GeneWatch Vol. 25 No. 4

GeneWatch THE MAGAZINE OF THE COUNCIL FOR RESPONSIBLE GENETICS | ADVANCING THE PUBLIC INTEREST IN BIOTECHNOLOGY SINCE 1983

Volume 25 Number 4 | July-August 2012

Interviews: Laura Rodriguez, National Human Genome Research Institute,

on returning genomic research results Robert Green, geneticist and physician,

on incidental findings in medical genomics ISSN 0740-9737 Also:

Ostrer’s Flawed Genetic History of the Jews

by Diana Muir Appelbaum and Paul S. Appelbaum

GeneWatch July-August 2012 Volume 25 Number 4

Editor and Designer: Samuel W. Anderson Editorial Committee: Jeremy Gruber, Sheldon Krimsky, Ruth Hubbard GeneWatch is published by the Council for Responsible Genetics (CRG), a national, nonprofit, taxexempt organization. Founded in 1983, CRG’s mission is to foster public debate on the social, ethical, and environmental implications of new genetic technologies.

The views expressed herein do not necessarily represent the views of the staff or the CRG Board of Directors.

Address 5 Upland Road, Suite 3 Cambridge, MA 02140 Phone 617.868.0870 Fax 617.491.5344 www.councilforresponsiblegenetics.org

board of directors

Sheldon Krimsky, PhD, Board Chair Tufts University Peter Shorett, MPP Treasurer The Chartis Group Evan Balaban, PhD McGill University Paul Billings, MD, PhD Life Technologies Corporation Sujatha Byravan, Phd Centre for Development Finance, India Robert DeSalle, Phd American Museum of Natural History Robert Green, MD, MPH Harvard University Jeremy Gruber, JD Council for Responsible Genetics Rayna Rapp, PhD New York University Patricia Williams, JD Columbia University staff

Jeremy Gruber, President and Executive Director Sheila Sinclair, Manager of Operations Samuel Anderson, Editor of GeneWatch Andrew Thibedeau, Senior Fellow Magdalina Gugucheva, Fellow Editorial & Creative Consultant Grace Twesigye Unless otherwise noted, all material in this publication is protected by copyright by the Council for Responsible Genetics. All rights reserved. GeneWatch 25,4 0740-973

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Editor’s Note

Samuel W. Anderson

You are a research subject. You have agreed to provide a DNA sample for a medical study. The study’s consent form gives you two choices: A) The researchers keep your name and contact information on file and inform you if they come across serious health concerns in your genome; or B) The researchers will not inform you of any of your results. Which do you choose?

You are a researcher. While analyzing a research subject’s genome sequence, you discover a variant that strongly suggests the subject will develop a life-threatening but preventable condition. However, on their consent form the subject specifically requested not to be informed of any results. What do you do?

You are a patient. Your doctor recommends clinical whole genome sequencing in order to screen for any genetic red flags related to a few conditions that run in your family. Your doctor informs you that there is a possibility of “incidental findings,” or results not related to the conditions being screened for. The predictive value of some of these results may not be well understood; other results could suggest serious health threats which you can do nothing about. Your doctor asks: Are there any results you would rather not be informed of?

You are a doctor. You ordered clinical whole genome sequencing for a patient who requested not to be informed about any incidental findings that suggest a serious health risk for which there is no medical intervention. The results include one such risk. Although the patient specifically asked not to be informed of this, you also see several members of the patient’s family, and you know that this result could affect them. What do you do?

Returning genomic test results and incidental findings is not as simple as just handing them off to a patient or a research subject.

These examples only scratch the surface of the complex challenges faced by everyone from researchers and institutional review boards to the parents of children receiving clinical genomic testing. The basic dilemmas are not unique to genomic information; many researchers have wondered whether they should offer to return individual results to participants, and as Marc Williams (p. 13) points out, “incidental findings are an inherent part of medical practice.” But while the dilemmas may be familiar, the scale is not. The enormity of information unearthed in whole genome sequencing is unprecedented, and as it begins to play an increasingly important role in human research and medicine, questions of how to handle results will become increasingly pressing. The genomic era is coming fast; now is the time to set precedents. nnn

Write to (or for) GeneWatch GeneWatch welcomes article submissions, comments and letters to the editor. Please email anderson@gene-watch.org if you would like to submit a letter or with any other comments or queries, including proposals for article submissions.

July-August 2012

GeneWatch

Vol. 25 No. 4

4 Genomic Incidental Findings: Metaphors and Methods Incidental results can come up in many areas of medicine. In genomic testing, they are practically guaranteed. By Jonathan S. Berg and James P. Evans 6 Returning the Favor Returning individual research findings to study participants may be the way of the future, but it’s more complicated than you think. Interview with Laura Rodriguez 9 What the Doctor Orders In clinical genomic testing, incidental findings are returned to your doctor. What happens when the results are more than you or your doctor had bargained for? Interview with Robert Green 11 Toward Inclusive Genomics Finding the right way to return results to genomic research participants from minority groups could be an opportunity to redefine the participant-researcher relationship. By Joon-Ho Yu and Wylie Burke 13 Déjà Vu All Over Again? Despite what you may have heard, incidental findings in whole genome sequencing may not be so different from incidental findings in other areas of medicine. By Marc Williams 16 Children First Adults may choose whether or not to be told about certain research results or unexpected findings—but who decides for children? By Bartha Knoppers 17 Who Has the Right to Know? Community partnerships help guide the return of results from genetic research with indigenous peoples. By Elana Brief and Judy Illes 19 Sharing and Carings There’s a right way and a wrong way for researchers to work with American Indian communities. Interview with Francine Gachupin 21 Returning Research Results: Unresolved Issues Which information should be returned to research participants—and who makes that decision? By Karen Maschke *** 22 Topic Update: Gene Patents U.S. Appeals Court Reaffirms Ruling in Favor of Myriad’s Gene Patents

23 A Problematic Reading of the Genetic History of the Jews Diana Muir Appelbaum and Paul S. Appelbaum review Harry Ostrer’s book Legacy: A Genetic History of the Jewish People.

