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

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

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 ​Tables44-​-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

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.

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 samples¹²¹ 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.

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.