A Brave New ‘Post-Mendelian’ World

Dec 12, 2014, 9:00 AM, Posted by

Lainie Ross, MD, PhD, is a 2013 recipient of the Robert Wood Johnson Foundation (RWJF) Investigator Award in Health Policy Research and a 2014 Guggenheim Fellow. During her fellowship year, she will work on a book tentatively titled, From Peapods to Whole Genomes: Incidental Findings and Unintended Consequences in a Post-Mendelian World.

Human Capital Blog: What are some of the incidental findings and unintended consequences you will discuss in your book?

Lainie Ross: First, let me explain what I mean by “incidental findings.” Incidental findings refer to unanticipated information discovered in the course of medical care or research that may or may not have clinical significance. They are not unique to genetics. In some studies, up to one in four diagnostic imaging tests have incidental findings, although most do not have immediate clinical consequences.

One example of an incidental finding that I discuss in the book involves incidental findings uncovered while screening candidates for research participation. This can range from discovering high blood pressure (known as the “silent killer”) to extra sex chromosomes in people who volunteer as “healthy controls.” This raises the question of what is a clinically significant or “actionable” finding, and what information should be returned to the research participant. These types of questions are critical, especially because many research consent forms have historically stated that “no results will be returned.”

Debates over this question continue. The concept and debate about genetic incidental findings underwent an upheaval in 2013, when the American College of Medical Genetics and Genomics (ACMG) published recommendations about identifying and reporting incidental findings in clinical exome and genome sequencing. The ACMG recommended that clinical laboratories analyze and report mutations identified from a list of 57 genes considered medically actionable (the list has now been reduced to 56 genes), whenever whole genome sequencing (WGS) is performed regardless of the reason that WGS is being performed or whether patients want to receive the results.

With colleagues, I have argued that this policy has the potential to turn the discovery of incidental findings into a mandatory hunt for particular genes that may or may not turn out to be as clinically significant as current data suggest. Even though these genes are known to be highly penetrant in high-risk families, we do not know how likely they are to cause health problems in the general low-risk population. We also object to the hunt because it includes searching for adult-onset cancer genes in samples obtained from children, which takes away children’s right to decide as adults what health information they want to know. This has led to a heated debate that I will address in my book.

HCB: In the title of your book, you refer to a “post-Mendelian” world? What do you mean by that?

Ross: When I was in high school in the 1970s, we learned about Gregor Mendel’s discovery about gene interaction—how two tall peapods can create a short one. The theory was based on the assumption that one gene caused one trait and, in effect, that our genes are our destiny. A lot has changed since then. We now know that most genetic traits are in fact non-Mendelian; most of our traits are complex and involve more than one gene. We also know that even if you have a certain Mendelian genetic condition, other genes, or the environment, can modify it. That is what I mean by a post-Mendelian world. And in this world, our genes are not our destiny; they are only part of a much more complex story.

As the medical and genetic communities move into a post-Mendelian paradigm, we have come to understand that many disorders involve many genes as well as gene-environment interactions. First, we studied one gene at a time; then, we studied a handful of genes simultaneously using gene chips. In the past decade, we have begun to use WGS to examine all 20,000-plus genes and the 3 billion base pairs that make up the whole human genome.

WGS enables researchers to find and analyze genes associated with numerous health conditions. In the course of their study, the researchers may also find genes that suggest that an individual is at increased or decreased risk for other unrelated health conditions, and they may discover some unexpected information—including information about extra chromosomes. They will also find a lot of genetic variants of unknown significance.

One big debate centers around what to do with WGS results over time—whether there is a duty to continually reanalyze results as new information is learned and then re-contact patients or research participants to inform them of the new findings or the new understanding of old findings. My book will examine the ethical implications of incidental findings and unintended consequences from WGS.

HCB: How does this project build on your previous research?

Ross: Much of my earlier work in genetics focused on ethical and policy questions about single gene conditions like cystic fibrosis and sickle cell disease. A main focus of this genetic work was focused on health care disparities. I examined the question of why we used race-based policies for prenatal screening of these conditions when universal newborn screening shows how erroneous the underlying assumptions of race-based policies are. I also looked at different methodologies in newborn screening for cystic fibrosis to show that they had different rates of false negative results (the failure to identify someone with disease), unintended results which were ignored in health policy discussions.