27 Endnotes

Genomic Incidental Findings: Metaphors and Methods Incidental results can come up in many areas of medicine. In genomic testing, they are practically guaranteed. By Jonathan S. Berg and James P. Evans

Much has been written about the promise of genome-scale sequencing in medicine, both for diagnosis of rare monogenic disorders and also perhaps as part of routine patient care.1 Yet no matter the indication, the vast majority of genetic variants in a given individual will be unrelated to the reason the test was performed, and thus could be considered “incidental” or “secondary” findings. Of these, nearly all will have minimal or no clinical implications, but each individual will have a heterogeneous assortment of clinically significant but unpredictable genetic variants: • A small fraction of individuals will be found to have a mutation that indicates the existence of a previously unsuspected genetic disorder with clear clinical consequences (ranging from very rare disorders such as Lynch syndrome to more common conditions such as hemochromatosis).

• Most individuals will be found to carry a handful of heterozygous mutations for conditions with recessive inheritance patterns.

• Everyone will have a complement 4 GeneWatch

of common genetic variants that have been implicated in pharmacogenomic variation or associated with modestly shifting their risk for common multifactorial disorders.

The task of a clinically-oriented genomic analysis will therefore be to effectively communicate to patients the range of potential incidental findings and to outline a structured process for identifying and reporting the relevant variants, balancing principles of medical ethics such as the physician’s “duty to warn” with the patient’s autonomy to determine what genomic information they desire to know about themselves.

How, then, do we communicate the wide range of potential incidental findings in a genome sequence? Making the task more difficult is that if we are to engage in any kind of meaningful informed consent with patients, the possible range of results waiting to be discovered in an individual’s genome must be communicated to them prior to sequencing so that they can make informed decisions.

One cannot wait until one happens to find, say, a presenilin mutation

that confers a virtual certainty of Alzheimer’s disease and then ask the patient if they want to know about the potentially disturbing mutation that was found.

Different metaphors have been used to describe genomic incidental findings with respect to incidental findings in other areas of medicine.

One familiar comparison is with the radiographically-detected “incidentaloma,” for which the differential diagnosis might include both benign and malignant entities. In any given study, a radiologist must routinely assess numerous minute details that vary slightly from “normal,” and decide whether and how to comment on them. Physicians do not routinely make their patients aware of the possibility of such findings when ordering imaging studies, yet they must cope with the consequences of such findings, including the potential need for follow-up imaging studies or more invasive biopsies. The challenge of applying this model to genomics is that while not infrequent, incidental findings in radiology are not the rule. On the contrary, they will be universally discovered when July-August 2012

one’s genome is sequenced and thus clear guidelines must be established for how to deal with them in a way that balances efficiency, provider duty and patient autonomy.

Another comparison can be made to laboratory biochemical findings, in which different flags are used to draw attention to values that are outside of the normal range. Laboratory “critical” values are those that must be attended to immediately due to the potential for imminent danger to the patient. In the setting of an acutely ill patient, such critical values can be of great diagnostic importance. In an otherwise healthy patient undergoing routine screening, the detection of a critical laboratory abnormality is more likely to represent a spurious analytic error than a true finding, and is made more likely when multiple assays are run simultaneously.

Both the radiology and the clinical laboratory metaphors articulate the essential idea that certain incidental findings are of sufficient importance to warrant reporting to physicians and patients as a matter of course.

However, neither accommodates either the frequency of their discovery in genomics (a certainty with each genome sequenced) nor the broad range of potential findings seen in genomic medicine—from highly deterministic to modestly predictive, from generally benign to potentially devastating, and from completely preventable to utterly futile with regard to possible medical interventions. Instead, these metaphors relate primarily to clinical situations in which the abnormal finding indicates a need for specific actions that would reasonably be expected to benefit the patient. In contrast, only a small minority of genomic findings rise to a level of clinical “actionability.” And critically, while some findings may be scientifically and clinically valid (for example, the discovery of the Volume 25 Number 4

presenilin mutation that confers near certainty of early-onset Alzheimer disease), such results will be ardently desired by some patients and just as adamantly not desired by others.

So while we can learn from the dilemma of the radiologist and the traditional laboratorian, such metaphors ultimately fail to fully capture the magnitude of the problem when it comes to genome sequencing, given that each individual will have millions of positions that differ from the “reference” genome sequence, the overwhelming majority of which are of no clinical importance. The hazards of interpreting incidental genomic findings have been capably outlined elsewhere.2 Further complicating the genomic situation is that our knowledge base is evolving very rapidly. The sheer number of genetic variants and the extremely low prior probability that such findings truly indicate the presence of a genetic disorder result in an imperative to avoid overwhelming the system with incidental findings of dubious clinical validity or utility, and instead to focus only on those variants that are highly likely to represent disease-causing mutations.

Clinically-oriented analysis of incidental findings in genome sequence data must therefore address these points of concern with a methodical, reproducible approach that allows both the clinician to efficiently discharge their responsibility while affording maximal autonomy to the patient. It seems to us that a case-bycase assessment of incidental findings could lead to unsystematic results that are not consistent between analyses. We therefore prefer the establishment of an a priori framework for the analysis of genomic incidental findings.3 In our proposed model, genes are organized into categories (“bins”) based on clinical actionability (Bin 1), clinical validity without

direct actionability (Bin 2), and no clinical implications (Bin 3). This model can then be used to facilitate pre-test informed consent so that it can be made clear that some types of incidental findings (Bin 1, expected to be very rare) would be obligatorily returned as a matter of course because the information would directly affect that individual’s or their family members’ clinical management, while other findings (Bin 2) reside in the realm of individual preference and are not routinely divulged without appropriately-informed decisions by the individual. Such an approach is enabled only by the appropriate use of computational algorithms that select variants for further review and reporting based on a high threshold of likely pathogenicity,4 thus streamlining the analysis and ensuring that each sample is subjected to precisely the same analytic criteria. Finally, the application of a structured informatics approach to analyzing the incidentalome provides “versioning” and allows one to revisit the analysis periodically since the underlying choices about which genes and variants are clinically “actionable” will certainly change as genomic medicine advances.

