aggression have continued to be positively selected for and maintained through the generations. Among preschool-aged children, temper tantrums can be considered normal [ 5 ], yet certain aggressive behaviors can develop into more severe pathological forms. Increased anger, irritation and frustration accompanied by persistent aggressive behaviors can have negative consequences throughout life such as peer rejection, relationship problems, poor academic performances and lower graduation rates, substance abuse issues, criminal behaviors, and financial and occupational difficulties [ 2 , 3 , 6 , 7 , 8 , 9 ]. Pathological aggressive behaviors not only lead to social and financial problems for the aggressor and the victims’ families, but can also have significant societal costs through increased needs for health and medical services, unemployment and welfare services, social services, and criminal justice services [ 3 , 10 , 11 ]. With a high prevalence of problematic aggressive behaviors, up to 30% of children in low income and single parent homes exhibit aggression [ 12 , 13 , 14 ]. Childhood aggression is a major public health concern that requires further understanding for better prevention and treatment strategies.

Although aggression can take on different forms and behaviors, researchers categorize aggression into two main categories: proactive and reactive aggression [ 15 , 16 ]. Proactive aggression represents aggressive behaviors that are predatory and have premeditated purposes to harm others for external or internal personal gains [ 15 ]. On the other hand, reactive aggression is the reaction to a perceived threat [ 16 , 17 ]. Proactive and reactive aggression are highly correlated and can co-occur or be expressed separately [ 15 ].

While maladaptive aggressive behaviors can exist without fitting into a specific diagnostic category, they can also be the core symptom of some of the psychiatric diagnoses such as oppositional defiant disorder (ODD), conduct disorder (CD), intermittent explosive disorder (IED) and antisocial personality disorder (ASPD) (For a review of disorders related to aggression, please see Blair et al. (2014) [ 18 ]). Symptoms of excessive aggressive behaviors start early and are highly stable [ 19 ], however expression of disruptive behaviors can change through development and can be different in children versus adults [ 18 ]. While persistent and extensive aggressive behaviors can be a symptom of ODD around age 12 [ 20 ], it can develop into CD during adolescence [ 21 ] and then further into ASPD in adulthood [ 18 ]. Therefore, it is crucial to assess aggressive behaviors from early childhood and adjust measurement methods and criteria based on the age and developmental stage of the patients. However, it is also important to note that aggressive behavior is not necessarily an essential symptom for these diagnoses.

Studies over two decades have demonstrated that there is a prominent genetic component to aggressive behaviors. It has been found that aggressive behaviors are highly heritable and genetic factors account for roughly 50–65% of the risk of high aggression [ 22 , 23 ]. Initially, chromosomal abnormalities were studied in relation to aggressive behaviors. While XYY individuals have shown to have increased aggressive behaviors [ 24 ], they do not form the whole picture [ 25 ]. Therefore, there have been numerous studies analyzing the association between genes and aggression. One of the first and landmark studies that found the genetic contributions to aggressive behaviors is the study by Brunner et al. [ 26 ]. Brunner and colleagues investigated a family with a history of criminal behaviors and found that all males were lacking monoamine oxidase A enzyme activity, which encodes the monoamine oxidase A (MAOA) enzyme that regulates catecholamine and serotonin levels [ 27 ]. Following that, Caspi et al. (2002) [ 28 ] further investigated the association between MAOA genotypes and aggressive behaviors in abused males, further supporting that variants within genes may influence aggressive behaviors. There has been significant research conducted on the genetics of aggression in adults [ 29 , 30 ]. Nonetheless, a study on two large population cohorts with ages from 12–73 years reported that effects of polygenic risk scores for childhood aggression appeared to decrease from childhood and adulthood to later life [ 31 ], suggesting that while child and adult aggression are genetically similar, it is conceivable that some genetic factors underlying ADHD in children and later life may be different [ 32 ], thus emphasizing the importance of studying the genetics of aggression in different age groups separately. There have been various genes in different biological pathways investigated in association to childhood aggression, including dopaminergic, serotonergic, vasopressin and oxytocin system genes (For an earlier review of the genetics of aggressive behaviors, please see Anholt & Mackat (2012) [ 33 ]). Researchers agree that childhood aggression is a polygenic trait, with numerous genes of small effects contributing to the phenotype.

Although numerous studies demonstrate evidence for genes underlying childhood-onset aggression and there are previous reviews focusing on certain genes, there has not been a review that systematically considers every gene that has been studied in relation to childhood aggression. The objective of this study was to systematically review the literature to provide a comprehensive summary and informed analyses of the genes influencing aggressive behaviors specifically in child and adolescent populations.

Literature search

The literature search was performed on May 20, 2022 using the PUBMED, MEDLINE, and PsycINFO databases. Pubmed search yielded 256 hits using the following search terms: ((aggression [MESH] OR aggressive behav* [TIAB] OR aggressive trait* [TIAB])AND (genes [MESH] OR genetics [TIAB] OR epigenetics [TIAB] OR genom* [TIAB] OR genot* [TIAB] OR GWAS [TIAB]) NOT (neoplasms [MESH] OR tumor* [TIAB] OR cancer* [TIAB])) and applying the filter for Child (birth to 18) and human studies. Ovid MEDLINE and PsycINFO searches yielded 111 and 280 articles respectively using the following search terms: ((aggression.mh. or aggressive behav*.ab. or aggressive behav*.ti. or aggressive trait*.ab. or aggressive trait*.ti.) AND (genes.mh. or genetics.ab. or genetics.ti. or epigenetics.ab. or epigenetics.ti. or genom*.ab. or genom*.ti. or genot*.ab. or genot*.ti. or GWAS.ab. or GWAS.ti.)); FILTER for “Child (0 to 18 years)” and (“human”). Five relevant articles were subsequently added as a result of manual search and articles available to the authors. Of the 652 hits, 215 articles were found to be duplicates and were removed, leaving 437 studies qualifying for initial screening. As a result of initial title and abstract screening, 137 articles were found to be irrelevant, leaving 300 articles eligible for full-text review.

Inclusion and exclusion criteria

Since the purpose of our systematic review was to provide an overview of studies examining genes associated with childhood aggression, only articles examining aggression in children and adolescents aged 18 years or younger were included in this study. There were a few articles, however, that were included in our review despite the participants being older than 18 years of age at the time of assessment, because the participants were asked to rate their aggression retrospectively for when they were younger than age 18.

Studies were excluded from further review if they were: (1) written in a language other than English, (2) dissertations & conference abstracts, (3) full text was not available, (4) review articles, (5) wrong patient population (ex: only studying children who were victims of aggression) or study design (ex:case studies), (6) included adult participants or (7) tested phenotypes other than aggression. As a result of these criteria, 212 studies were excluded. The most common reasons for exclusion were the inclusion of the adult population ( n  = 128), wrong patient population or study design ( n  = 36), and the outcome not being related to child aggression ( n  = 22). Eighty-seven articles were subject to data extraction and quality assessment. The PRISMA flow chart is shown in Fig. 1 .

Flow chart showing the number of studies from our literature search and the number of studies removed during title/abstract screen and full-text review together a text box showing the reasons for exclusion.

Data extraction and quality assessment

Data extraction was performed by three independent reviewers (CZ, TK, and EK). The following information was extracted for each study: First author, year of publication, population characteristics, study type (twin/pedigree studies, longitudinal, candidate gene etc.), participants’ ancestry or country of origin, sex, age, sample size, genes assessed, assessment of aggression, and key findings related to aggression (Table 1 ). The quality of each article was evaluated regarding the risk of bias on a 4 point scale (ranging from low risk to critical) using the following criteria: sample size, confounding, participant selection, measurement of outcomes, selection of reported results and overall risk of bias (Table S1 ). Abstract screening, full text review, quality assessment, and data extraction were managed in Covidence.

Eighty-seven studies were included in our data extraction and quality assessment. The general summary of these articles can be found in Table 1 . Seventy percent ( n  = 61) of the articles examined samples from European ancestry. Eighty percent ( n  = 70) of studies included both females and males, while 19% ( n  = 16) studies only included males. Only one study included only females in their study.

The first research study retrieved using our search strategy was by Twitchell and colleagues in 2001 [ 34 ], which examined the genetics of child aggression among offspring of alcoholic fathers. Until 2006, childhood aggression was examined in association with particular psychiatric disorders, such as ADHD, CD and ODD, and studies examining aggression as a transdiagnostic behavioral phenotype were rare. The first studies used the candidate gene approach, which continues to be the major research method (74% of all studies) used in studying the genetics of childhood aggression. Until 2007, studies focused on several key genes, including serotonin transporter, MAOA , and dopamine D4 receptor. From 2011, genome-wide association studies started to be published, although the sample size remained relatively small (n < 1000) until 2016 [ 35 ].

Twin / pedigree studies

Throughout the years, researchers focused on twin studies for heritability and understanding the contribution of genes to aggressive behaviors. Studies have demonstrated a significant heritability for aggressive behaviors of up to 60% [ 36 , 37 , 38 ]. However the influence of genes can be augmented by the environment such that it decreases with decreasing positive social feedback [ 37 ] or increasing parental negativity [ 38 ]. From the genetic influences, mainly additive genetic factors have been found to explain the variability; they accounted for 15-77% of the variance in social aggression [ 39 ] and up to 90% of the individual differences in baseline impulsive aggression in the longitudinal Quebec Newborn Twin Study [ 40 ]. Interestingly, the effects of genetic factors on aggressive behaviors can change over time [ 41 ] and the influence of genes on the variation of aggressive behaviors can change over development (18% genetic influence in early-middle adolescent to 47% genetic influence in middle adolescent) [ 42 ]. Although the magnitude of the influence may change, genetic factors still account for the stability of physical aggression as well as can explain the individual differences in the initial levels and the rate of change of aggressive behaviors over time in a longitudinal Canadian sample [ 41 ].

Candidate gene studies

The majority (77%; n  = 67) of genetic studies in childhood aggression used a candidate gene approach. The most commonly investigated genes include monoamine oxidase A ( MAOA; n  = 17), dopamine D4 receptor ( DRD4 , n  = 13), and catechol-o-methyltransferase ( COMT , n  = 12). Many of these candidate gene studies, however, suffer from methodological issues including small sample size (often <500), lack of psychometrically sound assessments of aggression, and inconsistencies in the cutoffs and categorization of repeat polymorphisms, thus making generalization of findings difficult.

Monoamine oxidase A—MAOA

The MAOA gene is located on the X-chromosome (Xp11.23) and encodes for MAOA, an enzyme which catabolizes monoamine neurotransmitters such as serotonin, epinephrine, norepinephrine and dopamine. In our systematic review, MAOA was assessed in over a quarter of the studies assessing candidate genes ( n  = 17 ; one study was categorized as epigenetic studies). The most commonly examined polymorphism is MAOA -uVNTR, the 30-bp repeat polymorphism, which can exist in 2 repeats (2 R), 3 R, 3.5 R, 4 R, and 5 R. Many studies regard the 2 R, 3 R, and 5 R to be low activity variants (MAOA-L), and the 3.5 R and 4 R to be high activity variants (MAOA-H) [ 27 ]. Nevertheless, there is great variation across studies in the categorization of low and high activity repeats (see Table 1 ), making direct comparisons of findings across studies challenging.

The first study that investigated the association between MAOA -uVNTR and childhood aggressive behavior in the context of ADHD reported that low transcription (3 R only) alleles of MAOA -uVNTR was associated with higher aggression among children with ADHD [ 43 ]. Similarly, different studies have also found that the low-expression (2 R, 3 R, and 5 R) MAOA -uVNTR to be associated with childhood aggression, although their categorization of low-expression alleles differ [ 44 ]. On the other hand although fewer in number, some studies have reported that the high-expression variant was associated with increased aggressive behavior in children [ 45 ].

While the reason for these inconsistent findings across studies has not been fully examined, several researchers have suggested that developmental age may have an influence on the observed effects of MAOA risk alleles. Pingault et al. [ 46 ] examined the age-dependent contribution of six MAOA SNPs on childhood physical aggression using a longitudinal dataset of 436 boys followed annually from ages 6 to 12 in Quebec, Canada.The results showed that the T-allele carriers for rs5906957 had lower initial levels of physical aggression and also a less steeper decline in physical aggression over time compared to the C allele carriers. In a similar vein, Kant et al. [ 47 ] examined the effect of MAOA -uVNTR on aggression and psychopathic traits by developmental age. The 194 male participants were divided into those below age 13 ( n  = 132) and those at or above age 13 ( n  = 62). While MAOA -uVNTR was not significantly related to aggression in either age group, there was an interesting pattern in that, in the younger age group, oppositional defiant problems and conduct problems were associated with the high-activity MAOA 4 R allele (MAOA-H), whereas in the older age group, oppositional defiant problems and callous-unemotional traits were more significantly associated with the low-activity MAOA 3 R allele (MAOA-L). More studies are required to confirm the age-dependent association of MAOA on aggressive behavior.

It should be noted, however, that the majority of studies reported no significant main effects for MAOA gene variants on childhood aggression [ 48 ]. Despite this, following the example of Caspi et al.’s [ 28 ] seminal study which reported no significant main effect of MAOA -uVNTR but a significant MAOA gene by childhood maltreatment interaction, several studies examining gene-by-environment interaction have been conducted. Various types of environmental exposure have been examined, including child maltreatment, abuse [ 49 , 50 , 51 ], and parenting behaviors [ 52 , 53 , 54 , 55 ]. These gene-environment interaction studies have sometimes been used to test theories regarding the role of genes and environment in childhood aggression. For example, Zhang et al. [ 54 ] sought to test two related hypotheses regarding the role of gene and environment: Diathesis-stress (i.e., carriers of certain genetic risk variants will show greater aggression when exposed to adverse environments) and differential susceptibility (i.e., not only do carriers of certain genetic variants show greater aggression when exposed to adverse environments, the carriers of the same genetic variants will show less aggression when exposed to supportive environments). This study with 1399 healthy Han Chinese adolescents supported the differential susceptibility hypothesis; males who had the T allele and females who had the homozygous for the T/T genotypes for MAOA rs6323 (T941G) were more likely to exhibit reactive aggression when the mothers exhibited low levels of positive parenting but were less likely to exhibit reactive aggression when mothers exhibited high levels of positive parenting.

Catechol-O-Methyltransferase—COMT

Catechol-o-methyltransferase (COMT) is an enzyme that metabolizes catecholamine neurotransmitters including dopamine, epinephrine, and norepinephrine. It has two isoforms, a longer membrane-bound (MB-COMT) isoform that is expressed mainly in neurons in the brain [ 56 ], and a shorter soluble (S-COMT) isoform that is expressed in other tissues such as blood, liver, and kidney. It is coded by the COMT gene, which is localized on chromosome 22q11.21. A common single-nucleotide polymorphism, rs4680 (Val158Met), within the coding region of COMT changes the amino acid Valine at position 158 of MB-COMT to Methionine, which decreases the thermostability and activity of COMT enzyme. The role of COMT in aggression was initially supported by observations of hostility in mice deficient in Comt and the negative correlation between COMT levels and hostility in men with behavioral problems as children [ 57 , 58 ]; reviewed in Qayyum et al. (2015) [ 59 ].

