by: Negin Vatanian
Magnetic Resonance Imaging, genomic information, gene sequencing, microarrays, ultrasound and radioisotopes are all part of routine clinical and medial procedures. They are also being used in research involving healthy and diseased participants. Unexpected diseases and risk of developing potential conditions and illnesses, which are beyond the scope of the clinical indication of the performed research, could be discovered through reviewing the tests performed during the research and clinical trials. Undiagnosed diseases and conditions that are discovered unintentionally or unexpectedly are called Incidental Findings (IF). They could have serious potential clinical and health effects on the participants in such research studies.
Incidental findings are not just limited to research and clinical trials. They can be discovered through autopsy, organ donation or transplantation. Biobanks and direct-to-consumer (DTC) medical testings, such as personal ultrasound machines and the whole-genome sequencing that can be purchased easily online for about $100, would add more challenges to the issues related to the incidental findings. Here are just an example of some of the concerns and questions that the research and medical communities are facing when it comes to incidental findings:
- What if the MRI shows a tumor at the base of spine or in the middle of a participant’s brain?
- What about genetic microarray that shows a chromosomal variant of a potential disease or a chromosomal mutation in a fetus?
- What if a misattributed paternity or parentage discovered through a genetic family study?
- How these findings should be handled? Should this information be shared with these research participants?
- Are the researchers obligated to provide medical care to the participants? Are the researchers financially responsible for such care?
- What if it was not clear whether the finding was incidental or it was an adverse event? And what if the finding would exclude a healthy participant from a clinical trial?
- What if the researcher is also the participant’s physician?
Managing incidental findings is complicated, challenging, and costly. Research participants are de-identified to keep their privacy. Going back to identify them is not an easy task and sometimes impossible when the data is secondary. In addition, keeping a research participant with an incidental finding in the research study requires more testing and treatments, and possibly would cause potential injuries and complications, while creating bias in the performed research. Incidental findings are the border of research and medicine, and there is no ethical and legal pathway for their management. How to handle incidental findings is rarely discussed by regulators. There is little guidance. In addition, researchers, companies and IRBs do not agree that they have responsibilities on analyzing, reporting and addressing these incidental findings to their research subjects and clients. The only exception is when the researcher is the participant’s physician, which makes the researcher responsible to report and manage the findings and treat the patient.
There have been a few initiatives in the past few years by research and educational institutes to properly address incidental findings. Several documents and white papers specific to an organ or a diagnostic method and research area have been developed and published. These documents can be implemented and used as guidelines for research community, and also can be used for future policy making and be expanded to include other research areas.
In 2005, some of the institutes of the National Institute of Health (NINDS, NIDA, NIBIB, NIMH, NIA) and Stanford University co-sponsored a workshop on “Detection and Disclosure of Incidental Finding in Neuroimaging Research”. The goal was to focus on key areas related to brain incidental findings such as detection, communication with participants, IRB and research protocols. The initial set of recommendations was developed focusing on handling the IFs. Some of the recommendations are:
- Potential findings should be anticipated in the experimental designs
- A process to handle the discovery of IFs by researchers should be developed and established
- There should be a pathway for follow up on the IFs and their cost of handling
- A pathway for Interpreting the results of testing for clinically significant findings should ne implemented
- There should be a pathway for disclosing the IFs to the research participants, PI, and physicians
- All the developed pathways should be addressed in consent forms and disclosed with the research participants
- Incidental findings and all the developed pathways should be addressed to IRB and reviewed by them
- Investigators should develop and provide templates for IF language in the consent forms for the study
- A centralized and national database of incidental findings should be developed
Since this preliminary initiative, more collaborative work has been done.
In 2010, the American College of Radiology formed an incidental findings committee with a few other radiologic organizations to develop an appropriate approach to managing incidental findings on CT scans of the abdomen and pelvis. The result was published as a white paper that provides guidance for addressing incidental findings in the kidneys, liver, adrenal glands, and pancreas.
In 2012, the American College of Medical Genetics and Genomics (ACMG) published a policy statement on clinical sequencing that emphasized the importance of reporting incidental findings to research participants. This policy statement also appointed a working group to make recommendations on responsible ethical management of the IFs in Clinical Exome and Genome Sequencing. This work was reviewed by a panel of outside experts, and produced recommendations that have been approved by the ACMG Board.
More work has to be done by regulators and policy makers. The research community needs to start recognizing the importance of managing such findings, and documenting the adverse health related outcomes due to missed IFs before a catastrophic event or significant legal action takes place.