The genome is a big place, full of information that varies from worthless to life-saving, from innocuous to terrifying. Approaching it in a planned and methodical manner will help patients, the public and providers alike navigate its immensity. nnn Jonathan S. Berg, MD, PhD, is Assistant Professor in the Department of Genetics at the University of North Carolina School of Medicine and Principal Investigator for the Carolina-Georgia Center of the Cancer Genetics Network.

James P. Evans, MD, PhD, is Bryson Distinguished Professor of Genetics and Medicine at the University of North Carolina School of Medicine.

GeneWatch 5

Returning the Favor Returning individual research findings to study participants may be the way of the future, but it’s more complicated than you think. Interview with Laura Rodriguez Laura Lyman Rodriguez, PhD, is the Director of the Office of Policy, Communications, and Education at the National Human Genome Research Institute (NHGRI).

GeneWatch: NHGRI has a new strategic plan this year which emphasizes translating science into clinical practice. Does the plan include more focus on the return of research results and incidental findings?

Laura Rodriguez: It’s not part of the strategic plan explicitly, but it is clearly an integral part of providing clinical care informed by genomics.

This is an emerging area with a lot of complexities. The science is moving very quickly, and law, as so often happens, is not up to date with current science. In this particular area, even the ethics considerations are still very fluid. It’s a very hotly contested domain with a lot of passionate feelings on all sides, because it is at the intersection of our genomic capacity and our genomic understanding. At the moment, we can produce a lot more

6 GeneWatch

information than we can understand.

To address this, we launched a new consortium earlier this year focused on the issues surrounding return of results. There were several new studies funded, along with a few studies we had already funded, which were all brought together in a consortium so that the investigators working on this can get together and try to chart recommended paths through the issues.

Are there firm NHGRI guidelines right now about returning results, or is it up to the researchers how to handle it?

There are existing guidelines in the form of CLIA (Clinical Laboratory Improvement Amendments), and as part of the federal government we abide by that law—that laboratories returning information for clinical purposes or with clinical context should be CLIA approved. We have labs that are working in this intersection, and they have developed different plans on how to work with these guidelines—for example, by partnering with a CLIA approved lab so that when there is a research finding appropriate for consideration to offer to return it can be confirmed in a CLIA lab. All of the projects are also operating under IRB (Institutional Review Board) review.

What we are trying to do is to build a foundation of data through our return of research results consortium from which we can make informed policy choices about considerations regarding the decision to offer to return results or not. At the

moment there is an accumulation of data, but there is not a consensus, which makes it premature to design a national policy.

Our consortium also addresses how to return the data. It isn’t simply a question of the wet lab having a finding and giving it back; there are a lot of questions about the appropriate way to offer to return this data to individuals so that it can be meaningful to them. Some of that has to do with ethical considerations of when the data is returned, and some of it also has to do with support and resources to make available to individuals, both before they decide whether they want the information, and afterward if they do choose to receive it.

Does it seem to you that more studies are tending to make it an option for participants to receive individual research results?

As you said before, our goal is to have research translated into the clinic and to have more applications in the realm of genomic medicine, and that’s going to involve providing more results to clinicians and patients in order to inform their decision making.

So I would say that yes, we’re going to see things move in that direction.

What we’re trying to do now is foster the data on participant perspectives about the scientific knowledge and the ethics conversation, so that we can be prepared to form the policies that will guide options to return results in practice.

Do you think the same is true of returning incidental findings—that July-August 2012

is, if the variant to be returned is something that the participant wouldn’t have thought about in advance?

Again, I would say that the norms about when it is appropriate to return an incidental finding—when is it even appropriate to look for incidental findings—are still developing. Right now, it’s important for laboratories to Volume 25 Number 4

work with their Institutional Review Boards on this question, because it’s going to be very case specific. From a national standpoint, it is difficult at all times to make policy that will fit every situation. Right now, when there are so many moving parts and so much changing knowledge in this field, it’s incredibly difficult to come up with a policy that could be applied across the board appropriately.

Part of what our researchers are looking at is what the obligations should be for offering to return findings, and if there is some obligation, how do you define which conditions you have an obligation to look for?

In some regards, returning findings that aren’t related to the purpose of the study might actually be very similar to returning the research findings to participants; but in some ways it GeneWatch 7

might be more difficult, because the investigators and physicians (if there are physicians involved) aren’t as likely to have expertise in diseases outside of their research area. That makes it even harder to think about the right way to provide the appropriate resources to the individual, let alone provide any clinical care for the individual.

At the same time, this is part of the dilemma when an investigator does run into something and feels that it’s important because there is some intervention or utility the individual might have, medically or on a personal level, from knowing this result.

That’s something I wondered about: What actually happens when a lab technician or a researcher realizes that they have information that could help someone, even save their life—what do you do next? What if there isn’t a clear protocol for what to do, or what if you’ve told participants you aren’t going to be returning any results? … Or is this just a hypothetical situation?

I don’t think it is just a hypothetical situation. I know there are investigators who have had a very difficult time with this. They have found things that could be important, and their IRBs have advised them that they should not return the findings because in a consent form five months ago or five years ago, a participant said “I don’t want this information.” That is very difficult for the investigators, because they believe the information is very relevant.

There would also seem to be a logistical issue of returning results to participants because if you agreed not to return results, you may have de-identified the samples and can no longer match them to the 8 GeneWatch

participants. But if you have an individual’s whole genome sequence, couldn’t you potentially use that to identify them?

It depends on what you’re testing. If you’re doing whole genome sequencing, you have enough information to find a unique pattern. But if you’ve made a commitment to de-identify it, there would be questions about changing the plan after the consent process. There’s also the problem of what other information you have that you can match back to the sample. When you de-identify a sample, you’re doing it for participant privacy and confidentiality, so you’re not keeping the other information you’d need in order to make a match to the sample. In order to re-identify the sample, you’d have to break the policies you put in place. It is very dependent on study design—and that has been a mechanism for solving this issue, to say “we don’t have sufficient information,” or “we don’t think the information we get back will be sufficiently informative to return to participants.” Then you can tell participants upfront that you won’t be returning results, that this is only for research purposes, and you can deidentify the data.