The COMT genetic variants, particularly rs4680, have received a similar level of attention as MAOA in association studies of child aggression. The first published study that examined a possible association between COMT gene and child aggression was in the context of ADHD, where Caspi et al. [ 60 ] reported an association among ADHD patients of Val/Val with increased aggression compared to Met-carriers; the association was replicated across three samples within this study. Other studies reported high aggression being associated with either Met-allele carriers [ 61 ], or no significant association [ 62 ]. Few studies examined SNPs other than rs4680, with one reporting rs6269 A/G heterozygotes being over-represented in cases compared to adult controls [ 63 ] and another reported non-significant results for rs6267 (Ala22/72Ser in S/MB-COMT) [ 64 ].

The possible association of COMT with child aggression has been examined in the context of interactions with environmental or demographic variables. For example, in a birth cohort study, among children who scored high on disorganized attachment, Val/Val carriers exhibited greater increase in aggression from 4 years to 6 years of age than Met-allele carriers [ 65 ]. The same research group also reported that, among those with stressful life events, rs4680 Val/Val homozygotes were more aggressive than Met-allele carriers, while the reverse was observed among those without stressful life events [ 66 ]. In a study on Chinese early adolescents, Val/Val carriers were reported to display higher reactive aggression compared to Met-allele carriers in the context of higher positive parenting scores, but lower reactive aggression compared to Met-allele carriers with lower positive parenting scores [ 54 ]. Age and sex may also be an effect modifier for the effect of rs4680 on risk of child aggression. For example, Kant and colleagues [ 67 ] demonstrated that among European males at least 13 years of age, Val-allele carriers had higher CBCL aggressive scores than non-carriers ( p  = 0.03). In contrast, among those younger than 13, Met/Met genotype carriers had increased conduct problems compared to Val-allele carriers ( p  = 0.03). These associations were not observed in females in their sample. A three-way interaction was reported, where carriers of the COMT low-activity rs6267 T allele and MAOA rs6323 T allele displayed higher aggressive behavior in the presence of high academic pressure than those with low academic pressure; this association was not observed in carriers of other genotype combinations [ 64 ]. Further efforts in large samples are needed to confirm these preliminary interaction findings and pursue more complex interaction analyses.

Dopamine system genes

The dopamine system is vital to the regulation of motor and cognitive behaviors, and dopamine dysregulation has been implicated in multiple psychiatric and behavioral disorders.

Within the dopamine system, aside from COMT mentioned above, the most studied dopamine system gene in child aggression is the dopamine D4 receptor-encoding DRD4 , which is localized on 11p15.5. The 48-bp exon III variable number tandem repeat (VNTR) polymorphism [ 68 , 69 ] is the extensively studied DRD4 polymorphism, for which between two to eleven repeats (R) have been observed in humans, with the 4-repeat (4 R), 2 R, and 7 R being the most commonly observed alleles. Functional significance of this polymorphism has been demonstrated [ 70 , 71 , 72 , 73 , 74 , 75 ]. The 7 R has been shown to reduce in-vitro DRD4 expression [ 73 ] and to be less likely to form heterodimers with the dopamine D2 receptor [ 76 ], while the 4 R allele appears to be less responsive to quinpirole-mediated DRD4 upregulation [ 74 ].

The larger repeat (7 R or 6-8 R) alleles were associated with high aggression in an Italian sample [ 77 ], the Mannheim Study of Children at Risk study [ 78 ], and the Ben-Gurion University Infant Developmental Study [ 79 ], while the 3 R allele ( p  = 0.014) and rs3758653 C/C genotype were nominally associated with aggressive behavioral impulsivity in the International Multicenter ADHD Genetics (IMAGE) study [ 80 ]. The VNTR was not associated with externalizing behavior in a longitudinal community sample of 87 boys [ 81 ], within our earlier sample of 48 clinically referred aggressive boys [ 81 ], or our later sample of 144 high aggression child cases and adult controls [ 82 ].

A number of gene-environment interaction findings have been reported for DRD4 . In a study on the Dutch Twin Registry sample, a significant VNTR-by-maternal sensitivity interaction was observed. More specifically, larger repeat allele (7 R or 6-8 R)-carrying genotypes were associated with higher externalizing behaviors or aggression compared to 7 R non-carrying genotypes (e.g., 2–4 R) only in the context of maternal insensitivity [ 83 ], high maternal prenatal stress [ 84 ], or low-aggression peer play environment [ 85 ]. Besides COMT and DRD4 , only few other dopamine system genes have been examined in child aggression, with our group reporting that DRD2 rs1799978 (A-241G) G-allele carrying genotypes, rs1079598 C/C genotype, and rs1800497 (TaqIA) T/T genotype were overrepresented in high aggression cases compared to adult controls [ 82 ]. A significant DRD4 -by-socioeconomic status interaction in high aggression scores has been reported, where the 6–8 R carriers with low socioeconomic status had higher aggression scores compared to other comparison groups [ 77 ].

Serotonin system genes

Under the serotonin system genes, the most extensively studied polymorphism is the 5-hydroxy-tryptamine-linked polymorphic region (5-HTTLPR) polymorphism of the SLC6A4 gene.

5-HTTLPR long allele (L/L genotype) was associated with higher CBCL aggressive behaviors score in 607 Italian children [ 77 ]. Interaction between low socioeconomic status and 5-HTTLPR long alleles further demonstrated significant effects on aggressive behaviors [ 77 ]. A smaller sample consisting of 62 European participants similarly reported an increased risk for behavioral disinhibition and aggressive behaviors with the L/L genotype when compared to S/S and S/L [ 34 ]. On the other hand, Beitchman and colleagues [ 86 ] reported a significant effect of 5-HTTLPR on aggression with the low expressing (S/S, Lg/S, Lg/Lg) genotypes in children with clinically severe aggression. Similarly, the S-allele was significantly associated with teacher reported aggressive behaviors at age 9 for both boys and girls [ 87 ] and with increased aggressive behaviors and hostility in a group of female Caucasian Russian swimmers [ 88 ].

There are also studies that did not yield significant 5-HTTLPR main effect findings on childhood aggression. Several studies on European children and adolescents [ 78 , 89 ] and Chinese adolescents [ 51 ] did not report a significant main effect of 5-HTTLPR on aggressive behaviors and related phenotypes. Similarly, the initial analyses of the study on 87 adopted children from the United States of America further failed to detect a main effect of 5-HTTLPR and aggressive scores [ 90 ]. However interestingly, when the biological parent status and sex of the children were included in the analyses, the results were significant. Male children with S/S or S/L (short) demonstrated increased aggressive behaviors while females with the SS and SL demonstrated lower levels of aggression. Moreover, when the biological parent of the child was considered antisocial, adolescents, but not preadolescents, demonstrated a significant increase in aggressive behaviors with the L/L genotype [ 90 ].

Although some studies failed to report a significant main effect of 5-HTTLPR on aggressive behaviors, they demonstrated a significant gene-gene interaction on behavior. Zhang and colleagues [ 51 ] reported that there was a three-way interaction between MAOA high activity, 5-HTTLPR and sexual abuse on aggressive behaviors. Children with MAOA high activity, 5-HTTLPR S/S allele and with increased sexual abuse experience exhibited higher aggressive behaviors [ 51 ]. Furthermore, there was a significant interaction between 5-HTTLPR S/S genotype and DRD4 7 R on increased aggression scores [ 78 ], while Nobile and colleagues [ 77 ] demonstrated increased aggression with DRD4 VNTR 6-8 R and 5-HTTLPR L/L genotype.

Other polymorphisms of serotonin system genes that have been studied in relation to childhood aggression include SLC6A4 VNTR polymorphism and tryptophan hydroxylase 2 ( TPH2) gene polymorphisms. Neither the SLC6A4 VNTR [ 86 ] nor the TPH2 rs4570625 polymorphism [ 91 ] demonstrated significant associations with childhood aggression. Furthermore, four SNPs of the 5-hydroxytryptamine receptor 2   A (HTR2A) gene that encodes for one of the receptors for serotonin failed to have a significant difference between the conduct disorder cases and controls in adolescents [ 92 ]. However, in adolescent cases, G/G genotype or the G allele carriers of rs2070040, C-allele carriers of rs9534511 and G-T haplotype of rs2070040- rs9534511 were associated with increased aggressive scores [ 92 ]. On the other hand, in adolescent controls T/C haplotype of rs4142900-rs9534512 was associated with the increased aggressive behaviors [ 92 ]. Other serotonin receptor encoding gene polymorphisms, including 5-hydroxytryptamine receptor 1B [ 93 , 94 ] , 1E [ 95 ] and 2   C [ 96 ] further demonstrated significant effects on childhood aggression ( Table 1 ) . Lastly, a recent comprehensive study analyzing the association between polygenic score indexing serotonin functioning and aggression demonstrated that adolescents with higher serotonin polygenic risk (lower levels of serotonin functioning) had an increased risk for aggressive and antisocial behaviors [ 97 ].

Hypothalamic-pituitary-adrenal (HPA) axis and hormonal signaling genes

HPA axis refers to the neuroendocrine system that involves the hypothalamus, pituitary, and adrenal glands and is responsible for stress response and regulation of various biological processes such as food digestion and immune response. The hypothalamus secretes corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in response to physical or psychological stress. These two neurohormones are transported to the pituitary through blood vessels and bind to the CRH and AVP receptors respectively and stimulate the release of adrenocorticotropic hormone (ACTH). ACTH then stimulates the secretion of glucocorticoids such as cortisol. Glucocorticoids in turn provide a negative feedback signal to inhibit the secretion of CRH and AVP from the hypothalamus and ACTH from the pituitary gland, respectively. Animal studies have consistently shown a robust association between the HPA axis and aggressive behavior [ 98 ]. Nevertheless, relatively few studies have interrogated genes along the HPA axis with regards to childhood aggression.

Several researchers have investigated the arginine-vasopressin related genes in association with childhood aggression. Zai et al. [ 99 ] examined eleven SNPs from the AVP receptor 1 A ( AVPR1A ), AVPR1B , and AVP genes in 177 children with high aggression and ethnicity and sex matched adult controls and found a significant association between childhood aggression and AVPR1B rs35369693, as well as the two-marker haplotype containing rs35369693 and rs28676508. Similarly, Malik et al.’s [ 100 ] study compared 182 clinically aggressive children of European ancestry with 182 sex, age and ancestry-matched non-aggressive controls and found that the A allele and the AA genotype of the rs3761249 SNP of the AVP gene was underrepresented in highly aggressive male cases, whereas AVPR1A rs1174811 G allele was over-represented in highly aggressive female cases. While the former studies examined SNPs in the AVP pathway, Vollebregt et al. [ 101 ] examined two microsatellites, RS1 and RS3, of the AVPR1A gene among children with pervasive aggression and non-aggressive age-matched controls. They found that the RS3 long repeat variants were nominally associated with non-aggressive status. It is noteworthy that Pappa et al.’s [ 35 ] genome-wide association study also found an association between the AVPR1A gene and childhood aggressive behavior in a post-hoc gene-based analysis, warranting further investigations of AVPR1A gene variants.

With regards to the corticotropin releasing hormone (CRH), Liu et al. [ 102 ] reported that the carriers of the G allele and the GG genotype for rs24924 of the corticotropin-releasing hormone receptor CRHR1 gene were overrepresented among young offenders of violent crime compared to non-violent control adults in a Han Chinese sample.

The FKBP5 is a co-chaperone of the glucocorticoid receptor. Studying the association of the FKBP5 gene with childhood aggression, Bryushkova et al. [ 103 ] did not find significant main effects with any of the SNPs within the gene, but found a significant gene-environment interaction in that A allele carriers of the FKBP5 rs4713916 who were exposed to maltreatment exhibited the highest levels of aggression.

Oxytocin (OXT) is a nonapeptide most widely known for its stress-reducing effects and has been shown to affect prosocial behaviors, emotional recognition and feelings of trust [ 104 , 105 , 106 ]. The gene coding for OXT receptor ( OXTR ) has been examined in association with childhood aggression. The study by Malik et al. [ 100 ] found that OXTR rs237898 A allele was over-represented in high aggression children. Other studies have found a gene-by-environment interaction between variants in the OXTR gene and stressful life events [ 107 ]. Glenn et al., [ 108 ] found that the variations in the OXTR gene moderated the effectiveness of, Coping Power, a disruptive behavior modification program.

Genome-wide association studies

We have identified 12 genome-wide association studies (GWASs) of child aggression, the majority of which were performed on children and adolescents with European ancestry. The first GWAS focused on the Dysregulation Profile from CBCL (which consists of Attention Problems, aggressive behavior, and anxious/depressed clinical subscales) among 341 ADHD children from 339 ADHD affected trio families [ 109 ]. This study found no genome-wide statistically significant associations ( P  < 5 × 10 –8 ); however, TMEM132D , LRRC7 , and STIP1 were identified as nominally significant [ 109 ]. The second GWAS on 398 ADHD child cases from Cardiff and 5,081 controls from the Wellcome Trust Case Control Consortium (Phase 2) found higher polygenic risk scores for ADHD (ADHD-PRS) scores in ADHD cases with diagnosis of conduct disorder compared to those without, and positive correlation between ADHD-PRS and the number of aggressive conduct disorder symptoms within cases [ 110 ]. The first GWAS by the EAGLE (Early Genetics and Lifecourse Epidemiology) Consortium performed quasi-Poisson regression on aggression scores across nine cohorts with a total of 18,988 participants from early childhood and mid-childhood/ early adolescence and reported a near genome-wide significant variant (rs11126630, P  = 5.3e–8) at 2p12 and a significant gene ( AVPR1A ) [ 35 ]. They also reported that the 450,000 tested common variants accounted for between 10% and 54% of the variance in aggression across three sample sets ranging from 3 to 6 years of age [ 35 ]. The authors suggested that the large range of observed SNP heritability could be due to different sample characteristics, environmental contributions, and ages across these samples [ 35 ]. With additional samples across the age ranges, we may be able to capture the pattern of genetic components across development. [ 35 ] The authors followed up with GWAS of aggression subtypes as well as a cross-trait gene-based meta-analysis of GWAS of aggression with GWAS of volume of amygdala, nucleus accumbens, or caudate nucleus [ 111 ]. They found the MECON (MDS1 And EVI1 Complex Locus) gene to be associated with cross-trait construct of aggression and nucleus accumbens volume, and the AVPR1A gene to be associated with the construct of aggression and amygdala volume. Another GWAS of aggressiveness during childhood on 1050 adult ADHD patients and 750 child ADHD patients reported the top suggestive variant in a long non-coding RNA gene on chromosome 10 (rs10826548) and the top suggestive gene to be WD repeat domain 62 ( WDR62 ) [ 112 ].

