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?

Researchers in the health sciences regularly discover information of potential health importance unrelated to their object of study in the course of their research. However, there appears to be little guidance available on what researchers should do with this information, known in the scientific literature as incidental findings (IFs). The study described here was designed to determine the extent of guidance available to researchers from public sources. This empirical study was part of a larger two-year project funded by the National Human Genome Research Institute (NHGRI) to generate guidance on how incidental findings should be managed in human subjects research, especially genetics, genomics, and imaging research. We generated empirical analysis of publicly available guidance and consent forms to help guide a multidisciplinary Working Group of experts in their formulation of normative recommendations reported in this symposium.

This paper explores the convergence of two recent and growing streams of bioethical work and concern. Each has originated independently, but each arises from the fact that the Common Rule that has shaped medical research ethics, as institutionalized in the United States and also abroad, is largely silent about what needs to be done in response to researchers’ positive obligations. One stream concerns what to do about the sometimes vast range of findings that may arise incidentally to performing research procedures. The other asks whether medical researchers owe their study participants any “ancillary care” — that is, medical care that their study participants need but that goes beyond what is required to do the science safely.

A physician-investigator conducting brain imaging research to study the pathophysiology of depression detects a suspicious finding in a healthy volunteer that suggests a possible brain tumor. Must the investigator disclose this finding to the research subject? Further, is there a duty to ensure that brain scans performed to answer research questions are evaluated clinically to identify potential health problems? If so, what in the nature of the investigator-subject relationship gives rise to such an obligation?

Investigators and Institutional Review Boards (IRBs) commonly struggle with the question of how to address incidental findings — that 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.” A working group convened by the National Institutes of Health has recommended that brain imaging research studies should establish protocols for handling incidental findings. However, there is little ethical guidance available to steer such efforts, and practices appear to vary widely. Although several articles have catalogued the ethical dilemmas surrounding incidental findings, with the exception of seminal work by Henry Richardson and Leah Belsky on the more general topic of researchers’ obligations to provide ancillary clinical care to research subjects, systematic ethical analysis of the incidental findings problem is lacking.

Human genetic and genomic research can yield information that may be of clinical relevance to the individuals who participate as subjects of the research. However, no consensus exists as yet on the responsibilities of researchers to disclose individual research results to participants in human subjects research. “Genetic and genomic research” on humans varies widely, including association studies, examination of allele frequencies, and studies of natural selection, human migration, and genetic variation. For the purposes of this article, it is defined broadly to include analysis of DNA collected from humans that has implications for human health (even if the purpose of the study is not medical). This paper addresses both research results of individual research participants that may be an intended product of the research, as well as unanticipated, “incidental” findings.

There are countless variations on this theme. The call can come from one of your own physicians who was called by the investigator. Your physician may or may not be well informed on what the reported finding about Disease Y means or how to respond. DNA testing can reveal more than susceptibility to disease. People can learn that they do not have the biological connections — parentage or evidence of ethnic origin — that they thought they did.

Colleagues who serve on the Institutional Review Board (IRB) in my institution tell me that they currently do not permit “cold calls” of the type portrayed in the opening paragraph. Such direct contacts have, however, occurred in the past, with or without the blessing of an IRB. Sharing findings with the individual’s physician, who is then supposed to serve as a learned and wise intermediary, is not without problems either, given that many physicians understand little about complex genetics. Yet the very existence of this project on managing incidental findings in research demonstrates that some people believe that some research findings ought to be available to participants.

Medical practice is poised to incorporate genomescale testing into treatment decisions. However, broad genome testing in laboratories may lead to discoveries not anticipated, yet highly significant to the health of the patient. Understanding the complexity of our genome and its relationship to our health is an overwhelming task. Currently, much of the effort to unravel this complexity is in the realm of research. However, researchers are often neither qualified nor prepared to deal with incidental findings of genetic abnormalities that influence health and disease. These incidental observations, referred to recently by Issac Kohane et al. as the “incidentalome,” may lead to complex legal, ethical, and financial problems that may seriously complicate the role of the research community in medical genomics. Currently, most genetics researchers, while aware of the potential for incidental findings, simply do not want to deal with them.