It seems that in a situation where you give the option to return the results, there needs to be a way to de-identify samples, but also to re-identify them. How is that navigated?

If you do plan to offer to return results, you would keep a link. You’re not working in the laboratory with individuals’ names on the test tube; you have an anonymous link so that the people working with the samples don’t know who it is, but if there is information determined to be of sufficient relevance to return, the

primary investigator or someone else can make that link and contact the participant.

Do you have a sense of whether having the option to receive results impacts how likely people are to participate in a study?

There have been studies that show this issue is a factor in participant perspectives about research participation, and there are anecdotes that suggest this is why some people choose to participate in a study—because of the possibility of having results returned. That’s not universal, and we need to understand the issues better. This issue is something we are struggling with in genetics and genomics, and we’re struggling with it both in cases where we might know what a given result might mean and, even more vexing, when we don’t know what a result might mean. It’s been a conversation that participants and investigators have long had in clinical trials: Their participation in the research is not a guarantee that they are going to benefit in any way, and in fact, a fundamental principle to convey during consent is that the research is not for the participant’s personal benefit. I think it’s something that physicians and their patients have struggled with for a long time. Many still make the decision that even though it might not help them to participate in a study, they want to help others. I think many make that same decision when they are participating in a genomic study but may not be able to receive individual results. But we need to understand the associated issues better before we make assumptions about what motivates participants, and before we start making policies based on those assumptions. nnn

July-August 2012

What the Doctor Orders In clinical genomic testing, incidental findings are returned to your doctor. What happens when the results are more than you or your doctor had bargained for?

Interview with Robert Green

Robert C. Green, MD, MPH, is a physician-scientist in the Division of Genetics and Department of Medicine at Brigham and Women’s Hospital and Harvard Medical School, Director of the Genomes to People research program, and a member of the Board of Directors of the Council for Responsible Genetics.

GeneWatch: How is it that incidental findings even come to be an issue? For example, if a physician orders a genetic test for a patient with heart problems, why would there be any results besides genetic variants known to be related to cardiac health?

Robert Green: It’s actually not much of an issue in the current way genetic testing is done, where specific genes are explored for suspected mutations as part of the workup for a particular phenotype or disease presentation.

But as we move into the genomic era—as it becomes easier and easier, and cheaper and cheaper, to sequence the entire exome or genome rather than just a few specific genes—the

Volume 25 Number 4

issue of incidental findings will become more relevant. It turns out that once you sequence all of the genes, even if you are only looking at one or several for a particular indication, it is relatively easy to also look for known pathogenic mutations that have been associated with other diseases. For example, you could perform whole exome sequencing or whole genome sequencing for a cardiac indication, but it would be relatively easy—especially as informatics get better and better—to also search for mutations in known cancer predisposition genes and therefore be able to tell someone whether they might be at increased risk for a particular kind of cancer.

You have been involved in creating guidelines for the American College of Medical Genetics and Genomics (ACMG) on returning incidental findings from genetic testing. Can you tell me anything about the recommendations that are likely to emerge from this?

There is a working group that has

GeneWatch 9

been asked by the ACMG to develop a policy on incidental findings, and I co-lead that working group, along with Leslie Biesecker from NHGRI. We have come up with a number of principles. One is that we think it may be useful for laboratories to look for limited sets of incidental findings, and these should be findings for which there is a well recognized medical intervention. We do feel like the report, both the primary information and the incidental findings, can go back to the physician, and that the physician can contextualize any findings. That’s extremely important, because it’s a reminder that we’re not talking about a direct to consumer scenario here. We’re talking about information that has the potential to be interpreted in many different ways, depending on the age, the clinical status, and the medical history of the patient. It is the classic job of a physician to integrate all sorts of laboratory information, using what he or she knows about the patient.

So we’re really treating incidental findings in genomics very much like incidental findings in the rest of diagnostic medicine: It goes back to the ordering physician, the ordering physician struggles to put it into context and uses their best judgment to go forward from there.

Does the patient have a point at which they can say: “Here are the things that I don’t want to know about?”

They are engaged in a conversation with their physician, and they can make that case about their genomic information the same way they could make that case about an X-ray. It is our position that the things that we would suggest to be on a recommended minimum list of incidental findings would be things that most people—not everyone, but most 10 GeneWatch

people—would actually want to know about.

You were lead author on a study published this spring which investigated whether specialists could agree on which variants to return as incidental findings in different situations. Although it was an exploratory study, did you see any important takeaways?

Yes, I thought it was quite interesting for a couple of reasons. First I should clarify that it was a non-representative survey of a number of genetics experts, and it was in no sense a policy document, recommendations, or anything like that. It just asked some expert geneticists and laboratory directors: If you were advising a molecular laboratory on what to return as incidental findings to the ordering physician, which of this following list of things would you suggest for the adult patients, and which would you suggest for children?

What was unique about this study was that no one had really posited this scenario before. Most genetic testing nowadays is ordered by medical geneticists, and it’s targeted testing. So here we posited what is really an inevitable scenario in the future, but something no one had asked before. You’ve got a clinician—they may or may not be an expert in genetics— and you have the capability, through whole exome or whole genome sequencing, to look at all these other disease genes. What would you give back to the physician? And I think the most surprising thing about the study was how many different disease variants the respondents suggested could be given back. That was very surprising.

But there were a few, right, that almost no one said they would return?

Like variants for an adult-onset

disease with no known medical intervention being returned when the patient is a child?

There were actually a number of people who voted to return things to the clinicians of children that I was frankly surprised about. I think that many people were surprised that so many of these experts would vote to return such information. I think one explanation, anecdotally, is that even if you might not intervene for, let’s say, an adult cancer predisposition in a child, you would be indirectly discovering something about that child’s parents that could benefit them. I don’t know for how many that was an issue, but it may have been behind some of the logic of returning results to children’s physicians.