A Polygenic risk score (PRS) is an estimate of the genetic risk for a phenotype of interest and is generally calculated based on the number of risk alleles each person possesses and the effect sizes of these risk alleles [ 113 ]. Genetic correlation is an estimate of the genetic similarity between two complex phenotypes by calculating the correlation of phenotypic effects across genetic variants [ 114 ]. In a longitudinal study of children of diverse low-income families from the Women, Infants, and Children Nutritional Supplement Programs (WIC) study, PRS for child aggression [ 35 ] based on all SNPs with p  < 0.05 or SNPs mapped to gene regions were not significantly associated with aggression at any age from early to mid-childhood, while PRSs enriched for SNPs with putative biological function were associated with aggression, with effect estimate appeared to change through early childhood (age 2–5 years) to mid-childhood (age 7.5–10.5 years) [ 115 ]. In a more recent study on the WIC sample, higher aggression-PRS based on the EAGLE Consortium GWAS [ 35 ] appeared to predict greater co-occurring internalizing/externalizing problems at age 14 via negative affectivity observed during parent-child play at age 3 [ 116 ]. In a sample of 404 participants from a school-based program consisting of two preventive interventions for early learning and aggressive/ disruptive behaviors, polygenic risk scores for conduct disorder from the SAGE (Study of Addiction: Genes and Environment) sample, an interaction between polygenic risk scores and exposure to community violence was observed such that among those who endorsed witnessing violence, conduct disorder PRS was negatively associated with likelihood of being in the high-aggression group (or positively associated with likelihood of being in the lowest aggression group [ 117 ]). In the most recently published GWAS of aggression with multiple observations in 87,485 children from ages 1.5–18 across multiple sites, instruments, and study designs, SNP heritability was reported to be 3.31% [ 118 ]. Though no genome-wide significant SNPs were found, three genes emerged as showing association with childhood aggression from gene-based analysis: ST3GAL3 ( p  = 1.6e–6), PCDH7 ( p  = 2.0e–6), and IPO13 ( p  = 2.5e–6). The authors also reported significant genetic correlation between aggression and 36 phenotypes, including positive correlations between aggression and ADHD, smoking, major depressive disorder, and autism spectrum disorder, as well as negative correlations between aggression and age at smoking initiation, intelligence, and educational attainment [ 118 ].

Mendelian randomization studies

One potentially powerful way in which genes have been used in the research literature is to clarify the causal mechanism between a predictor variable and outcome. This approach, known as Mendelian Randomization, uses genes as an instrumental variable, that is, a variable that predicts the predictor variable but not other confounding variables. Because genetic variants are inherited at random from the parents to their child, it can act as a quasi-randomized experiment.

Only one study was identified that used Mendelian Randomization to examine childhood aggression. Chao et al. [ 119 ] sought to examine the causal effect of alcohol consumption during adolescence and externalizing behaviors (including aggression; evaluated by Youth Self Report [ 120 ]) in 1608 Chinese adolescents. The Glu504Lys (rs671) polymorphism within the aldehyde dehydrogenase 2 family member-encoding ALDH2 gene, having established effects on enzyme function [ 121 , 122 , 123 ] and consistent associations with alcohol use-related phenotypes [ 124 , 125 ], was used as the instrumental variable. The results showed that decreased ALDH2 function was significantly associated with lower alcohol use, and also with lower aggression problems. Alcohol use was found to be a significant mediator of the relationship between ALDH2 and aggression, thus supporting the hypothesis that alcohol use causes adolescent aggression.

Epigenetic studies

Our search resulted in two epigenetic studies. Provençal and colleagues [ 126 ] conducted a case-control study for 8 high-aggression case and 12 control participants and studied T cell DNA methylation using methylated DNA immunoprecipitation (MeDIP) followed by hybridization to microarrays. Their results reported that 227 and 171 distinct gene promoters were methylated significantly more in the control and high aggression group, respectively. From the differentially methylation genes, AVPR1A , HTR1D and GRM5 were less methylated while DRD1 and SLC6A3 were more methylated in the high aggression group. More recently, Cecil and colleagues [ 127 ] demonstrated that there were seven differentially methylated sites across the genome in children who developed early onset conduct problems from an epigenome-wide association study (EWAS). Results of their follow-up studies with 15 candidate genes that were previously studied in relation to childhood aggression demonstrated that MAOA, BDNF and FKBP5 were further associated with early onset of conduct problems in children [ 127 ].

To our knowledge, this is the first systematic review that specifically focuses on the genetics of childhood aggression. Overall, there is growing interest in this research area, as evidenced by the growing number of studies since 2001 (Fig. 2 ). Twin and pedigree studies support a prominent genetic component in liability for childhood aggression, which encourages further research to replicate and clarify findings from existing literature. The majority of gene association studies were candidate gene studies, which have focused on the MAOA, DRD4 and COMT genes with mixed findings of their main effects. For the majority of candidate genes we reviewed, the positive findings (if any) have not been replicated in childhood aggression GWASs thus far [ 128 ]. It should be noted that many of the earlier childhood aggression candidate gene studies and GWASs were limited by insufficient sample sizes, lending itself to potential spurious relationship reportings and overestimation of effect sizes, a phenomenon known as the winner’s curse [ 129 , 130 ]. Nonetheless, we found converging evidence for a role of AVPR1A in child aggression coming from genome-wide association [ 35 ], epigenomic [ 126 ], and candidate gene [ 101 ] studies. This warrants further investigation into the mechanism through which AVPR1A affects risk of child aggression and demonstrates that the use of diverse genetic study methodologies can facilitate genetic discoveries.

Number of childhood aggression studies. A histogram showing the number of childhood aggression genetic studies published per year.

The conclusions from this review should be interpreted with the following considerations. Firstly, only studies that were in the English language were included, which may have biased the results to studies examining primarily European participants. Second, because our main focus for this systematic review was to shed light on the genetics of childhood aggression using only mesh terms of variants of the word aggression, studies that did not have direct assessments of childhood aggression or used only psychiatric diagnoses (e..g, ADHD, conduct disorder, oppositional defiant disorder) as proxies for aggressive behaviors would have been excluded. Furthermore, with null findings possibly not being reported and statistically significant findings tending to be published, publication bias is likely when drawing generalized conclusions from these published results [ 131 ].

Quality assessment of studies included in this review identified a number of areas where improvements will help advance the field of child aggression genetics. Sample size is a major limitation, with 74% of the studies being rated as moderate to serious in our quality assessment (Supplementary Table S1 ). Although it is more apparent in earlier candidate gene studies, it also remains a limiting factor in identifying genetic markers for child aggression GWASs. As many genetic studies also examined gene-gene and/or gene-environment interactions, even larger sample sizes are required. Another consideration is the definition and measurement of child aggression, for which 75% of the studies have been rated as moderate to critical (Table S1 ). The assessment methods of aggression varied substantially across studies in terms of tools and informants ( Table 1 ) , which may have increased heterogeneity and limited comparability across studies. Another consideration is the variability in the inclusion of potential confounding factors as well as that of environmental factors being examined in interaction with genetic factors, for which 95% of the articles have been rated as moderate to serious (Table S1 ). There are numerous prenatal and postnatal environmental factors, such as socioeconomic status, childhood trauma, abuse and maltreatment, parenting styles, maternal sensitivity, prenatal stress, parental psychiatric disorders and alcohol use, that may influence the effects of genes on aggressive behaviors (reviewed in [ 132 ]). Studies using standardized measures of aggression and considering multiple environmental and confounding factors will help to disentangle the complexity surrounding child aggression.

Moreover, studies were limited with their participant selections where 92% of the studies has been rated as moderate to serious ( Table S1 ) . While the majority of the studies included only participants of European ancestry (Table S2 ) in order to limit spurious findings due to population stratification, the results may not be generalizable to participants of other ancestries [ 63 , 133 ]. More studies on participants of non-European ancestries are important in gaining additional insights into biological pathways for child aggression [ 134 ], as demonstrated in multi-ancestry GWASs of other phenotypes such as asthma [ 135 ] and rheumatoid arthritis [ 136 ]. Moreover, 16 studies included in this review only included male participants, while only one study included only female participants. Sex is a major factor that may modify the gene-behavior association. While males are three times more likely to exhibit aggressive behaviors than females due to both biological and cultural factors [ 137 , 138 , 139 ], the effects of genes on behavior may also be modified by sex-specific factors such as the levels of testosterone and Y-chromosome genes [ 140 , 141 ]. Therefore more studies focusing on females are necessary to understand the genetics underlying female youth aggressive behaviors.

Furthermore, developmental age is another major factor that may change the effects of genes on childhood aggression [ 142 ] due to factors including the changing levels of gene expression, hormones, and enzymatic activity during development [ 142 , 143 , 144 ]. Study designs and data analyses that account for age and/or development in their study designs and data analyses, as age-stratified analyses [ 47 , 67 ] and longitudinal assessments for changes in aggressive behavior and related factors may uncover novel associations and clarify mixed findings in the literature.

Lastly, it is important to note that GWAS does not directly interrogate other types of genetic variants, such as repeat polymorphisms (e.g., MAOA -uVTNR, 5-HTTLPR, DRD4 exon III VNTR, AVPR1A RS1 and RS3). Examining the correlation between SNPs and these repeat polymorphisms will help in incorporating this type of polymorphisms in GWAS. Incorporation of rare variants, copy number variants, and other genetic variants besides SNPs and repeat polymorphisms in whole-genome analyses would likely help in explaining additional portions of the risk for child aggression and understanding the genetic architecture underlying child aggression [ 145 , 146 , 147 , 148 , 149 ]. Building consensus on the designation of risk vs. non-risk alleles, low vs. high activity genotypes, and short vs. long allele cutoffs in repeat polymorphisms will also facilitate the interpretation and generalizability of research findings across studies.

There are many future directions that can be followed from the results and limitations found from our systematic review of the literature. Most prominently, with candidate gene studies continuing to dominate the field of childhood aggression research, there is a greater need for more varied approaches, including epigenetic studies, gene expression studies, interrogation of rare [ 145 ] and/or more complex variants [ 148 ] in addition to SNPs, gene system studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, as well as studies examining causal mechanisms related to aggressive behavior.

With the exception of ADHD and autism spectrum disorder, there is a paucity of well-powered GWASs in pediatric populations [ 150 , 151 ], especially for aggressive behaviors and related phenotypes such as disruptive behavior disorders, conduct disorders, as well as externalizing and internalizing behaviors. There are a few studies that have investigated aggression-related phenotypes in the context of ADHD and other psychiatric disorders using summary data such as the Psychiatric Genetics Consortium, with one study noting an increased contribution of common genetic variants to ADHD with disruptive behavior disorder compared to ADHD without disruptive behavior disorder, with a portion of that increase attributed to genetic variants associated with aggression [ 152 ]. Genomic analyses of the genetic architectures of aggression and related phenotypes in youth as well as their co-occurrences will improve our understanding of the unique and shared genetic components across these phenotypes and across the lifespan [ 110 , 152 ]. Therefore, future research is warranted focusing on the shared genetic architecture of aggression and the related phenotypes.

Extreme and persistent childhood aggression continues to be a public health concern worldwide with potentially serious lifelong consequences to the perpetrator, the victim, and their loved ones, as well as incurring major costs to the society as a whole [ 153 ]. To devise effective early identification, intervention, and prevention strategies, an understanding of the biological mechanisms and environmental determinants of excessive childhood aggression is paramount. However, it is crucial to consider the factors such as sex, environment, development, and ethnicity when analyzing the effects of genes on child aggression. Although we found that the quality of the reviewed studies improved over time, the overall risk of bias for 95% of current evidence were rated as moderate to serious (Table S1 ). Improvement to the research design including larger sample size and standardized, reliable assessment of aggressive behavior, as well as triangulation of research evidence using diverse genetic research methodologies, will facilitate the advancement of genetic research in childhood aggression.

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Acknowledgements

This manuscript was written in memory of the late Dr. Joseph H. Beitchman, whose dedication, devotion and extensive work in genetics underlying childhood aggression continues to inspire.

We would like to acknowledge the following funding sources: Platform Program for Promotion of Genome Medicine (JP23km0405214) from the Japan Agency for Medical Research and Development (AMED), JSPS KAKENHI under Grant Numbers 21H02855 and 22H02991 (AT); CAMH Foundation (JLK, EK, TK, CCZ) and Brain and Behavior Research Foundation (CCZ).

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Emiko Koyama, Tuana Kant, James L. Kennedy & Clement C. Zai

Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, Wako, Japan

Emiko Koyama & Atsushi Takata

Department of Psychiatry, University of Toronto, Toronto, ON, Canada

James L. Kennedy & Clement C. Zai

Institute of Medical Science, University of Toronto, Toronto, ON, Canada

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Clement C. Zai

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

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EK, TK, CCZ designed and carried out the literature searches. EK, TK, and CCZ performed title/abstract screening and full-text reviews. EK, TK, and CCZ performed data extractions and quality assessments. EK, TK, and CCZ wrote the first draft. EK, TK, CCZ, AT, and JLK reviewed the manuscript.

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JLK is a member of the Scientific Advisory Board of Myriad Neurosciences Inc. JLK and CCZ are authors on patents for pharmacogenetic interventions and suicide markers. EK, TK, and AT reported no conflict of interest related to this paper.

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Koyama, E., Kant, T., Takata, A. et al. Genetics of child aggression, a systematic review. Transl Psychiatry 14 , 252 (2024). https://doi.org/10.1038/s41398-024-02870-7

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Received : 17 March 2023

Revised : 07 March 2024

Accepted : 11 March 2024

Published : 11 June 2024

DOI : https://doi.org/10.1038/s41398-024-02870-7

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Managing Incidental Findings in Human Subjects Research

Researchers, institutional review boards (IRBs), participants in human subjects research, and their families face an important but largely neglected problem — how should incidental findings (IFs) be managed in human subjects research. If researchers unexpectedly stumble upon information of potential health or reproductive significance, should they seek expert evaluation, contact the participant’s physician, tell the research participant, or respond with some combination? What should consent forms and the entire consent process say about how IFs will be handled in research? What should IRBs require?

An IF is a finding concerning an individual research participant that has potential health or reproductive importance and is discovered in the course of conducting research but is beyond the aims of the study. This means that IFs may be on variables not directly under study and may not be anticipated in the research protocol. Examples include:

• an IF on a genomic microarray suggesting a genetic or chromosomal variant of potential clinical importance beyond the variants or genotypephenotype associations directly under study,
• an IF of misattributed paternity or parentage in a genetic family study,
• an unexpected mass or aneurysm visualized in the course of structural magnetic resonance imaging (MRI) of the brain, and
• an unexpected mass at the base of the lung discovered in computed tomography (CT) colonography.

We focus here on IFs discovered in the course of research, not clinical care. A significant literature already addresses incidental or accidental findings discovered in the course of non-research clinical care or screening ( e.g ., an adrenal tumor serendipitously discovered, sometimes called an “incidentaloma”). 1 However, attention to IFs in research is at an earlier stage. No consensus exists as yet on how to handle them.