In Phillip Kerr’s 1994 spellbinding novel A Philosophical Investigation, the medical test to which the protagonist refers is a functional brain scan based on positron emission tomography (PET). It is used to run large studies of male and female brains and, following a lead suggested by animal studies, has been used to identify rare cases of human male subjects who lack the ventral medial nucleus (VMN). This nucleus, in the experiment (and the story), is hypothesized to inhibit the activity of the sexually dimorphic nucleus (SDN), a preoptic area of the male brain believed to be a repository of male aggressive response. Prior research, we learn from the plot, shows that 3 in 100,000 human males are VMN-negative. Thirty percent of those affected are believed to be in prison or to have a criminal record; 70% are believed to stabilize levels of aggression by producing increased levels of estrogen. Identities of subjects participating in the brain scan studies are protected through the conversion of real names to those of famous figures of the past — Bertrand Russell, Charles Dickens. Those for whom results are unfavorable are recontacted, and they are offered counseling.

The question of how to handle incidental findings (IFs) has sparked a heated debate among neuroimaging researchers and medical ethicists, a debate whose urgency stems largely from the recent explosion in the number of imaging studies being conducted and in the sheer volume of scans being acquired. Perhaps the point of greatest controversy within this debate is whether the magnetic resonance imaging (MRI) scans of all research participants should be reviewed in an active search for pathology and, moreover, whether this search should be performed by a radiologist. Resistance to routine readings performed by radiologists, as opposed to selective review of those scans on which investigators have spotted a possible IF, has been fueled in part by the obvious and enormous cost — financial and logistical — of engaging radiologists to read massive numbers of scans. This cost would be especially burdensome, even prohibitive, to investigators who are not affiliated with a medical center, because of their limited access to radiologists and other medical expertise.

Magnetic resonance imaging (MRI) is a noninvasive imaging tool that utilizes a strong magnetic field and radio frequency waves to visualize in great detail organs, soft tissue, and bone. Unlike conventional x-rays (including computed tomography [CT]), there is no exposure to ionizing radiation and at most field strengths (generally below 7 Tesla) the procedure is considered safe for nearly every age group. Because it is non-invasive (i.e., does not break the skin or harm the body) and possesses excellent spatial resolution (down to millimeters), the use of MRI as a research tool has increased exponentially over the past decade. Uses have ranged from add-ons to a clinical study (e.g., after scanning a child who has fallen from a bicycle, the radiologist might do an extra sequence to explore ways of obtaining higher resolution images) to studies of brain development in typically developing children. In addition, a major effort has been made in recent years to use MRI to study brain function (so-called “functional MRI” [fMRI]). Because the clinical utility of fMRI has not yet been realized, fMRI is still considered highly exploratory, and we cannot yet identify incidental findings of a functional (as opposed to structural) nature.

Just over ten years ago, the first human trials of virtual colonoscopy, or computed tomography (CT) colonography, were performed. CT colonography (CTC), as it is now called, is a low radiation dose CT examination of the abdomen and pelvis following bowel purgation cleansing and insuflation (inflation) of the colon and rectum. High spatial resolution CT datasets of the abdomen and pelvis are obtained while the patient is lying in the prone and supine positions, with the entire procedure lasting about ten minutes. The resulting images are interactively reviewed on a dedicated computer workstation using 2D multiplanar images and 3D endoluminal displays of the colon. Over the past decade, rapid technological advancements in image acquisition, 3D display techniques, colonic insuflation, and stool tagging (i.e., labeling of stool with ingested radio-opaque contrast) have occurred, which have greatly improved the ability of CT colonography to detect colorectal polyps and cancer.

Incidental research findings, as defined in this symposium’s consensus paper, are unexpected findings discovered in the course of research but “beyond the aims of the study.” These include findings generated by research methodology, such as imaging or genetic analysis, findings related to clinical screening for inclusion or exclusion, or direct observations of physical abnormalities or behavior. Decisions about managing incidental research findings involve important ethical considerations regarding a researcher’s obligations to provide care, minimize harms, and respect research participants’ wishes. When the research participant is a child, the triadic relationship between the researcher, child participant, and parent makes these considerations more complicated. (See Figure 1.)

The possibility of generating incidental findings — in both research and clinical contexts — has long been regarded as a risk of these enterprises. Should incidental findings (IFs) in research also be regarded as potential benefits? At first glance, it would seem they ought to be. After all, in particular circumstances or given a particular set of values, any piece of information can be beneficial. Therefore, it may seem incoherent or unduly paternalistic to regard IFs only as risks. Moreover, developments in science and technology increasingly transform what was once of uncertain meaning and dubious value into information that is likely to have clear meaning and potential personal value, if not obvious clinical utility. For these reasons, it would seem that in the future, IFs should be treated as potential benefits in the design and regulation of research.