What have you noticed about the range of opinions on how to return incidental findings?

There are clearly clinicians, genetic counselors, and interested laypeople who have widely divergent views on this. There are people who strongly believe that the information should be treated very cautiously and that disclosure should be reserved for unusual circumstances, where there is very clear discussion about the nature of the disclosure before it occurs; and there are other people who feel that genetic information should not be treated differently than other medical information, and people—clinicians, patients, consumers—have a complete right to know information of any type about themselves. So you really have a huge divergence in the degree to which people think that genetic information should be restricted or filtered by professionals. nnn

July-August 2012

Toward Inclusive Genomics Finding the right way to return results to genomic research participants from minority groups could be an opportunity to redefine the participant-researcher relationship. By Joon-Ho Yu and Wylie Burke Twenty years after the inauguration of the Human Genome Project, we have the ability to sequence a person’s entire genome both rapidly and at diminishing cost. As a result, it is now feasible to sequence the genomes of hundreds or thousands of research participants in a single study. This research offers an unprecedented opportunity to advance our understanding of the genetic contributors to human health, potentially informing improvements in prevention, disease management and drug discovery. But in order to ensure broad benefit, researchers need to solve a persistent problem: the underrepresentation of minority populations in the research process.

Without better minority representation, genetic studies may fail to reveal the full extent of human genetic variation, and as a result may ultimately offer fewer benefits to minority patients, exacerbating disparities.

Addressing this problem will require recruitment strategies and Volume 25 Number 4

study procedures that take into account the perspectives and concerns of potential minority participants. In the case of studies involving whole genome sequencing, the issue of whether and how to share the emerging genetic information with research participants may prove to be among the most significant. This issue arises because of the broad scope of sequencing technology. Most genomic studies are focused on a particular question, such as the search for the genetic contributors to a particular disease; but with the capacity to sequence the whole genome comes the ability to identify nearly all genetic abnormalities present in a particular individual. The researcher is faced with the dilemma of how extensively to search for abnormalities unrelated to the study and what information to return to participants. If fully analyzed, the whole genome sequence will generate anywhere from a handful to dozens of clinically meaningful results per individual. These results

may be completely unexpected or incidental to the main reason for the research study and will vary widely in their potential impact, ranging from information about moderately elevated risks for common diseases to rare but dramatic risks for inherited disease.

People from underrepresented minority groups often have an understandable mistrust of medicine and research. The recently publicized Henrietta Lacks story, demonstrating how tissues from a poor black woman were taken for research without her consent or even knowledge, resonate with other research experiences of minority communities.

Studies have been undertaken with little attention to the interests or needs of the communities who provided the samples. They have sometimes involved deceit, as in the case of samples taken from the Havasupai Tribe without full disclosure of the intended research, or even explicit harm, as in the shameful example GeneWatch 11

of the U.S. Public Health study of syphilis. This history fuels a general mistrust of biomedical research and a specific expectation that research will not be done for the benefit of minority peoples. The question before us is: How does the prospect of returning whole genome results fare in this context? What does parity mean in the context of receiving results?

Genomic studies focused on understanding disease biology offer more promise for minority communities if those communities are part

“Genomic studies focused on understanding disease biology offer more promise for minority communities if those communities are part of the research process.� of the research process. Genomic studies, therefore, represent an important opportunity to build trust and reestablish, perhaps even redefine, the participant-researcher relationship. Offering results could play an important part in this process because tangible health benefits such as new drugs or procedures will take time. In the interim, offering participants the chance to receive clinically meaningful results may be viewed both as a prospect for personal and familial benefit, and as an avenue to demonstrate respect, two core elements in the creation of a reciprocal research partnership.

If reciprocity suggests that results 12 GeneWatch

ought to be offered, the practice of transparency and respect suggest how results might be chosen for return and what procedures might be most appropriate. Many results from whole genome sequencing are currently of uncertain clinical value, and uncertainty is likely to be greater for people of racial and ethnic minorities because most studies of genetic variation to date have been limited to populations of European descent.

However, every whole genome sequence will provide some results with clear clinical meaning. For example, the presence of mutations well documented to be associated with colon, breast or ovarian cancer risk, if present, point to the need for earlier or more intensive cancer screening.

Even among this type of result, however, the risk implications may vary, with some gene variants indicating high risk and others only small increases above average risk. Further, not all clinically meaningful results can be addressed with prevention or treatment.

A partnership-based approach to returning results would seek to involve participants in decisions about what results to return, and how, especially among clinically meaningful results. Methods for offering results perhaps should vary. Family relationships may span great distances within recent refugee and immigrant communities, and honoring reciprocity may mean giving due consideration to the range of family structures present in these communities. Personal circumstances and cultural expectations may influence how different people respond to the offer of results. In addition, partnership-based dialogue may lead to the return of aggregate study results in accessible formats or even greater dissemination of scientific or health information, either in lieu of or in addition to individual results. These

considerations point to the need for empirical research to understand attitudes among diverse communities toward receiving research results and to devise strategies that respect and support personal and family preferences. Just as the meaning of sequencing results may change over time due to a changing base of genetic knowledge and changing priorities at different points in life, participantresearcher relationships will need to evolve into long term conversations.

Nowhere is this more important than in the context of research relationships with underserved minorities.

Returning results in the context of a partnership-based approach may do more than increase minority participation in genomic research. It provides an opportunity to engage minority communities in discussions about the purpose of genomic research, the potential for long term benefits, and the methods researchers use to ensure that research procedures are trustworthy. Understanding participants’ views about how and why results should be offered will also provide the groundwork for making best use of genomic technology in clinical settings. nnn Joon-Ho Yu, MPH, PhD, is a Senior Postdoctoral Fellow in the Department of Pediatrics, Division of Genetic Medicine at the University of Washington. His research focuses on the intersection of genetics and racial and ethnic minority communities.

Wylie Burke, MD, PhD, is Professor and Chair of the Department of Bioethics and Humanities at the University of Washington and Principal Investigator of the University of Washington Center for Genomics and Healthcare Equality. Her research addresses the social, ethical and policy implications of genetic information.