Research IFs can arise in collecting and analyzing research images and data, but may also arise in determining whether a potential research participant qualifies for inclusion in the study population or in collecting baseline physiological information. Examples of eligibility and baseline IFs include discovery of an anomalous EKG of potential clinical concern in determining whether a potential research participant qualifies as a normal control for a cardiac study, or similar unexpected findings of abnormal blood pressure, blood chemistry, or pregnancy.

We focus here on physiological and genetic IFs, rather than social and behavioral IFs. An example of the latter would be observed signs of alcohol abuse in an adolescent serving as a research participant in a functional MRI (fMRI) study of adolescent cognition that is unrelated to alcohol use. Other examples would include signs of physical abuse or suicidality in studies unrelated to those phenomena. Social and behavioral IFs raise somewhat different issues. For instance, some may be harder to ascertain than physiological and genetic IFs, and law may compel reporting signs of abuse to authorities.

We further focus on IFs in two major research domains, genetic/genomic research and imaging

An IF is a finding concerning an individual research participant that has potential health or reproductive importance and is discovered in the course of conducting research but is beyond the aims of the study. This means that IFs may be on variables not directly under study and may not be anticipated in the research protocol.

research. Commentators are beginning to recognize the tremendous importance of IFs in genetic and genomic research, particularly as we now face a genomic revolution in medicine. 2 Genetic family research actually yielded one of the earliest discussed types of IF, misattributed paternity. 3 With the later growth of genomic research and now genome-wide studies, substantial debate exists on whether to return individual research results to participants. 4 Less discussed is the equally important question of whether to return IFs, including IFs that emerge in reanalysis of archived datasets.

Comparison to IFs in imaging studies is instructive. Defining IFs in imaging studies tends to be easier ( e.g ., an extracolonic finding in CT colonography research). Further, both empirical study of IFs and normative discussion of how best to handle them are more advanced in imaging than in genetic and genomic research. 5 Our imaging comparisons focus on neuroimaging research using MRI and CT colonography research, two specific domains in which progress has been made on IFs.

We consequently analyzed:

• IFs in genetics/genomics, examining a range of research methodologies from (a) genetic family studies to identify genetic and/or chromosomal variants associated with phenotypic disease, susceptibility, or carrier status; to (b) large-scale genomic analysis of stretches of the human genome including whole-genome analysis (WGA) (or genome-wide association studies (GWAS)) often using some type of microarray chip in order to identify genetic, genomic, and/or chromosomal variants; to
• IFs in imaging, using as our examples anatomic imaging of the brain by MRI (whether in structural studies of the brain or as a structural prelude to functional studies of brain activation in fMRI) and imaging of the colon and extracolonic torso in CT colonography.

These comparisons allowed us to explore the contrasts among these research domains shown in Table 1 .

Research Domains Studied to Form Recommendations on Handling Research IFs

This paper thus offers recommendations for how to anticipate and manage IFs in genetic and genomic research and in imaging research, focusing on neuroimaging using MRI and CT colonography as examples. However, our analysis suggests broader application to other domains of human subjects research.

A growing literature calls for guidance on how to manage research IFs and attempts to document the prevalence of IFs in different kinds of research. Studies vary in their methodology and sample, yielding a wide range of prevalence figures, but nonetheless suggesting that researchers face the IF problem with some frequency. Thus, the literature reports:

• an IF of misattributed paternity at a prevalence often cited at 10% for the general population, though this figure is hard to verify and a range of numbers have been found in different populations in both research and non-research settings, 6
• an IF in 13%-84% of brain fMRI or MRI scans, 7 and
• an IF defined as an extracolonic findings in 15%-89% of participants’ images. 8

Clearly, more research is needed to clarify prevalence for different kinds of IFs in different research populations including affected participants and normal controls. However, the data to date suggest that researchers and IRBs should anticipate IFs and consider in advance how best to manage them. 9

Research IFs raise difficult questions including:

• Do researchers, including non-M.D. researchers, have an obligation to examine their data for IFs and recognize them?
• What should researchers do once they see a suspected IF? For example, should they seek a consult with a specialist with expertise in clinically evaluating the data or scan in question ( e.g ., a radiologist, neuroradiologist, or a clinical geneticist)? In the case of a genetics IF, should they seek testing from a genetics laboratory approved to perform clinical tests under the Clinical Laboratory Improvements Amendments (CLIA)? 10
• What, if anything, should the research participant be told?
• What should the guardian of the minor participant or representative of an adult participant with diminished mental capacity be told?
• What should research protocols and consent forms say about how IFs will be handled and what should IRBs require?

These are some of the key questions we addressed in performing a multi-disciplinary evaluation of how IFs are being approached now and should be handled. We examined the ethical, legal, scientific, and clinical questions. This paper presents our normative conclusions, schooled by empirical analysis of the guidance on IFs currently available to researchers. Thus, we analyzed whether and how model research consent forms on the websites of the 100 universities receiving the most National Institutes of Health (NIH) research funding currently address IFs; whether and how research consent forms publicly available on the Internet currently address IFs; what federal authorities recommend, if anything (including NIH, the Food & Drug Administration (FDA), Centers for Disease Control (CDC), and Department of Veterans Affairs (VA)); and what key professional societies germane to the research domains on which we focus recommend, if anything. Those data are reported and analyzed elsewhere. 11 However, they show that there is little guidance available on how to handle IFs in research and no consensus as yet on the best approach. We sought to address this problem.

I. How Do IFs Arise?

We found that IFs arise somewhat differently in each research domain on which we focused.

A. Genetic Family Studies

Individuals, couples, and families may seek genetic analysis in the course of clinical care and reproductive planning. 12 Here, however, we are focusing on genetic family studies in the course of research. Researchers may identify a genetic or chromosomal variant that they suspect causes or increases susceptibility to phenotypic disease or disability; the researchers may then seek to study genetic and phenotypic patterns in an affected family or families to better understand the underlying genetics. Conversely, researchers may start with a phenotypic disease or disability and pursue genetic analysis of a family or families to seek the genetic cause or susceptibility.

Typically in such studies, researchers seek to perform genetic analysis of family members known to be affected as well as others in the family to clarify whether the latter are affected, carriers, or unaffected. The family pattern, or pedigree, may shed light on the underlying genetics. The genetics itself may be clarified through linkage analysis, molecular DNA analysis, analyzing the metabolic products of genetic variants, or chromosomal analysis (by a range of methods including karyotyping and array comparative genomic hybridization (aCGH)). Thus, although we discuss below large-scale studies using genomic microarrays, microarrays may also be used in smaller-scale family genetic studies.

In the course of performing family studies, misattributed paternity or other misattributed lineage may be discovered by the researchers. 13 For example, if a child is affected by a disorder recessively transmitted and the mother but not the father is a carrier, this will suggest misattributed paternity. If neither parent is a carrier, this may suggest undisclosed adoption, embryo donation, or some other scenario in which the rearing parents are not the genetic parents. Though studies report roughly a 10% incidence of misattributed paternity, there is wide agreement that this figure is poorly supported and more data are needed. 14 Perhaps the most ethically challenging finding of misattributed paternity in a genetic family study would reveal incest; we have found no incidence figures on this. Ravitsky and Wilfond also note misattributed ethnic or cultural identity in ancestry studies and a finding bearing on genetic basis of tribal affiliation. 15

A second form of IF in genetic family research is unexpected discovery of a genetic or chromosomal variant of potential clinical concern that is not the variant under study. Chromosomal analysis could reveal unexpected abnormalities in chromosomal regions not under study. Similarly, linkage analysis could reveal unexpected mutations in the regions under study or nearby regions. We have found no studies reporting the incidence of this kind of research IF.

A substantial amount of genetic family research is performed in research labs that are not CLIA-certified to perform testing for clinical diagnosis. For some genetic conditions under study there simply is no CLIA-approved laboratory offering testing. 16 According to Gene Tests ( www.geneclinics.org ), genetic testing is available for approximately 1500 diseases in its database, but for approximately 20% of those conditions, genetic testing is only available in a research laboratory. 17 This means that some IFs will be found by labs that are not certified to perform clinical genetic testing and further, that for some of those genetic IFs, no confirmatory testing by a CLIA-approved laboratory will be available.

B. Large-Scale Genomic Studies Using Microarrays

While genetic studies tend to focus on one gene or a small number of genes, genomic studies focus on many genes and their interaction by studying segments of the genome. Increasingly, research involves collecting data on the entire genome (as in GWAS). Genomic research tends to involve large numbers of subjects in population-based investigation of the relationship between genomic and phenotypic variations. Typically these studies utilize genomic microarrays to allow efficient analysis of large numbers of data points in many subjects.

Genomic microarrays use chips (pieces of DNA or RNA (probes) deposited in an array on a solid surface such as a microscope slide) to analyze genetic or chromosomal variants over large stretches of the genome. There are several kinds of microarrays, including those capturing data on DNA and on RNA expression and microarrays for analysis of cytogenetic abnormalities. Microarrays perform analysis at different levels of genomic resolution depending on the probes used and how the applicable software analyzes the data points. Thus, microarray analysis may reveal the sequence of base pairs, the presence of genes, gene expression, or chromosomal variation.

A chip may target only areas under study or may not be targeted and indeed may cover the full genome. Even a targeted chip may be designed to include genomic regions bordering the region of focal concern and so may pick up IFs in those adjacent regions. The chip is coupled with computer software to perform the analysis. Even when the chip itself is not targeted to areas under study, the software may be designed to mask all except the domain to be analyzed. Here again, however, the software may analyze regions adjacent to those directly under study. Though some laboratories design their own chip and software to address their research questions, others purchase commercially available products, which may or may not be tailored to the research question at issue.

The potential for genomic microarrays to generate IFs depends on the research question under investigation. If microarray analysis is used to identify genomic patterns associated with certain phenotypic pathologies or susceptibilities, then an IF would be a genomic pattern of potential clinical concern beyond those patterns under study. This could include copy-number variants (CNVs), genetic insertions, deletions, and duplications whose meaning is not clear but whose deviation from normal is great enough to raise health concerns. 18 If the chip is not targeted to the domains under study and the software does not mask other results, the opportunities for IFs will increase. However, even if the chip is targeted or the software masks other results, unexpected patterns not under study in the genetic and chromosomal regions being examined may yield IFs, as may unexpected pleiotropy (the phenomenon whereby a single gene can code for multiple phenotypic traits, such as in the case of APOE alleles, which can affect susceptibility to both cardiac and Alzheimer disease, so that research on the genetics of susceptibility to cardiac disease may thus also reveal susceptibility to Alzheimer disease). In addition, IFs may appear in analysis of boundary regions, as noted above.

Microarrays can also be used in research ranging over large stretches of the genome or the whole genome to seek associations between genetic patterns and phenotypic pathology in populations. Increasingly, tissue sample biobanks and DNA databanks are being set up to facilitate this kind of large-scale genomic epidemiology often pursued as “discovery research.” 19 In such discovery research it is harder to identify what might be an IF, as any genomic pattern correlating with pathology may be captured and studied. However, if the declared aim of genomic research analysis is to study certain pathologies ( e.g ., cardiac illness, high blood pressure, or asthma), genomic patterns suggesting other clinical concerns for an individual may be considered IFs.

We have found almost no literature on IFs in genomic microarray analysis and no studies of incidence. One recent article argues statistically that genomic medicine using microarray analysis can be expected to produce an abundance of IFs, many of which will turn out to be false positives in normal populations. 20 This study, however, did not focus on research IFs distinguished from clinical IFs. 21

Much genomic analysis will be conducted in research labs that are not CLIA-approved to perform clinical genetic testing. 22 Thus, IFs may be discovered in such labs and, depending on the genetic IF of concern, confirmatory testing by a CLIA-approved lab may or may not be available.

C. MRI of the Brain

Structural MRI of the brain reveals anatomical structures in the brain and elsewhere in the skull, depending on the field imaged. Although MRI is not the only neuroimaging methodology (others include CT scans, positron emission tomography (PET) scans, and single photon emission computed tomography (SPECT) scans), MRI research is sufficiently active that it has yielded the most developed discussion of IFs to date. 23 This may be because, as compared to other imaging technologies, MRI is more commonly used to study normal populations due to its signal characteristics and lack of ionizing radiation. The literature on IFs in MRI research on the brain focuses on structural (as opposed to functional) anomalies of potential health concern on MRI scans. Data on what constitutes normal versus anomalous function in the brain are not yet robust enough to discriminate reliably functional anomalies of potential clinical concern. Thus, we focus on structural IFs generated by MRI, whether generated by structural or functional imaging.

Whenever the brain and other contents of the skull are imaged, anatomical malformations, masses, evidence of cranial bleed or stroke, evidence of infection, evidence of injury, and evidence of dementia may be discovered. However, research scans are typically not optimized to image these IFs; the scan sequences are different in research, yielding less detailed information about brain anatomy. 24 Further, researchers investigating the brain using MRI may not be trained to interpret the scan clinically; they may not be neuroradiologists, radiologists, or even physicians. Much neuroimaging research is conducted by Ph.D.s, particularly functional MRI research. Even the broader research team may not include someone trained to read scans clinically. Thus, IFs may arise when a Ph.D. principal investigator, co-investigators, or students read a research scan but happen to notice something that looks unusual.

As noted above, studies report IF prevalence rates of 13%-84%. Prevalence may be affected by the study population, scanning protocol, and definition of IF. IFs are classified as needing immediate referral, urgent referral, routine referral, or no referral. (See Table 2 .) IFs needing immediate referral were found in up to 1.2% of participants; IFs needing urgent referral were found in 0.4% to 14% of participants; IFs needing routine referral were found in 1.8% to 43% of participants; and IFs needing no referral were found in 13% to 40.4% of participants. 25

Comparison of Classification Systems for Incidental Findings in Imaging

Recommendations to date on how to handle IFs in neuroimaging focus on issues including whether researchers have a duty to seek consultation from a neuroradiologist or radiologist to determine whether an IF requiring further clinical attention is present and to whom the IF should be reported. 26

D. CT Colonography Research

CT colonography is an imaging technology moving rapidly into clinical use. However, significant research continues including The National CT Colonography Trial (“ACRIN 6664”). 27 Unlike traditional colonoscopy, which invasively visualizes the colon and rectum after bowel cleansing and sedation by intubating the colon with an endoscope, CT colonography uses low-dose CT scans to image the colorectum following bowel preparation and air insufflation. CT colonography images the entire pelvis and abdomen as well as the lung bases. CT colonography thus has the capacity to identify IFs throughout the torso. Indeed, a recent report compiling the prevalence of extracolonic findings found in a number of studies shows that 40% of patients are recorded as having IFs. 28 These IFs include anatomical malformations, masses, aneurysms, evidence of infection, and evidence of injury or trauma. However, CT colonography at a low-radiation dose and without the use of intravenous or oral contrast material may fail to detect important extracolonic low-attenuating lesions ( e.g. , gastric carcinoma). 29

Our analysis of key ethics sources concludes that researchers have an obligation to address the possibility of discovering IFs not only in their protocol and communications with the IRB, but also in their consent forms and communications with those being recruited to the study and research participants.