With rapidly expanding technological capacity, research has outpaced the existing infrastructure of ethical and regulatory guidance. In the area of incidental findings (IFs), this is particularly true.

The regulations under which most Institutional Review Boards (IRBs) operate were established over 25 years ago and have not been substantially altered in the intervening years. The technology available today that creates the opportunity for IFs was not conceived of, or considered, in the crafting of those regulations. Therefore, little guidance can be derived directly from these regulations. Rather, aspects of existing ethical guidance and regulations can be adapted to assist IRBs and researchers in dealing with issues surrounding IFs.

Magnetic resonance imaging (MRI) and functional MRI (fMRI) are important tools for neuroscience research because of their capability for investigating both the structure and function of the brain. The fMRI image extends traditional anatomical imaging of the MRI to include maps of human brain function. The ability to observe brain function opens an array of opportunities to research brain organization, neurological status, and neurosurgical risk. Neurological research is, thus, burgeoning. For example, Columbia University currently has several ongoing protocols investigating fMRI’s future role in neurosurgical planning, pain management, and understanding the physiological basis for neurological disorders as well as cognitive and perceptual events. One can imagine research proposals, both important and trivial, on such topics as whether brain imaging can shed light on the nature of dreams, memory, speech development, love, anger, or addiction.

Technology has outpaced the capacity of researchers performing research on human participants to interpret all data generated and handle those data responsibly. This poses a critical challenge to existing rules governing human subjects research. The technologies used in research to generate images, scans, and data can now produce so much information that there is significant potential for incidental findings (IFs), findings generated in the course of research but beyond the aims of the study. Neuroimaging scans may visualize the entire brain and even the entire head; computed tomography (CT) colonography research may visualize the entire torso, from the base of the lungs to the pubis; genetics studies may reveal “extra” and sometimes unwanted information about the family, such as misattributed paternity and undisclosed adoption; and genomic microarray research increasingly involves whole-genome analysis (WGA) revealing an individual’s complete genotype, with enormous potential for uncovering unexpected information about an individual’s genetics and risks of developing future conditions.

The human papillomavirus (HPV) is the most common sexually transmitted infection worldwide. In the United States, more than six million people are infected each year. Although most HPV infections are benign, two strains of HPV cause 70 percent of cervical cancer cases. Two other strains of HPV are associated with 90 percent of genital warts cases.

In June 2006, the Food and Drug Administration (FDA) approved the first vaccine against HPV. Sold as Gardasil, the quadrivalent vaccine is intended to prevent four strains of HPV associated with cervical cancer, precancerous genital lesions, and genital warts. Following FDA approval, the national Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination for girls ages 11-12 with three doses of quadrivalent HPV vaccine. Thereafter, state legislatures around the country engaged in an intense effort to pass laws mandating vaccination of young girls against HPV. This activity was spurred in part by an intense lobbying campaign by Merck, the manufacturer of the vaccine.

Screening for prostate cancer with the prostate-specific antigen (PSA) blood test is controversial, as evidence to date has not demonstrated such screening does more good than harm. While the potential benefit of PSA screening on reducing prostate cancer mortality has not been documented in randomized trials, many risks of PSA screening have been well documented. These risks include a substantially higher risk of a prostate cancer diagnosis over a screenee’s lifetime, false-positive and false-negative test results, possible complications from biopsies done in response to suspicious test results, and substantial risks of side effects from subsequent prostate cancer treatments. Nevertheless, PSA screening is widespread in the United States, and many physicians in a national survey reported supporting routine PSA screening as well as getting PSA tests themselves, despite the lack of evidence.

Despite governmental and private antismoking initiatives, tobacco smoking remains a significant public health and economic challenge. The Centers for Disease Control and Prevention (CDC) estimates that for each year between 1997 and 2001, cigarette smoking and exposure to secondhand smoke caused approximately 438,000 U.S. residents to die prematurely, resulting in 5.5 million years of potential life lost, and in $92 billion dollars of lost productivity. Also, despite convincing scientific data that laws against indoor smoking protect people from the negative health effects of cigarette smoke, not all states have afforded their residents this protection. As of July 2007, 16 states neither restricted nor banned indoor smoking in restaurants, private worksites, or government worksites, and many state statutes only required separate rooms for smokers rather than eliminating all smoking inside buildings. In several states, local governments have attempted to fill this gap by adopting their own antismoking measures.