July-August 2012

DĂŠjĂ Vu All Over Again?

Despite what you may have heard, incidental findings in whole genome sequencing may not be so different from incidental findings in other areas of medicine. By Marc Williams In response to the precipitous drop in the costs of whole genome and exome sequencing, groups are now implementing this technology in a variety of research and clinical settings.

Whole genome and exome sequencing (WGS) has remarkable power to detect causal genetic disease variants in populations of patients who had eluded diagnosis despite extensive diagnostic odysseys, particularly when one considers the challenges of interpreting the vast amounts of data coming off of the next generation sequencing machines.

A consequence of doing WGS is that one ascertains all of the variants from the portion of the genome that is being analyzed. Some of these variants will occur in genes. The vast

majority of these variants will have no effect, but a small subset will be deleterious. In some cases the mutation will affect one allele in a gene associated with an autosomal recessive condition (CFTR and cystic fibrosis) in which case the individual would be a carrier, but would not have any manifestations of the disease. More infrequently a deleterious mutation in a gene could predispose the individual to disease. Examples could include autosomal dominant cancer predisposition genes (e.g. BRCA1/2); autosomal recessive genes where an individual is found to have a mutation in each allele (HFE and hemochromatosis); and X-linked genes where males or female hemizygous carriers could be identified (PRPS1

and Charcot-Marie-Tooth X-linked recessive 5 or GLA and Fabry cardiomyopathy). In some cases these variants will be identified as being causally related to the indication for performing WGS, but there is also the possibility that these could be found in situations where WGS was done for other reasons. In the latter case the findings would be considered incidental or secondary. The recognition that clinically significant variants would be discovered in the course of WGS has generated much discussion from a variety of groups involved in the performance and interpretation of WGS. For this article I will focus on one aspect of the debate: The contention that incidental information in the context of WGS represents a novel problem in medicine and, as such, consent to testing should allow the patient and/or provider the choice to opt out of receiving clinically important variant information that is unrelated to the indication for testing in order to protect patients from unneeded or unwanted stress.

Is this new? Is this different?

Based on 30 years of medical practice I can say unequivocally no—incidental findings are an inherent part of medical practice. Most agree that whether uncovered as part of a history and physical examination or as a consequence of a diagnostic test this is a part of medicine. Perhaps the more relevant question is: Are incidental findings from WGS different from those found in traditional medical practice? Here there is much more disagreement.

A non-exhaustive list of potential

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differences include: impact on other family members; identification of risk for adult-onset conditions in children; lack of information about the risk of specific variants (or findings for non-genetic situations) in particular information about the penetrance and variability of expression of the identified variant; and cost to the system of confirming incidental findings. While these all merit consideration, I’ve experienced each of these issues in my general pediatric practice.

Example 1 In a well-child examination, I identified a heart murmur that I thought was not an innocent childhood murmur. Echocardiography identified a hypertrophic cardiomyopathy that ultimately required heart transplantation for the infant. Most of the cardiomyopathies are genetic with the majority being autosomal dominant (impact on other family members). Recommendation was made for echoes to be done on the parents and siblings of the patient. While these turned out to be normal, the variability of expression and penetrance for these conditions in families presented uncertainty in counseling. Should serial echoes be done over time and, if so, in both parents and children? At what age are we certain that a cardiomyopathy would be present on an echo? Clearly these issues affect not only the clinical issues but also impact the cost of care to the system related to the incidental finding. This case occurred long before genetic testing, but application of genetic testing in the form of a cardiomyopathy gene panel could have helped with some of the questions. If a causal variant was identified in the child, is it present in one of the parents? If not, this is likely a new mutation and other family members would not be at increased risk. If so, 14 GeneWatch

the questions of variability of expression and penetrance would still need to be addressed, but at least the number of family members that would be offered screening is restricted to those who carry the variant lowering the impact on the cost of care.

Example 2 I performed a well-child examination on a 3 year old asymptomatic child of missionaries who were temporarily back in the US. They informed me that their mission was in an area where tuberculosis is endemic, so their child had received a BCG vaccine. Because the vaccine rendered the recommended screening test (intradermal PPD) uninterpretable, I performed a screening chest X-ray to check for occult disease, as

“In no other area of medical care do we allow patients to ‘opt out’ of receiving clinically significant incidental findings.” the child would be attending day care while in the US. The X-ray revealed a 10 cm paraspinous mass which, at surgery, turned out to be a cystic neuroblastoma. In reviewing the Xray finding, none of the consulting physicians could definitively define the risk of the specific finding and thus the need for surgery. Cystic neuroblastoma is a very rare tumor type, so even with a pathologic diagnosis, it was unclear if additional treatment with chemotherapy and radiation was necessary as some of these tumors do not progress, and occasionally resolve spontaneously. Ultimately no additional treatment was given and the

child did well on interval visits. Several questions occur: If the X-ray had not been done, would the mass have ever led to problems? Would it have spontaneously regressed? Should additional treatment have been given beyond surgery? What are the risks and benefits of such treatment?

Example 3 At the time of a sport’s physical on a 13 year old girl, a family history was obtained that was clearly consistent with a breast/ovarian cancer syndrome in the mother’s family.

No genetic testing had been done in the family, but segregation analysis showed that the patient’s mother was at a 50% risk, thus the patient was at a 25% chance of carrying a highly penetrant mutation in a cancer predisposition gene (most likely BRCA1/2).

In the context of obtaining a medical history the incidental finding of a family history of breast/ovarian cancer identified high risk for an adult onset condition in an adolescent.

The mother was referred for genetic counseling. If testing confirms a BRCA mutation in the patient’s mother, should the child be tested?

If so, when? If testing is deferred to adulthood to preserve autonomy, who is responsible for communicating the information to the child when she reaches adulthood? Has her ability to choose already been compromised? When should surveillance begin? When should chemoprevention and/or prophylactic surgery be offered? These questions reflect uncertainty not only in the risk of the specific finding, variable expression and penetrance but also introduce a host of questions about choice and autonomy.