Because CT colonography involves insufflation of the colon through a rectal catheter and carries a small risk of colonic perforation, 30 the procedure is performed in a clinical setting. The exam itself is generally performed by a radiologic technologist and nurse (or radiologist), with the researcher-physician interpreting CT colonography datasets at an off-line computer workstation. Depending on the study design, CT results may be communicated to an endoscopist prior to subsequent colonoscopy to provide a comparison reference standard. Research participants in CT colonography studies may be at normal or at increased risk for colon cancer, symptomatic or asymptomatic, or may be referred following an incomplete endoscopy. In this research context, then, IFs generally refer to extracolonic findings (those outside of the colon) or less commonly colonic findings unrelated to colonic neoplasia ( e.g ., inflammatory bowel disease). Note that some CT colonography studies such as ACRIN 6664 have prospectively included evaluation of extracolonic findings as a specific sub-aim of their study, so that IFs in this research context are greatly reduced by the broad aims of the study.

Research CT colonography datasets are generally interpreted by specialized abdominal radiologists, who are familiar with the clinical implications of IFs and potential follow-up tests. Faced with a scan that images the entire torso, research colonographers routinely examine the colorectal data for neoplasia and extracolonic abdomen and pelvis for other findings of potential health significance. Extracolonic findings in research colonography are considered IFs and are usually dictated at the time of the procedure. 31 IFs of high clinical significance, defined as those requiring medical or surgical attention, 32 are communicated to the participant or the participant’s physician through a variety of mechanisms, including a formal clinical report, a letter or fax to the physician, or direct participant contact. 33 While many colonography researchers report discussing the potential for IFs with research participants prior to CT scanning, fewer researchers have included an explanation of IFs in their written consent form. 34 The cost of diagnostic imaging to follow up on IFs is estimated to be approximately $24–$34 per participant in the study. 35

A scale for grading and reporting extracolonic findings (E0 to E4) based on their significance and specificity (“C-RADS”) has been developed by the Working Group on Virtual Colonography. 36 (See Table 2 .) An E0 indicates “limited exam” and an E1 a “normal exam or anatomic variant.” An E2 marks a “clinically unimportant finding” for which a work-up is not indicated. An E3 finding signals a “likely unimportant finding, incompletely characterized” for which a “work-up may be indicated.” Most serious is an E4 designation, for a “potentially important finding;” reporting the finding to the referring physician is required. This scale tries to tailor response to the probable gravity of the finding and avoid over-reporting of unimportant findings, as these can lead to unnecessary costs and burdens of work-up, participant anxiety, and even harm resulting from the follow-up tests.

It is tempting to define IFs in CT colonography simply on the basis of anatomical location, that is, all findings outside the colon. However, some findings within the colon may be unexpected and beyond the variables of immediate concern. This would include structural abnormalities ( e.g ., diverticulitis) unrelated to disease processes of concern, objects in the colon, and evidence of injury or trauma ( e.g ., perforation at prior endoscopy).

As noted above, studies have found IFs in 15% to 89% of study participants, depending on the population’s risk profile. Though the majority of these findings are considered clinically insignificant, approximately 10% of participants have an extracolonic finding of potential medical significance needing further clinical response. 37 Thus, radiologists have begun to address the question of which IFs are insignificant and should not be reported. Some CT colonography researchers have adopted a practice of reporting only highly significant IFs, as some radiological findings are nonspecific or common. 38 Further, the Fleischner Society of thoracic radiologists now recommends that for non-smokers at low risk, no follow-up surveillance

If an IF is identified and thought to merit a clinical evaluation, it may turn out to be a false-positive, once the suspected pathology is ruled out, or it may yield ambiguous results at work-up, with pathology neither verified nor ruled out. In both of these cases, identification of the IF yields burden with no clear benefit.

is needed when an incidental pulmonary nodule of 4 mm or less is discovered at CT. 39 This is part of a larger emerging debate in CT colonography over the net benefit or burden of identifying specific extracolonic findings. 40

E. Reanalysis of Archived Data

Each of these research domains may generate data archived for future reanalysis. In genetic family research, the blood or other cells analyzed may be preserved or the genetic data derived from samples may be archived to allow further analysis. Genomic micro-array research is particularly likely to yield datasets archived for future reanalysis. Indeed, researchers may intentionally gather more data than needed for their own research in order to permit further analysis later. A number of researchers, research institutions, and commercial laboratories are establishing DNA biobanks to permit successive analyses over time and important public databases have been established, with requirements that researchers deposit their data. 41 Neuroimaging and CT colonography datasets are generally archived digitally on computer hard drives, or preserved as part of the patient record using PACS (picture archiving and communication systems) along with clinical radiological images. 42

Archived data preserved for reanalysis in future research studies raise the question of what constitutes an IF in the future study — should it be defined with reference to the aims of the original study or the reanalysis or both? Further, what obligations do secondary researchers (and those following) have to identify and report IFs? Do the original researchers who collected the data retain an obligation to the research participants that would create ongoing duties with respect to subsequently identified IFs? 43 Underlying these questions is the issue of whether these datasets should be anonymized and if so, to what degree. 44

If the data are fully anonymized and identification of research participants is impossible, even for the original researchers, then IFs cannot be reported to individual research participants. Moreover, the research no longer meets the definition of human subjects research in the federal Common Rule setting ethics standards for human subjects research. 45 However, archived data may be less fully anonymized, so that secondary researchers have access to identifying information or a code rendering subjects identifiable. Secondary researchers may have direct access to that information, access through the original researchers, or access through an independent intermediary. Controversy surrounds research on data that the secondary researcher cannot identify but that the original researchers or an independent intermediary can indeed identify because they hold the code: does this research qualify as human subjects research and impose obligations accordingly, even on the secondary researchers? 46

At the bottom line, whenever archived data are not fully anonymized (that is, the original researchers, secondary researchers, or an independent intermediary can identify individual research participants), the IF problem may remain. Indeed, one can argue that data should not be anonymized simply for the purposes of avoiding the IF problem, as this may deprive research participants of potential clinical benefit. 47 NIH policy for genome-wide association studies (GWAS) conducted or supported by NIH provides for later submission to a GWAS repository without identifiable information but in coded form, with the keys held by submitting institutions. Thus, “the NIH GWAS data repository and secondary data users...will not be able to return individual results directly to subjects. Secondary investigators may share their findings with primary investigators, who may determine whether... to return individual or aggregate research results to participants whose health may be affected....” 48 Consequently, an IF likely to be life-saving or allow the research participant to avoid or ameliorate grave disease would raise the question of whether the institution holding the code should be notified of the IF to consider contacting the research participant. We consider this further below.

II. Framework for Recommendations

Researchers have ethical duties to research participants that derive from several primary sources. Federal regulations governing human subjects research (both the Common Rule used by a large number of federal agencies 49 and variants at other agencies such as the FDA 50 ) set substantive requirements for ethical research and a procedural system for applying them through local IRBs. However, a large literature on research ethics interprets those rules and bases further researcher obligations on additional statements of research ethics ( e.g ., by professional societies and international bodies) 51 as well as analysis of the research participant’s vulnerability and the researcher’s special obligations toward participants. 52

Our analysis of key ethics sources concludes that researchers have an obligation to address the possibility of discovering IFs not only in their protocol and communications with the IRB, but also in their consent forms and communications with those being recruited to the study and research participants. Researchers have a further obligation to establish a pathway for handling suspected IFs and to communicate that to the IRB and research participants. In many, but not all circumstances, researchers have an obligation to offer to report IFs to research participants. In the case of minor or incompetent participants, this duty obligates the researcher to offer IFs to the participant’s guardian or representative. In research on archived data not fully anonymized, IFs of high importance should prompt researchers to consider an effort to contact research participants; that effort may best be undertaken by the original researcher who had contact with the research participant rather than the secondary researcher who had none. We elaborate below.

It is important to recognize at the outset of our analysis that IFs raise the question of when the researchers should initiate evaluation and disclosure of information uncovered in research. There is a distinct debate on returning research information at the request of research participants . Federal privacy rules under HIPAA are relevant to the latter question, 53 as is NIH and NHGRI policy. 54 However, the rules on participant-initiated disclosure do not resolve the question of how researchers should define, evaluate, and handle IFs.

While federal regulations on human subjects research do not address IFs explicitly, a number of provisions apply. With studies increasingly documenting the prevalence of IFs, IFs are both a predictable risk and benefit of research. This dual character makes a number of protections germane.

First, federal regulations require that consent forms and the consent process address both risks and benefits of the research. Consent forms must describe “any reasonably foreseeable risks” and “any benefits.” 55 For a research participant recruited as a normal control, discovery of an IF suggesting pathology may trigger anxiety, burdens, and the costs of further evaluation to verify or rule out a clinical problem. Even research participants with known pathology risk discovery of an unrelated IF, triggering the same. These risks are present whether or not discovery of the IF leads to a clinically useful diagnosis.

If an IF is identified and thought to merit a clinical evaluation, it may turn out to be a false-positive, once the suspected pathology is ruled out, or it may yield ambiguous results at work-up, with pathology neither verified nor ruled out. In both of these cases, identification of the IF yields burden with no clear benefit. Identification of such IFs is a predictable risk of research. However, some IFs will lead to diagnoses of clinical importance. Identifying an operable brain tumor in a college student serving as a normal control in an fMRI study of cognition, for example, may prove life-saving. For such a research participant, taking part in the study imposes both the risk of discovering an IF and potential benefit of discovering serious pathology in time to intervene.

These risks and potential benefits are intrinsic to research modalities that have the potential to yield information beyond the variables directly under study. Imaging research is a classic example, with fMRI neuroimaging research visualizing cranial anatomy and CT colonography research imaging extracolonic anatomy throughout the torso. But genetic family research similarly reveals genetic relatedness or nonrelatedness, even when that is not the object of the study and is unacknowledged within the family. Both genetic and genomic research may also reveal genetic or chromosomal variants of concern beyond the specific genes, chromosomes, or genomic relationships under study.

The risks and benefits of discovering IFs in research require explicit discussion in the consent process. 56 Without that, research participants may not appreciate the risk of discovering an IF, being offered information they did not expect, and triggering an evaluation. They may also have unrealistic expectations on the benefit side. Here, two errors are likely. Participants may underestimate benefit by failing to appreciate that the burden of discovering an IF will in some cases be offset by ultimate clinical benefit. But more likely (given relative inattention to research IFs until recently) is that participants may overestimate benefit by expecting that any anatomy imaged or genetics/genomics being studied is thereby being screened for clinical problems. This is a new form of the well-documented therapeutic misconception, research participants’ mistaken assumption that research interventions will benefit them clinically. 57 In the IFs context, the misconception is not that the research intervention ( e.g ., a drug under study) will yield clinical benefit, but that the research process itself ( e.g ., the imaging or genetic analysis) will yield such benefit. Research participants may assume that researchers will identify and report any clinical problems in anatomy imaged or genetic regions analyzed; researchers’ silence on the topic of clinical problems may be misinterpreted by research participants as a clean bill of health. Research participants may not appreciate that the MRI sequences and scans used to image their brain in a study were not optimized for clinical diagnosis, because the purpose was research. Participants in a genetic or genomic study similarly may not understand what genetic or chromosomal domains were not analyzed as part of the research and that the analytic tests used were not validated for clinical use.

Thus, it is essential to address the risks and benefits associated with IFs in the consent process. This is reinforced by regulatory provisions that IRBs may require consent forms to include a “statement that significant new findings developed during the course of research which may relate to the subject’s willingness to continue participation will be provided to the subject.” 58 An IF suggesting a brain tumor or an aneurysm requiring immediate work-up may well affect a participant’s willingness to continue in neuroimaging research. In genetic or genomic research, discovery of an IF suggesting a serious genetic problem not under study may derail a participant’s willingness to continue in the research. In genetic family research, an IF revealing undisclosed adoption or other nonrelatedness may affect the participant’s willingness to continue in the study; indeed, that individual’s genetic makeup may no longer be relevant to the research.

So far, we have simply suggested that researchers should address with participants the risks and benefits associated with IFs. However, researchers need to do more, to address both with participants and with the IRB how IFs will be handled as part of the research protocol. Indeed, the pathway established for handling IFs will determine the character and magnitude of the risks and benefits involved. For example, a non-M.D. neuroimaging research team with no process for consulting a radiologist or neuroradiologist may both miss IFs of concern and misconstrue normal images as suggesting an IF. Further, with no process set up for fast consultation, they may not be able to provide the benefit of timely identification of an IF meriting immediate work-up.

Researchers have an obligation to set up a process for recognizing IFs, verifying whether there is indeed a suspicious finding of concern, and offering the finding to the research participant (or the guardian or representative of a minor or incompetent participant) for clinical evaluation and follow-up. The regulations require not only that risks to participants be communicated as part of the consent process, but that risks be minimized. 59 This suggests that researchers should minimize several risks relating to IFs: the risk of failing to recognize an IF that may require clinical follow-up, the risk of identifying an IF but ignoring it or failing to offer information to the research participant, and the risk of communicating an IF to a participant causing anxiety and follow-up when more careful scrutiny shows no IF or the finding turns out to be benign. All of this suggests an obligation to set up a process for identifying, assessing, and communicating IFs.

That obligation is further supported by the regulatory requirement that risks be “reasonable in relation to anticipated benefits, if any, to subjects.” 60 The risk of IFs is intrinsic to research generating any information beyond the variables directly under study. That risk must be offset by the benefits that can flow from timely identification, assessment, and communication of IFs, allowing clinical evaluation and intervention. We recommend below specific steps for managing IFs.

Recognizing researcher obligations to offer participants information on IFs of likely health or reproductive importance is consistent with an emerging view that researchers bear some clinical obligations toward research participants. Research ethics has traditionally drawn a sharp distinction between the responsibilities of health professionals rendering clinical care and the responsibilities of researchers. Clinicians’ duty of care has not been imposed on researchers. However, Richardson and Belsky have challenged this paradigm, arguing that research participants’ vulnerability and researchers’ discretion mean that researchers might owe participants a limited duty to provide ”ancillary care,” including evaluating research brain scans and then following up appropriately on life-threatening findings. 61 They argue that researchers are neither personal physicians with a full-blown duty of care, nor “mere scientists” with no obligation of care, but instead occupy an intermediate category. Research participants entrust aspects of their welfare to researchers, and within that scope of entrustment, may be entitled to identification, evaluation, and communication of clinically important IFs. 62

Note that this view would impose full duties of care on a personal physician acting as researcher toward the patient/participant, and lesser duties of care on the researcher who is not personal physician. Even the non-M.D. researcher would have duties by virtue

We strike a middle ground. We show respect for research participants’ objective welfare as well as their subjective interests by including IFs of likely health or reproductive importance to the participant. At the same time, we focus on participants’ health and reproductive interests, not all conceivable interests.

of the research participant’s trust, vulnerability, and dependency. The Ph.D. researcher performing fMRI research may alone have information suggesting that the participant’s brain may harbor a life-threatening aneurysm in need of work-up. Thus, that researcher may have a duty to share the scan with a neuroradiologist who can verify the presence of a suspicious finding of likely health importance, and then a duty to offer this information to the research participant for follow-up.