My interest in genetics recently collided with my interest in organ transplantation, which has also focused on health care disparities. Research has shown that black living kidney donors are at greater risk of developing kidney failure than other living kidney donors. This led me to wonder if the sickle cell trait might be at least partly responsible for the increased risk of kidney failure in black living donors, since the sickle cell trait is known to be associated with decreased ability to concentrate urine. The vast majority of transplant programs do not screen donors for the sickle cell trait.

To that end, I decided to examine the genetics of living donors who had developed end-stage kidney disease. For the study, my colleagues and I located 150 kidney donors who went into kidney failure themselves. We know that at least another 200 donors have developed kidney failure, and we know there are more.

In our small sample, we found that while most living donors are white females, our sample has a disproportionately large number of black males. And while one-third of living donors donated to a sibling, two-thirds of our sample are siblings, suggesting there may be a genetic component to end-stage kidney disease. We are now working to identify a proper control group in order to use WGS to determine if there may be some key genetic risk factors not previously known.

But this project, like other projects involving WGS, may have unintended consequences. As we try to determine why some donors develop kidney failure, our findings may change what constitutes an informed consent from future donors. Our findings may lead to new transplant policies that require genetic testing prior to donation. Such policies could help ensure that donors have the information they need to make informed choices, but it is also possible that they could prevent from donating some potential donors who are at risk but would never develop any problems. Some may see these changes as protective, but others may view them as paternalistic because our genes only explain a portion of the risk. To avoid unintended consequences, we need to be very careful in how we present our data to ensure that policymakers appreciate the probabilistic nature of genetic information.

The Guggenheim project is actually an outgrowth of the collision between my interest in genetics and transplantation because I realized that the problem of unintended consequences pervades genetics health care policies. By making these results transparent, we may be able to reduce the disparities that they cause.       

HCB: Last year, you received an RWJF Investigator in Health Policy Research Award to study ethical and policy issues raised by living donor transplantation. What are some of those issues?

Ross: Bob Veatch, PhD and I just completed the second edition of a book entitled Transplantation Ethics 2nd edition, which focuses on procurement and allocation of deceased donor organs for transplantation. Living donors are another potential source of organs. There are ongoing discussions within the transplant community about how to expand the number of living donors, and I aim to address the ethical and policy issues raised by living organ and tissue donation in my RWJF-supported book.

Deceased donor organs are a public good, but living donors provide a private good. Whereas deceased donor organ transplantation must focus on good stewardship and balancing equity and utility, in living donor transplantation, there needs to be special focus on issues such as autonomy and its limits from the perspective of the donor and from the transplant team.

We will also focus on “vulnerabilities,” some of which involve certain populations like children or prisoners. When, if ever, can children or other persons who lack decisional capacity serve as solid organ or tissue donors? When, if ever, can prisoners serve as living donors? And do competent adults ever experience situations that may call into question the efficacy of their consent? How can we ensure that competent adults are acting voluntarily and are not under family pressure to donate?

Our book will also address justice-related concerns. While discussions around deceased donor organ transplant focus on distributive justice, our focus on living donor transplantation has more to do with social justice (although in some cases there is significant overlap). For example, in deceased donor allocation we see a gender gap: a greater percentage of men who are on dialysis get placed on the waitlist compared to women, and a greater percentage of men who are on the waitlist get a deceased donor kidney. In living donor transplantation, women are much more likely to be living donors than men, but again men are more likely than women to be living donor organ recipients.

Many initiatives currently focus on increasing the rates of living donors, but not on what impact that may have on social justice concerns. In our book, we will explore the ethical implications of different policy proposals to increase living donation rates as well as the ethics and policy issues of creating an organ market.

HCB: Has the RWJF Investigator Award influenced your current work and, if so, how?

Ross: Yes. First I would like to thank RWJF for selecting this project for support. It has given Dick Thistlethwaite, MD, PhD, and me some much-needed protected time to continue our collaboration, which began almost two decades ago. I just returned from my first national RWJF Investigator Award meeting, where I had the opportunity to present our work. We received interesting and valuable feedback from the larger RWJF community and look forward to continuing these conversations in the years to come. 

This commentary originally appeared on the RWJF Human Capital Blog. The views and opinions expressed here are those of the authors.