The questions raised by these examples illustrate that while the application of WGS in the clinic may impact the number of incidental findings quantitatively compared to July-August 2012

any other single test, the questions raised by the incidental findings are not qualitatively different.

An instructive analogy?

One “advantage” of having been in practice for several decades is that it is easier to understand historical perspectives one has personally experienced. In thinking about clinical WGS and incidental findings, the analogy of chemistry panels seems useful, if somewhat imperfect. The primary motivation for the introduction of chemistry panels into practice was economies of scale. If one wanted to order a test covering sodium, potassium, calcium and phosphorus, it was cheaper to run these tests on a panel of 20 (or 36 or more) than it was to run two or more of the tests individually (a similar argument to WGS over gene by gene testing).

When chemistry panels moved into clinical practice, with very few exceptions the entire panel was ordered and reported, as this was more convenient. The challenge is that if you are doing 20 tests where the normal range is defined by 95% confidence intervals derived from populations, there is a near certainty that one of the 20 tests will be out of range (i.e. ‘abnormal’). Clinician responses to these out of range results varied. An aspartate aminotransferase (AST) a couple of points out of range in a context where liver disease was not suspected (i.e. a low prior probability of disease for the specific test) could reasonably be ignored and was by many if not most clinicians. However, more compulsive (or less secure) clinicians would pursue more specific liver function tests, or even imaging studies despite the low prior probability of disease leading to higher likelihood of subsequent false positive out of range tests and added cost to the system without additional benefit and, in some cases, creation of Volume 25 Number 4

harm. An extreme example of this is whole body CT scanning as a screening test, where 37% of scans detect an ‘abnormal’ finding that vast majority of which are inconsequential given that the testing is being done outside of a clinical indication, therefore the prior probability of disease is low.

Indiscriminate use of incidental findings from WGS has the same potential to lead to cascades of evaluation, particularly if the finding is not contextualized through the use of other information like family history. In chemistry testing, the trend has been to require clinicians to order the specific tests they are interested in based on the clinical context. For economy’s sake, the tests are still run as part of a larger panel; however, only the results of the requested tests are reported to the clinician. This eliminates the requirement to follow-up on other tests that are statistically out of range, but are unlikely to be of clinical significance. The exception is a value that is so out of range that it must be assumed to be clinically significant.

Findings such as these are categorized as “panic values” and the clinician will be contacted even though they did not order the test. The challenge as I see it over the near future for WGS is to develop a list of genetic ‘panic values’ based on an accepted level of certainty of pathogenicity for the variant and known clinical interventions so that if a given variant is found that is not relevant to the indication for the test it will still be reported. An example could be a known deleterious mutation in the MLH1 gene that causes Lynch syndrome discovered through WGS in an individual being evaluated for adult onset deafness.

Disclosure of this information could have important implications for the patient, in that earlier and more frequent colonoscopy has the ability to identify and remove pre-cancerous adenomatous polyps dramatically reducing the risk of developing colon

cancer. At present several organizations, including the American College of Medical Genetics and Genomics, the National Human Genome Research Institute and the Evaluation of Genomic Applications in Prevention and Practice as well as many private groups are examining the content and ramifications of such a list. Implicit in this work is the requirement for a regularly updated centralized repository of well-annotated deleterious variants that can be accessed by laboratories and clinicians to aid in the interpretation of variants identified through WGS. Finally, there is one additional issue relevant to this topic that should be addressed. Some have called for consent for WGS to allow patients and/or providers to ‘opt out’ from receiving incidental findings. If this were to be implemented it would be true genetic exceptionalism; in no other area of medical care do we allow patients to ‘opt out’ of receiving clinically significant incidental findings. Take the examples presented above and imagine the conversation with the parents: “I’m going to do a physical examination and I may find a heart murmur, but I want you to tell me now if you want me to disclose if I find something since it may not be information you want to deal with.”

While meant to elicit a smile, the reality is that this is not the standard of medical practice nor does it reduce the clinician’s liability. What it does require is agreeing on an acceptable level of certainty about the clinical impact of the variant that can inform the decision to disclose as has been done with incidental findings in all other areas of medicine. As such the aforementioned proactive attempts to address incidental findings from WGS are most welcome. nnn Marc Williams, MD, is Director of Geisinger Health System’s Genomic Medicine Institute.

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Children First Adults may choose whether or not to be told about certain research results or unexpected findings—but who decides for children? By Bartha Knoppers With the advent of next generation sequencing technologies such as whole genome and exome sequencing, no subject has so captured the attention of policymakers and researchers as that of the return of research results and unexpected incidental findings. This is because these technologies can now provide the sequence “map” of each individual tested, and with the costs of next generation sequencing decreasing rapidly, they are moving closer to becoming a standard element of clinical care.

Yet pediatric issues have been lost in the cacophony of “must’s”, “should’s” or “may wish to consider returning” recommendations. Indeed, the proposed choice to know or not to know individual research results and incidental findings currently offered to adults, together with the array of responsibilities of ethics review boards, “incidentally” neglect the child.

The same cannot be said for the inclusion of children in research policies generally, or in drug trials or biobanking. Why, then, is there a presumed “one size fits all” for the return of results?

The Scope of Parental Authority

While ultimately it is the duty of the State to protect the vulnerable citizen, for minors it is the parents who are recognized by law as health care decision makers. There may however be particular legal age limits which allow adolescents to seek confidential medical care or advice prior to the legal age of majority.

This legislation, particular to minors declared or presumed to be mature, 16 GeneWatch

or, as determined by physicians on a case by case basis for medical care, may not be applicable in the research setting where more stringent requirements apply. Indeed, even though assent is sought for research from children as they mature, parental consent is required until the legal age for research is attained. Irrespective, in all cases legislators, physicians, researchers and parents are obliged to act in the best interests of the child and the child has the right to be heard where possible (as set out in the 1989 U.N. Convention on the Rights of the Child). If this is so, what pediatric-specific concerns need to be addressed?