This view that researchers have some duties toward research participants including identifying, verifying, and communicating IFs of health or reproductive significance can be based on researcher duties to respect the autonomy and interests of research participants. 63 Shalowitz and Miller, discussing research participants’ interest in being told individual research results of clinical importance, state that participants have a “presumptive entitlement to information about themselves.” 64 In addition to respect for persons, Illes et al. cite reciprocity as a principle supporting an obligation to disclose IFs of potential health importance to research participants. 65 Beauchamp and Childress discuss “a reciprocity-based justification for obligations of beneficence.” 66 In the research context, reciprocity captures the notion that research participants are contributing to the research enterprise and are entitled to receive in return information about IFs of likely health or reproductive significance.

Recognizing a researcher duty to handle IFs responsibly and disclose them to research participants is also consistent with recent trends in the law. The Grimes case in Maryland held that researchers in that state had special obligations to research participants, citing international codes such as the Nuremberg Code and Helsinki Declaration as well as legal cases. 67 Though the case has been controversial, the court concluded that a “special relationship” grows out of researchers’ knowledge of the risks that participants face and research participants’ vulnerability 68 — this relationship grounds researchers’ duties toward research participants. In addition, researchers’ promises to participants in research consent forms can ground researcher duties toward participants. 69 Research participants have brought a number of other lawsuits against researchers and their institutions claiming that a duty owed by the researcher was breached. 70 The Office for Human Research Protections (OHRP) and other federal regulators and funders have long recognized that researchers have duties toward subjects; violation of those duties can provoke federal investigation and sanctions. 71 The ethical and legal trend toward recognizing researchers’ duties toward participants is apparent.

Including among researcher duties an obligation to offer to disclose to participants IFs that have likely health or reproductive importance is consistent not only with legal recognition of researchers’ special obligations toward participants, but also with legal doctrine imposing a duty to warn of foreseeable harm. 72 This doctrine is more familiar in the context of patient care, not research. However, it is based on recognizing that the physician may have unique access to information of health importance, the physician has obligations to prevent harm, and the patient is dependent upon the physician. All three of these propositions apply to researchers in their relationship to research participants (laying to one side, for now, the complex case of secondary researchers using archived data that their team did not collect). Certainly the researcher will have access to less information than the physician providing patient care, a more limited set of obligations that are grounded in averting harm in the research process, and usually a participant less dependent than is a patient relying on a physician for health care. This suggests that researcher obligations will be more limited, but that researchers do shoulder obligations that include the proper handling of unexpected information of potential health or reproductive importance, including disclosure to participants when potential harm may be averted.

Specifying how researchers should handle IFs to meet these obligations is challenging. It is instructive to compare the literature on offering individual research results to participants (as opposed to offering aggregate research results to a study population, as in a newsletter 73 ). The literature on returning research results has evolved over time. 74 (See Table 3 .) In 1999, NBAC argued that disclosure of individual research results should be the exception, not the rule. 75 Disclosure should occur only when findings are valid and confirmed, have significant health implications, and the health problem can be treated. In 2001 a CDC-sponsored group focusing on population-based genetic research echoed NBAC recommendations: “When the risks identified in the study are both valid and associated with a proven intervention for risk reduction, disclosure may be appropriate.” 76 In 2004 an NHLBI Working Group considering return of genetic research results conditioned return on a significant risk of disease (specific relative risk >2.0), the disease having important health implications (fatal or substantial morbidity or significant reproductive implications), and the availability of therapeutic or preventive interventions. 77 Debate continues on these issues. (As noted above, there is separate policy addressing research participants’ requests for research data — policy from DHHS under HIPAA 78 and from NIH and NHGRI. 79 )

Comparison of Recommendations on Returning Individual Research Results

While it is tempting to see IFs as merely a species of research results, there are key differences. As noted above, research results are on variables under study, the research aims to understand these data, and thus the researcher is likely to have whatever expertise exists to interpret those data. In contrast, because IFs are not on variables under study and may be beyond the researcher’s interpretive expertise, interpreting them may well require clinical experts beyond the research team. Second, the literature on whether to return individual research results commonly discourages returning results that lack clinical validity and clinical utility 80 ; much of the debate focuses on results whose uncertain meaning and importance is the reason for the research. However, because IFs are not on variables under study, the key question will more often be whether the suspected anomaly ( e.g ., an unexpected tumor) is really there; if so, its health importance may be clear.

That said, aspects of the debate over offering research results are relevant. First, insistence on checking analytic validity and trying to establish clinical validity before offering research results suggests the importance of taking several steps when the research team identifies an IF of potential importance: (1) recheck the scan or data to confirm analytic validity (Is it this participant’s scan or analysis? Was the scan or analysis run properly? Should we run another sample?), (2) collaborate with an expert consultant (if the research team does not have adequate expertise) to confirm that there indeed is a suspicious finding and one of likely health or reproductive importance (analytic and clinical validity), and collaboratively determine whether the IF should be disclosed based on factors including its seriousness and likely importance to the research participant. (See Tables ​ Tables4 4 and ​ and5.) 5 .) For example, a Ph.D. principal investigator on an fMRI study may well want a neuroradiologist to review the research scan and confirm the presence of a suspicious finding of likely health importance before the researchers offers this information to the research participant, triggering anxiety and follow-up. In the case of a genetic IF, step 2 may involve sending the sample to a CLIA-approved lab. Note, however, that for some conditions, testing in a CLIA-approved lab will not be available. This raises a problem: the NHLBI Working Group suggested that an IF could still be disclosed as long as it was labeled a research finding rather than a clinical finding and this was explained, but there is concern that this may not comport with CLIA’s restrictions. 81 More work may need to be done to resolve this problem. As in the case of research results, a third step should involve evaluating the seriousness and likely utility of the IF to determine whether the IF should be disclosed, though we define “utility” to include informational importance to the research participant even if no treatment is available. 82 We elaborate below.

Recommended Pathway for Handling IFs in Research

Recommended Classification of Incidental Findings

Second, the literature on returning research results cautions that such results should be offered to research participants, not foisted upon them. 83 This is consistent with the literature on genetic testing in particular, which recognizes a right not to know results. This caution is probably appropriate for IFs as well, though researchers may understandably be hesitant to accept a research participant’s waiver of information about an IF likely to be life-threatening or grave and ameliorable, unless the participant appreciates that the information being waived may be of high health importance.

Third, the literature on offering research results states that results should have important implications for health in order to justify causing anxiety and follow-up in research participants and burdening researchers with the duty to offer these results. NHLBI’s Working Group urged that health importance includes significant reproductive implications; genetic or genomic data may lead participants to take steps to avoid serious as well as fatal genetic conditions for offspring. 84 The requirement of health importance, including reproductive importance, would apply to IFs. However, determining what kind of findings would have such importance is not easy. 85 Stanford’s Working Group on Reporting Results of Genetic Research distinguishes 3 categories of findings. Category I findings have “analytic validity, high clinical validity and utility and...a high probability and magnitude of harm resulting from not offering the information (i.e., life threatening, serious consequences...), and...effective preventive measures exist, or it is easy to avoid exacerbating risk factors.” 86 Category II findings “do not rise to the level of Category I and do not fall into Category III.” Category III findings fail to “meet baseline analytic...or clinical validity standards.” The Working Group argues that Category I findings should be offered to participants, Category II findings may be offered, and Category III findings should not be provided even if requested by the participant. Other authors have similarly focused on analytic and clinical validity plus clinical utility or value to distinguish the kind of results that should be offered to research participants, 87 though some commentators have argued for greater information sharing. 88

This category framework cannot be imported wholesale to IFs. It was developed focusing on research results in genetic and genomic studies. There, the primary concern is giving research participants the results of genetic or genomic tests before the tests are validated and the phenotypic implications are understood, when most genetic and genomic results will not have immediate health implications. However, some IFs (especially from imaging studies) will indeed have immediate health implications. They will require clinical work-up and verification, at which point clinicians will often be able to use established clinical tests of clear validity. Unlike research results, whose ambiguity may be the very reason they are under study, a number of IFs may be entirely susceptible to clinical validation and management. The IF issues focus more on what duties researchers have to identify, evaluate, and communicate these findings of potential clinical importance.

Nonetheless, researchers properly note an IF of potential health or reproductive importance and then kick off the evaluation process (leading to decisions about the likely importance of the IF) when the suspected finding may affect the research participant’s health in the foreseeable future or affect the participant’s reproductive decisions. Emphasizing “health” importance means that we are addressing findings that a research participant would be likely to find important for their health care or health planning, not all findings that may change diet, lifestyle, or individual behavior. We are not suggesting that researchers become clinicians, but rather that when research unexpectedly yields information of likely importance to the participant’s health or reproductive decision-making, the researcher may have an obligation or discretionary option to communicate that information, depending on the seriousness of the finding.

In so defining those IFs that researchers may have a duty or option to disclose to research participants, we reject two extremes. At one extreme, researchers would disclose only IFs of established analytic and clinical validity, clear clinical utility, and grave health importance. This would anchor the category on what a clinician would deem highly significant to avert harm, ignoring the broader category of what a research participant might find important health or reproductive information. At the other extreme, researchers would have a duty to disclose any IF of analytic validity, so that the research participant could decide if the information was useful and important. 89 This would anchor the category on what a research participant might find important for any reason. Under this definition, researchers would have a very broad duty to communicate findings, so broad that it would become difficult to distinguish some forms of research from therapeutic intervention. 90

We strike a middle ground. We show respect for research participants’ objective welfare as well as their subjective interests by including IFs of likely health or reproductive importance to the participant. At the same time, we focus on participants’ health and reproductive interests, not all conceivable interests. Further, we envision that the researcher and expert consultant ( e.g. , a neuroradiologist reviewing a brain scan for a suspected IF) will make a determination of what a reasonable research participant would likely find relevant to their health or reproductive decisions. This determination can be individuated and guided by asking the research participant at the time of consent to participate in the research what categories of information they would like to receive. 91 We thus recognize what Richardson and Belsky call researchers’ “ancillary-care responsibilities” (discussed more below), without turning researchers into clinicians. 92 We also try to identify a reasonable and practical limit to researchers’ duties to identify, evaluate, and disclose IFs.

This approach is consistent with recommendations on offering research findings that recognize the importance of a finding’s validity and health or reproductive utility, but we define “utility” to include information that a research participant is likely to find important, even if clinicians cannot use that information to alter the participant’s clinical course. We thus recognize a spectrum of utility to the participant, ranging from life-saving to ameliorative to useful in heightening surveil-lance to useful in thinking and planning about health. This rejects an approach to utility grounded solely in what a clinician would find useful. We broaden “utility” to ask also what a research participant would find useful, recognizing not only treatment utility but also health or reproductive information utility. Working to harmonize recommendations of research findings and IFs is important because in some research contexts, such as discovery research using genomic microarrays, the line between research findings and IFs will be hard to discern. Our approach advances thinking in both realms by reconceiving what is properly meant by “utility,” recognizing that researchers may need to collaborate with expert colleagues to evaluate the validity and broad utility of research or incidental findings, and by recognizing some key differences between research findings and IFs, particularly the clear need to plan for prompt evaluation of IFs, possible disclosure to research participants, and clinical referral. We consider below how this chain of events should best occur to properly handle IFs, what duties devolve on researchers, and what actions are permissible even if not required.

III. Recommendations for Managing IFs

Our project group agreed on the following recommendations for managing IFs in human subjects research. Table 4 schematizes the pathway we recommend and Table 5 summarizes the categories we suggest for classifying IFs and determining what action to take.

It is unrealistic to place on researchers an affirmative duty to search for IFs. Researchers may not be qualified to screen for IFs; a Ph.D. researcher performing fMRI research cannot be expected to review scans with the expertise of a neuroradiologist. Further, the data with which the researcher is working may not allow researchers to spot the anomalies a clinician would who was using a clinically validated test.

A. Address IFs in the Consent Process

Researchers should anticipate the possibility of identifying IFs in the research process and should address this explicitly in the process of seeking research participants’ informed consent to be part of the research. Researchers should explain the potential for discovering IFs, offer examples of the kinds of IFs this type of research may yield, indicate the probability of discovering IFs when the literature or past experience yields statistics, and describe the steps researchers will follow to handle IFs (as discussed further below and indicated in Tables ​ Tables4 4 - ​ -5). 5 ). By describing planned consultation to verify and evaluate IFs, researchers will be alerting research participants to the possibility of consultation with an expert beyond the research team and will be seeking the participant’s consent. Researchers should include this information concerning IFs on consent forms.

Researchers should elicit in the consent process whether each research participant wishes to be notified of IFs likely to offer strong net benefit or possible net benefit as indicated in Table 5 . Thus, researchers should try to find out whether participants would want to learn of a condition (or significant genetic risk of a condition) likely to be life-threatening that can (or cannot) be treated, a condition (or significant genetic risk of a condition) likely to be grave or serious that can (or cannot) be treated, or genetic information that can be used in reproductive decision-making to avoid or to ameliorate a life-threatening, grave, or serious condition in offspring. Alternatively, researchers following our recommendations can tell research participants in the consent process what IFs the researchers intend to disclose or withhold (as indicated in Table 5 ) and offer research participants an opportunity to state a different preference. Research participants may assert a right not to know certain categories of information; that right is well-recognized in the genetics literature. 93 However, researchers may decide to check back with a research participant in whom an IF reveals a life-threatening or grave condition that may be treated, but who has asserted at initial consent a preference not to know. Without revealing the information itself, the researchers may try to confirm that the research participant indeed wants to refuse even information of high health importance and utility.

Researchers should strive to use standard terms such as “incidental findings” in their protocol and consent documents. A confusing range of terms and definitions for IFs appear in the literature and on consent forms. Terms include “unexpected findings” and “extracolonic findings” (in colonography). 94 Some discussions fail to distinguish between research results on variables under study and IFs. 95 There is also a potential to confuse IFs with adverse events, though the latter more strictly refer to iatrogenic harm caused by the research intervention itself, such as morbidity or mortality resulting from taking a drug in a research protocol. 96

Greater uniformity in terminology and definition would be advantageous. It would allow comparisons and meta-analysis across studies using similar research methods and across research methods. This would aid our understanding on a range of issues including the prevalence of IFs, what proportion turn out to be clinical findings of importance, and whether identifying IFs yields net benefit to research participants and at what cost.

Researchers and consent forms should define IFs as findings of potential health or reproductive importance that are beyond the aims of the study. This definition is better than “findings on variables not under study” because our definition would include IFs on variables or data points that were collected but not the focus of study ( e.g ., anatomy visualized on a scan but not under study, genes included in an untargeted genomic microarray but not under study, and chromosomes visualized in karyotyping but not under study). Our definition is also an improvement over “variables not planned for in the research protocol” because we urge that investigators and IRBs routinely anticipate IFs and create a plan for managing them.

What if the aims of a study evolve over time? IFs should be defined relative to the aims consented to by the research participants, as our definition suggests. It is they who will bear the health and psychological consequences if they are told of an IF, experience anxiety, potentially undergo follow-up, and benefit or suffer from identification of the IF. Similarly, it is research participants who will live with the consequences if an IF of importance is not identified or communicated to them. Thus, it is the research participant who most critically needs to understand through the consent process what this category of information is and how IFs will be handled by the investigators.

Research participants need to understand that research can uncover not only research results of potential health or reproductive importance, but also incidental findings of such importance. They need to know in the consent process how both categories of information will be handled. A given study may handle them differently. Genetic or genomic research, for example, yielding research results whose meaning is not validated and understood, may nonetheless uncover an IF of a well-understood mutation or chromosomal abnormality of clear health importance. In such a case, the investigators and IRB could reasonably decide not to return individual research results but to offer to disclose the IF to the research participant.

This suggests that research participants need to understand how both categories of information will be handled. Fairness to research participants means that the arrangement to which they consent should prevail unless and until investigators ask them to reconsent to a new arrangement.

B. Address the Potential for IFs in Future Analyses of Archived Data

What about research participants consenting to future reanalyses of their archived data? In some cases, complete anonymity of the data will make notifying participants of IFs impossible. 97 Research participants should be told when they are asked to consent to future research if anonymity or anonymization will make reporting IFs impossible. 98 However, the literature suggests that data should not be anonymized for the sole purpose of avoiding a possible responsibility to communicate research results or IFs, 99 and some data will be archived and reanalyzed without full anonymization. An example is DNA databanks that follow research participants prospectively to correlate genotype and phenotype. Again, the terms of the research participant’s consent should prevail. If the participant consented to data collection relative to a certain set of research aims, with “research results” and “IFs” defined accordingly, then that arrangement and those definitions should prevail unless and until the research participant agrees to a modification. This means that a later study on data archived from an initial study could uncover information of potential health or reproductive importance on variables directly under study that would nonetheless be considered IFs under the terms of the first study and governing consent form. 100

The logistics of identifying, evaluating, and communicating IFs will be more complex when archived data are analyzed by secondary researchers who did not collect the original data. The original researchers may have the only access to identifying information that would permit communication with individual research participants. Further, the original researchers may be the only researchers with a direct relationship with the research participants. In such cases, the original researchers may be best situated to communicate IFs to the research participants. However, there will be circumstances in which data are long-archived and it is not possible or realistic to work through the original researchers. Indeed, an intermediary — rather than the original researchers — may hold the codes allowing identification of research participants. 101 In such cases, consulting with an IRB may be essential to devise a feasible way to contact research participants. It is important to plan ahead when data are first collected for archiving and future reanalysis, anticipating the possibility of later IFs.

A substantial literature discusses the ethics of recontacting research participants with research results of potential health importance. 102 That literature acknowledges that recontact can be disruptive. Some research participants may wish to avoid recontact no matter how important the health or reproductive information to be conveyed. Others may wish recontact if the information may be valuable in preventing serious medical harm. 103 Because individuals may differ on their willingness to be recontacted regarding IFs discovered in the future, they should be asked to consent to recontact. Most informative will be to ask

Whenever IFs are to be disclosed, they should be disclosed directly to the research participant. Some of the literature and consent forms available suggest that IFs should instead be disclosed to the research participant’s primary care physician. However, this gives the research participant no control over the information and compromises the participant’s privacy.

their recontact preferences for each category of information listed in Table 5 under “Strong Net Benefit” and “Possible Net Benefit.”

Realistically, recontacting or attempting to recontact research participants to communicate IFs discovered by secondary researchers using archived datasets may be difficult. Moreover, the passage of time from the initial data collection to discovery of an IF by secondary researchers may reduce the potential health significance of some IFs. Some limitations are appropriate. It is not unreasonable to limit attempts to recontact participants to IFs offering strong net benefit as defined in Table 5 .

A standard this high may also be appropriate when considering whether to offer to disclose IFs discovered in research for which consent was never obtained. The Office for Human Research Protections (OHRP) has determined that research using previously collected specimens and data does not involve “human subjects” and so falls outside the scope of the Common Rule as long as the information was not originally collected for that research and the information is coded so that the individuals’ identifiers are not known to the investigator. 104 Such research protocols often involve patients’ data and specimens and are not required to undergo IRB scrutiny. Individuals may not even know the research is being conducted. Given the lack of consent and potential for surprise, it may be appropriate to limit attempts to contact these patients to IFs offering strong net benefit.

C. Plan for the Discovery of IFs

Researchers generally have no obligation to act as clinicians and affirmatively search for IFs. The goal of research is to seek generalizeable knowledge, not to provide health information to individuals. Thus, recommendations to date on handling IFs in neuroimaging state that researchers are not obligated to perform extra MRI scans or modify their scans to provide clinical information. 105

An exception to the general proposition that researchers do not have a duty to search for IFs may occur when the researcher is also the research participant’s treating physician. A treating physician in a doctor-patient relationship has an obligation to use professional care in analyzing all information about a patient, even a patient who is also the doctor’s research participant. This does not mean that the physician-researcher is obligated to collect extra research data or do extra research scans or scans optimized for clinical diagnosis, but it does mean that in reviewing research data and scans the physician-researcher is obligated to spot IFs that a professional of his or her training would ordinarily recognize. Whether or not the researcher is also the treating physician, if the researcher or a member of the research team spots an IF of potential concern, the principal investigator bears a duty to handle this IF responsibly and promptly. An IF has the potential to reveal a condition that is serious or even life-threatening. As noted above, researchers’ duties of respect for research participants, duties to maximize benefits and minimize harms, duties to alert research participants to any developments that may affect their willingness to continue in the study, and more recently recognized duties of reciprocity toward research participants generously willing to bear the burdens of research for societal benefit all support a duty to attend to IFs rather than ignoring them.

The particular qualifications of the principal investigator (Ph.D., M.D., or other) do not change the obligation to plan for IFs and handle them responsibly. These duties fall on the principal investigator, not on a less experienced member of the team. Trainees cannot be assumed to have the expertise to handle IFs. This means that the principal investigator must instruct members of the research team to promptly communicate a suspected IF so that the principal investigator can handle the IF from that point.

In planning for the discovery of IFs, the researcher will need to consider how quickly members of the research team should bring a suspected IF to the attention of the principal investigator and how quickly the principal investigator should act to evaluate the IF. The researchers should consider what kinds of IFs the protocol may produce and how rapidly the identification and evaluation process needs to proceed to provide timely information to the research participant and avoid harm.

D. Plan to Verify and Evaluate a Suspected IF, with an Expert Consultant if Needed

Researchers should take steps to validate an IF and confirm its health or reproductive importance before communicating the finding to a research participant. Communicating an IF may provoke anxiety in the research participant and cause the participant to undertake clinical evaluation. Consequently, the researcher’s first step when faced with an IF of potential health or reproductive importance should be to examine the data or scan to confirm that an IF appears to be present, that the data or scans appear to have been created properly, and that they belong to a particular research participant. These steps begin to confirm analytic validity. The researcher may consider whether it is feasible to test another sample or compare another scan to see if the IF is still apparent.

The next step will be to seek confirmation that an IF appears to be present that is likely to have enough health or reproductive importance that its disclosure offers possible or strong net benefit, as described on Table 5 . This is a reconfirmation of analytic validity and begins to address clinical validity as well as utility in the broader sense we have discussed above.

The researcher will often not have the expertise to make this assessment and will need to consult a clinical colleague who can review the research data or scan. The purpose of this review is not to generate a clinical diagnosis; the research data or scans often will not be adequate to that purpose. Instead, the limited goal of this review is to verify that there appears to be a suspicious finding that is likely to offer enough health or reproductive importance that notification of the IF may or even must be offered to the research participant. (See Table 5 .) Note that the researcher will have initially identified an IF of potential importance and that the expert consultant will be helping confirm both the IF and its likely importance.

Thus, a genetics or genomics researcher may need to consult a clinical geneticist or genetic counselor, a neuroimaging researcher may need to consult a neuroradiologist, and a CT colonography researcher may need to consult an abdominal radiologist. Because some IFs will require urgent follow-up, this consultation pathway must be set up before beginning to enroll research participants and must be capable of generating a prompt consult. How quickly consultation may be needed depends on the type of IF a study may generate; neuroimaging studies that may reveal an aneurysm will require faster consultation capability than genetics studies that are unlikely to reveal an IF that requires urgent intervention. The neuroimaging IFs literature addresses planning for immediate, urgent, and routine referral. (See Table 2 .)

In order to obtain consultation without compromising the research participant’s privacy and breaching confidentiality, the researcher should inform the research participant of this consultation pathway in seeking consent for participation in the study and should seek the consultation without providing information that would reveal the research participant’s identity. This means that the consultant’s conclusion will be recorded in research records, not the research participant’s clinical medical records. Handled in this way, consultation should not raise concerns under HIPAA because the research participant’s identity is protected.

The cost of compensating the consultant for IF verification and evaluation should be built into the research budget. Handling IFs responsibly is a researcher obligation. This could reasonably be regarded as either a direct cost or an infrastructure cost. Agencies funding research should support this expense as a cost of performing research ethically. 106

Verifying and evaluating genetic IFs raises the question of whether to seek retesting in a CLIA-approved lab. Only such a lab is authorized to generate clinical test results. 107 As previously noted, though, genetic testing in a CLIA-approved lab is not available for all genetic conditions. 108 While CLIA-approved confirmation is ideal, we note the suggestion of the NHLBI Working Group that research lab results that cannot be verified in a CLIA-approved lab can nonetheless be disclosed to research participants, as long as those results are labeled “research” rather than “clinical” results, and the difference is explained. As we further note above, however, more work may be needed to resolve the question of whether this approach comports with CLIA regulations or regulatory change is needed to permit this.

As genetic, genomic, and imaging research technologies become more powerful, the IFs problem will grow. Genetic and genomic research will predictably include larger populations. Genomic research will cover larger stretches of the genome, up to the entire genome. Imaging research will increasingly incorporate functional (non-structural) information and quantification of imaging data will lead to additional information provided by even structural ( i.e. , anatomic) images. Data produced in all of these research domains will increasingly be archived and reanalyzed, thanks in part to federal data-sharing policies and the growing capabilities of computers and bioinformatics.

E. Plan to Determine Whether to Report IFs, Based on Likely Health or Reproductive Importance

The principal investigator rather than the consultant bears ultimate responsibility for determining whether the IF should be disclosed to the research participant, though consultation with the consultant may be helpful in making this determination. It is the researcher who undertakes duties of respect and reciprocity, minimizing risk, assuring a positive risk-benefit relationship, and alerting the research participant to any developments that may affect willingness to continue in the study. Further, discovery of an IF should not be the first occasion for researcher-participant communication about IFs; as part of agreeing to participate in the study, the research participant should receive information on the potential for IFs and should be asked to indicate on the consent form whether he or she wishes to receive such information. Information about IFs should generally be offered only to research participants who indicate at the time of consent to participate in the study that they wish to receive this information. However, if researchers identify an IF that is likely to be life-threatening or grave and can be ameliorated or treated, they should reconfirm with a research participant who indicated refusal that he or she is electing to decline information on all IFs, even those revealing conditions of high health importance that can be treated.

When should an IF be disclosed? We distinguish between 3 categories. (See Table 5 .) An IF whose disclosure offers Strong Net Benefit is one revealing a condition likely to be life-threatening or a condition likely to be grave that can be avoided or ameliorated. As the label for this category suggests, these are IFs whose disclosure is likely to offer markedly more benefit than burden to the research participant. The researcher should offer to disclose an IF in this category to the participant. This gives the participant health information likely to be very important to the participant. This includes information about a condition likely to be life-threatening, even if it cannot be treated. This category would include genetic information that reveals significant risk of a condition likely to be life-threatening or that can be used to avoid or ameliorate a condition likely to be grave. It would also include genetic information that can be used in reproductive decision-making to avoid significant risk for offspring of a condition likely to be life-threatening or grave or to ameliorate in offspring such a condition.

An IF that offers Possible Net Benefit is one that may offer more benefit than burden to the research participant. An IF in this category reveals a health condition, including a grave or serious one that cannot be avoided or ameliorated, when a research participant is likely to deem that information important. This category would include genetic information revealing significant risk of a condition likely to be grave or serious, when that risk cannot be modified but a research participant is likely to deem that information important. It further includes genetic information that can be used in reproductive decision-making to avoid significant risk for offspring of a condition likely to be serious or to ameliorate a condition likely to be serious, when a research participant is likely to deem that information important. Researchers may reveal this kind of IF in order to show respect for the research participant’s informational needs and preferences, even though the information is not likely to change the participant’s own clinical course. However, researchers are not obligated to offer this information.

IFs that have Unlikely Net Benefit should not be offered to research participants, because they probably offer more burden than benefit. IFs in this category reveal a condition that is not likely to be of serious health or reproductive importance. This category also includes IFs whose likely health or reproductive importance cannot be ascertained. In this category, there is no justification for subjecting the research participant to the anxiety and burden of receiving this information.

Examples in the research domains we studied may help illuminate these categories. In genetic studies, an IF revealing alleles associated with hereditary nonpolyposis colorectal cancer (HNPCC) would be in the “strong net benefit” category, as they reveal a condi-

The problem of IFs is important and deserves broad discussion among researchers, research participants, IRBs, funders, and oversight bodies. Handling IFs responsibly requires clarity about the difference between research and clinical care, coupled with attention to the ethical duties of researchers when faced unexpectedly with information that could save a life, significantly alter clinical care, or prove important to the research participant.

tion likely to be life-threatening or to impose grave harm that may be avoided by alerting the research participant. 109 However, an IF of APOE4 indicating susceptibility to Alzheimer disease at some point in the far future would be in the “possible net benefit” category, as the risk of Alzheimer disease is serious but cannot now be avoided or ameliorated. An IF of misattributed paternity would usually be in the “unlikely net benefit” category, particularly because communicating misattributed paternity may carry serious burdens for research participants. However, this IF could be in the “possible net benefit” category when learning of misattributed paternity would likely be of health or reproductive importance to the participant; an example would be an IF relieving a research participant’s anxiety about inheriting (and passing on to offspring) genes conferring significant risk of a condition likely to be serious.

In large-scale genomic microarray research, again an IF revealing alleles associated with HNPCC would be in the “strong net benefit” category. An IF revealing serious pharmacogenetic information, that a research participant is likely to suffer life-threatening or grave effects from taking certain medications or common doses of certain medications, would be another IF in this category. However, an IF for genes predisposing the research participant to schizophrenia would be in the “possible net benefit” category, as no intervention is available to reduce risk of this serious illness.

In neuroimaging research using MRI, an IF indicating a brain tumor, aneurysm, or arterio-venous malformation (AVM) would be an IF of “strong net benefit.” These are urgent medical problems requiring intervention to avert grave medical harm or death. However, an IF revealing lack of a posterior communicating cerebral artery would be an IF of “possible net benefit.” This anomaly could affect the severity of a stroke by limiting cerebral reperfusion, but nothing can be done about that. An example of an IF of “unlikely net benefit” would be unusual variation in the size of the amygdala; this cannot be avoided or ameliorated and is not likely to be of importance to the research participant at this time, because the significance of this size variation, if any, is unknown. Thus, the information is likely to impose only the burden of suggesting there is something wrong with the research participant’s brain with no corresponding benefit.

In CT colonography research, discovery of an extracolonic neoplasm or abdominal aortic aneurysm would be an IF of “strong net benefit” because the condition is likely to be life-threatening or grave and amenable to treatment. However, discovery of multilevel degenerative disk disease in the lumbar spine would be an IF of “possible net benefit” because the condition is likely to be serious but cannot be corrected and the research participant is likely to find this information of importance. Discovery of a lung nodule less than 4mm in a nonsmoker would be an IF of “unlikely net benefit” because this information is not likely to be of serious health or reproductive importance, as discussed above.

Whenever IFs are to be disclosed, they should be disclosed directly to the research participant. Some of the literature and consent forms available suggest that IFs should instead be disclosed to the research participant’s primary care physician. 110 However, this gives the research participant no control over the information and compromises the participant’s privacy. The primary care physician is likely to record the information in the participant’s medical record before even consulting with the participant. This chain of events is not consistent with respect for the research participant and the participant’s decisional authority. The research participant should control the information and decide whom to consult, if anyone.

The researcher should communicate the IF to the participant in a way that is sensitive to the issues raised. Communicating a genetic IF, for example, may require the assistance of a genetic counselor or clinical geneticist. 111 Similarly, disclosing an unexpected life-threatening condition or advanced cancer may require the assistance of a clinician such as an oncologist who can immediately address questions and concerns. When the possibility of finding grave IFs in a research study is expected to be high, researchers should consider asking research participants during the consent process if they will agree to disclosure of medically significant IFs to their primary care physician, with whom they have a preexisting relationship. Whether or not this is part of the initial consent process, a researcher disclosing an IF to a research participant should offer to communicate the IF directly to the research participant’s physician. If the research participant has no physician, the researcher should offer to suggest one. Depending on the specific IF revealed, the research participant may ask the researcher to suggest a specialist, such as oncologist. The researchers should respond to such requests with recommendations or referral. The goal in this process is to enable the research participant to address rapidly an IF that may be clinically important and anxiety-provoking.

Paying for clinical follow-up should not be the responsibility of the research team. Research teams are generally not set up or funded to provide significant and ongoing clinical care. The researcher should make clear to the research participant that paying for clinical follow-up will be the participant’s responsibility. What if the participant has no health insurance? The researcher should be prepared to advise the participant on available avenues for accessing follow-up or should know to whom to refer the participant for information and counseling. If the study population lacks insurance, then the researcher and IRB must address in advance how research participants with IFs will access clinical follow-up services.

F. Investigators and IRBs Should Create and Monitor a Pathway for IFs

Researchers have an obligation to anticipate IFs, set up a pathway for handling IFs responsibly, and address in the consent process with research participants the possibility of IFs and how they will be handled. IRBs have an obligation to address directly the issue of planning for IFs and handling them appropriately. IRBs should do this both in reviewing individual protocols and in crafting guidance and model consent forms for investigators. Our review of guidance and model consent forms offered on publicly available Internet sites by the IRBs of the 100 universities receiving the most NIH funding found that while some IRBs offered recommendations on how to handle IFs, many did not. 112

When IRBs review protocols, they may face the question of whether a protocol that poses minimal risk and thus is eligible for expedited review under the rules governing human subjects research, 113 creates a sufficient risk of uncovering IFs as to challenge the minimal risk classification and require full review. 114 A protocol that threatens to yield a substantial number of IFs whose health or reproductive importance would counsel disclosure to research participants should indeed be afforded full review, particularly because the challenging ethical issues surrounding IFs have not yet been settled.

In addition to offering guidance on IFs and reviewing proposed protocols, IRBs have an important role to play in overseeing the adequacy of a study’s procedures for handling IFs. An IRB may conclude, for example, that a protocol is uncovering a large number of IFs or IFs of grave importance, without an adequate means for evaluating them promptly. IRBs may also be asked to provide consultation on difficult IF problems that arise, such as whether researchers should disclose to a research participant an IF of ambiguous clinical validity that may prove important to health decisions. IRBs may also be asked to consult on the difficult questions surrounding recontact of research participants when secondary analysis of archived data yields IFs of importance.

G. IFs in Pediatric and Adolescent Research Participants

Studies have begun to document and analyze IFs in research on children and adolescents. 115 Because disclosing the potential for IFs and the plan for handling them is an important part of the consent process, it should be integrated into the consent process for pediatric and adolescent research. This information should be disclosed to the parent or guardian giving permission for the research and to the older child or adolescent giving assent under the regulations governing human subjects research. 116 There are some special considerations that apply to handling IFs in pediatric and adolescent research.

First, certain categories of research on children and adolescents are approvable under the federal regulations on human subjects research only if they pose “no greater than minimal risk” to the minor research participant; involve greater than “minimal risk” but present the prospect of direct benefit; or represent “a minor increase over minimal risk” with no prospect of direct benefit, but are likely to yield generalizable knowledge about the minor participant’s disorder. 117 The National Human Research Protections Advisory Committee has interpreted these terms, emphasizing that “[r]isks include all harms,...indignities, embarrassments, and potential breaches of privacy and confidentiality associated with research.” 118 We recommend that both researchers and IRBs routinely address the question of whether the expected likelihood and gravity of IFs in a proposed study raise the risk of the research above “minimal risk.” As more data emerge on the prevalence of IFs in different forms of pediatric and adolescent research, it may turn out that some kinds of research pose a sufficiently high probability of uncovering IFs of significance, that this challenges the conclusion that the research poses only minimal risk or a minor increase over minimal risk and thus alters the risk-benefit calculus.

Second, we recommend above that all individuals agreeing to the research also be asked if they would like to receive information about IFs. This means that the parent or guardian would be asked, but also the older child or adolescent assenting to research participation. Ideally the parent or guardian’s answer will accord with the research participant’s. However, when they disagree, the researcher will have to consider how to handle an IF that would otherwise be disclosed. Consultation with the IRB may be necessary. When the parent or guardian wishes the information but the research participant does not, the answer may be to disclose to the parent or guardian and counsel them regarding the need for further clinical evaluation and therefore disclosure to the child or adolescent. The more difficult case will be when the minor research participant wishes the information but the parent or guardian asserts a preference not to know. This will require case-by-case evaluation. When an IF reveals a grave or life-threatening condition that requires clinical evaluation, the parent or guardian has a responsibility to learn of this information and act in a way to preserve the child or adolescent’s health. In such cases, an asserted right not to know should be overridden.

In some cases, an IF may reveal sensitive information that the child or adolescent may not want to be shared with the parent or guardian. An IF indicating substance abuse or pregnancy in a child or adolescent may fall in this category, as may an IF suggesting that the child or adolescent has suffered physical abuse. These social and behavioral IFs are beyond the scope of this paper, but researchers should consider what pathways they will follow to evaluate and disclose such findings in a way that respects the minor research participant’s interests, privacy, safety, and well-being.

Genetic and genomic IFs raise special issues for minor research participants because the literature on genetic testing in children generally urges that testing be delayed until adulthood unless the child will receive therapeutic benefit from earlier testing; accordingly carrier testing and screening as well as predictive testing for late-onset disorders are generally discouraged. 119 This recommendation is based on recognition of the serious psychological and social consequences that can flow from genetic information, including stigma and discrimination as well as negative impact on the parent-child relationship. 120 In keeping with this recommendation, only genetic or genomic IFs that are likely to confer therapeutic benefit and thus more benefit than risk should be offered to minor research participants, their parents, or guardians. An exception may be made for adolescents with mature decisional capacity, who indicate at consent a desire to receive IF information.

What about IFs uncovered in secondary research on archived data collected from minor research participants? By the time secondary analysis uncovers IFs, the minor may have reached the age of majority. The question of how to handle IFs in these cases is related to a larger debate under way on the proper scope of genetic and genomic research on children using identifiable samples 121 and whether minor research participants, including those who have contributed samples to DNA databanks, should be asked at majority to reconsent to continued use of their samples. 122 The questions do not arise when samples have been fully anonymized and research participants are no longer identifiable, but if researchers can identify participants, even through a coding system, the problems may remain. If research recommendations move toward seeking reconsent at majority, it would make sense to reconsent at that time on how IFs should be handled as well.

H. IFs in Adult Research Participants Without Decisional Capacity

We have found no studies focusing on IFs in adult research participants who lack decisional capacity. However, the prevalence figures emerging on the IFs on which we focus above would predict IFs in this research population as well. There has been persistent and wide debate on the appropriate scope of research on decisionally-incapacitated adults and the procedural protections that should attend such research. 123 Recommendations limiting research in this population to that posing minimal risk or a minor increase over minimal risk would again raise the issue flagged above for children, that is, whether the expected incidence and nature of IFs in a proposed study would impose more than minimal risk or a minor increase over minimal risk.

An even more difficult problem is whether the research participant’s legally authorized representative (LAR) can and should be counted on to make appropriate decisions at consent about the return of IFs and subsequent decisions about appropriate clinical follow-up once an IF is disclosed. A “‘legally authorized representative’ is an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research.” 124 It is not clear that current law facilitates LARs’ fulfillment of the decision-making duties envisioned in ethics recommendations. 125 Further, deciding whether and how to follow up clinically on IFs discovered in research may be beyond the LAR’s role, as the LAR is supposed to make research decisions. Thus, handling IFs may require coordination between a research participant’s LAR and their surrogate for treatment decisions. This set of issues requires careful consideration by researchers and IRBs contemplating research on populations including those decisionally impaired.

I. Handling Social and Behavioral IFs

Though we did not focus on social and behavioral IFs, researchers and IRBs should consider how they will handle IFs that are social or behavioral as well as those that are genetic or physiological. Researchers in many states have mandatory reporting responsibilities under state law when faced with child abuse, elder abuse, and suicide risk. However, research interaction may unexpectedly reveal potentially important information not covered by such reporting laws, such as signs of alcohol abuse in an adolescent research participant. Potential research participants are entitled to know how researchers will respond if they discover this kind of information, as discovery poses risks to the participant as well as providing potential benefits.

IV. Process Responsibilities and Oversight

Making this approach work will involve a number of actors and oversight bodies. Investigators, IRBs, research funders, and regulatory authorities such as OHRP should take the problem of IFs seriously. Investigators should anticipate discovering IFs in their research and expect secondary researchers to discover IFs in reanalysis of archived data. Investigators should consequently plan for IFs in their research protocol. This means articulating the kinds of IFs anticipated, consulting the literature to state the expected prevalence of such IFs in their research population, considering which IFs will be referred to a consultant to determine whether they merit further clinical evaluation or may be of importance to research participants, and stating what will qualify as an IF that should be disclosed to the research participant because of its likely health or reproductive importance. Researchers should specify to the IRB and to potential research participants how IFs will be handled. They should consider including clinical consultants capable of reviewing IFs on their research team. If such consultants are not part of the team, researchers need to establish an arrangement with the consultants that will allow prompt review of IFs. Researchers will need to build into their research budget the funds needed to compensate such consultants for review of IFs and any funds needed to compensate clinical colleagues (such as genetic counselors or radiologists) who may be needed to help communicate IFs to research participants.

Clearly, the IRB has a crucial role to play in assuring that the research protocol anticipates IFs, sets up an appropriate plan and pathway for handling them, and then responds to IFs (including those not successfully anticipated in the protocol) in a responsible way. This means that the IRB must make sure investigators have in place a solid plan at the start of research, but that the IRB must also perform continuing oversight as IFs emerge, researchers respond to those IFs, and the pathway for handling IFs proves adequate or requires improvement. IRBs and programs overseeing human subjects research in and outside of universities should issue written guidance for researchers including model consent forms showing how to plan for and handle IFs in research.

Finally, federal agencies that fund and supervise human subjects research (including NIH, FDA, the Centers for Disease Control (CDC), and Department of Veterans Affairs (VA)) should address IFs in the guidance documents they issue for researchers and IRBs. These agencies perform a leadership role in setting standards for human subjects research and providing oversight. OHRP has a special role to play as a key federal body safeguarding the interests and welfare of research participants. Our research indicates that federal guidance documents do not yet adequately address IFs and attention to this problem is needed.

V. Conclusion

As genetic, genomic, and imaging research technologies become more powerful, the IFs problem will grow. 126 Genetic and genomic research will predictably include larger populations. Genomic research will cover larger stretches of the genome, up to the entire genome. Imaging research will increasingly incorporate functional (non-structural) information and quantification of imaging data will lead to additional information provided by even structural ( i.e. , anatomic) images. Data produced in all of these research domains will increasingly be archived and reanalyzed, thanks in part to federal data-sharing policies and the growing capabilities of computers and bioinformatics.

This suggests that we are early in the development of the problem of how to handle IFs in research. Research would be helpful to clarify the types of IFs generated by different kinds of research, the statistical prevalence of these IFs, the costs of evaluating them and clinical following-up, and the positive and negative impacts on research participants. Meanwhile, we need to assure that IFs are handled responsibly and research participants understand what information they may be offered. These recommendations, generated by considering IFs in genetic, genomic, and imaging research, suggest the importance of looking at this problem comparatively across research domains and grounding ethics recommendations in the critical study of approaches currently in use.

Our recommendations are limited by considering only genetic, genomic, MRI neuroimaging, and CT colonography research. Further, we informed our recommendations by considering research consent forms, university model consent forms, statements by professional societies, and federal guidance documents publicly available on the Internet. 127 We reasoned that these forms and documents are likely to exert the most influence on researchers and IRBs because these are the materials that they will most readily find when researching guidance and models. We refrained from seeking forms and university documents that were not posted on the Internet and we did not perform observational research to find out whether researchers are deviating from consent forms or supplementing those forms by discussing IFs with research participants.

Acknowledgements

Preparation of this article was supported by the National Institutes of Health (NIH), National Human Genome Research Institute (NHGRI) grant #R01-HG003178 for a two-year project on “Managing Incidental Findings in Human Subjects Research” (Susan M. Wolf, Principal Investigator; Jeffrey P. Kahn, Frances Lawrenz, Charles A. Nelson, Co-Investigators). This project was based at the University of Minnesota’s Consortium on Law and Values in Health, Environment & the Life Sciences. Thanks to Charlisse Caga-anan, Barbara Figari, Britta Orr, Michelle Oyen, Suzanne Sobotka, and Lindsey Yock as well as Lisa Jones, Ph.D., for research assistance at various stages of the project and to Audrey Boyle for excellent project management. Special thanks to Elizabeth Thomson, D.N.Sc., R.N. at NHGRI for her support and insights. The contents of this article and symposium are solely the responsibility of the authors and do not necessarily represent the views of the NIH or NHGRI.