Return of Results

Generally, there has long been consensus that there should be no pediatric testing of children and minors for adult onset conditions. In other words, if there is no preventive treatment or palliative interventions available during childhood itself, the decision to be tested can wait until the child has reached adulthood.

Next generation sequencing of a person’s whole genome or exome not only reveals rare mutations (mostly undecipherable and untreatable), but also conditions of clinical significance that were not even the object of the research. Adults are asked during the informed consent process whether they wish to receive such unsolicited, clinically significant findings or not. However, should parents be able to deny the communication of such findings to them or to the child’s physician on behalf of the child?

It could be argued that parents cannot refuse to receive results or incidental findings if three conditions are met: the result can be scientifically validated in another laboratory; it has clinical utility; and it can be acted on—that is, prevention or treatment is available during childhood. Under this approach, for a parent to refuse to receive such information could be considered neglect. Parents then should be told that if these three conditions are met, results and incidental findings will be communicated to them or to their child’s physician.

It goes without saying that there are many other issues surrounding next generation sequencing in the pediatric context, but children should come first when addressing the return of results and incidental findings. nnn Bartha Maria Knoppers, PhD, holds the Canada Research Chair in Law and Medicine. She is Director of the Centre of Genomics and Policy, Faculty of Medicine, Department of Human Genetics, McGill University.

Funding for this article came from FORGE (Finding of Rare Genes Canada Consortium) July-August 2012

Who Has the Right to Know?

Community partnerships help guide the return of results from genetic research with indigenous peoples. By Elana Brief and Judy Illes When designing genetic studies with human subjects, researchers address the question of whether and how to return results to participants, and also face the challenge of how to handle incidental findings—results that were not part of the aims of the study but may be important to the participant. Much of the discussion about return of results and incidental findings has focused on ethical implications for individual research participants. The general consensus is that results should be returned (or not returned) based on an informed consent process that has given a participant the right to choose.

These matters become more complicated, however, when the individual participant is part of a group

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that has consented to the research as a community. Special considerations must be made when the group is a geographically or culturally distinct community, such as an indigenous population. When returning research results—and particularly incidental findings—to someone within one of these communities, a researcher must consider not only the implications for the individual, but for other community members and community agencies as well.

Key questions in these situations are: Upholding confidentiality. How can researchers uphold individual confidentiality in a rural or remote community in which “everyone knows” who is interacting with whom?

Rights of other community members. How can researchers balance an individual’s privacy with the rights of others in the community who may be affected by the results (e.g., if a genetic mutation is found incidentally in some members of a community, then the entire community might be labeled as carrying that mutation)?

Rights of community agencies. If community organizations and other agencies will be affected by results obtained for an individual (e.g., genetic prediction of a disease for which treatment planning may be necessary) do they have a right to know the results?

Indigenous communities often draw the interest of researchers because of the likelihood of increased

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genetic homogeneity within the community as well as the potential for unique genetic findings.

Researchers have a long history of unethical practices with indigenous communities, however, including inaccurate dissemination of primary results that have led to stigma, not reporting study results back to community members, and improper handling of biological tissues. In 2006, The United Nations Declaration on the Rights of Indigenous Peoples outlined the rights of indigenous peoples to their artifacts and knowledge: “Indigenous peoples have the right to maintain, control, protect and develop their cultural heritage, traditional knowledge, and traditional cultural expressions, as well as the manifestations of their sciences, technologies, and cultures, including human and genetic resources.”

In Canada, the First Nations Principles of OCAP (Ownership, Control, Access, and Possession) guide researchers regarding the handling of data and results in studies involving aboriginal peoples. We have outlined below how these principles may apply to genetic research.

Ownership: When biological samples have been collected from members of an indigenous community and stored in a research biobank, the community owns those materials.

Control: The indigenous community controls primary and secondary research and dissemination.

(If they disapprove of the research being conducted or do not want it to be disseminated, they can put a stop to it.)

Access: The indigenous community has access to the results of any research conducted using those 18 GeneWatch

samples.

Possession: OCAP also suggests that the indigenous community must possess the materials. This may be straightforward in the context of social science data, but is far more complicated for biological tissues.

Few communities have the capacity to bank DNA samples.

Nonetheless, OCAP guidelines offer an opportunity to researchers to ensure that they are conducting studies that are respectful, mutually beneficial, relevant and responsible. OCAP makes it clear that the community owns and controls the data, and that community representatives must be part of the research team that develops and implements a study.

While the OCAP principles and the UN Declaration on the Rights of Indigenous Peoples provide fundamental guidance to agreements between researchers and indigenous communities, other questions remain: Who consents for a community: the research participants themselves or also non-participants affected by the research; the elected chief and council, or the hereditary chief? The answers to this question directly relate to how to handle and return results: To whom should results be returned: only to a participant; amalgamated to the whole community?

These questions and more are best answered through partnership; partnership between researchers and communities. Community collaboration facilitates the ability of the research team to conduct relevant research for the community, to recontact study participants in order to return results, to prepare individuals and the community before results are returned, and to support them after receiving their results. Community partnerships can also help guide the dissemination of findings.

We believe that all researchers,

those involved in genetics research and others, have a responsibility to understand the specific perspective and desire of the community about unexpected findings. We believe the best approach is for researchers to develop and implement a management plan for unexpected findings in collaboration with community representatives. The management plan itself will require some research, but all research agreements should include management plans for incidental findings and return of individual research results.

There is no pan-Indigenous ethical framework to guide researchers on handling return of results and incidental findings, and there is an almost complete absence of relevant literature. In order to meet their responsibility to design a communityengaged management plan for unexpected results, researchers’ work must begin long before any data samples are acquired. nnn Elana Brief, PhD, is a Research Fellow at the National Core for Neuroethics at the University of British Columbia (UBC).

She received her doctorate in physics from UBC. At the Core, Dr. Brief leads a project investigating Aboriginal views on brain health, aging and dementia.

Judy Illes, PhD, FCAHS, is Professor of Neurology, Canada Research Chair in Neuroethics, and. Director of the National Core for Neuroethics at UBC. Dr. Illes’ research focuses on ethical, legal, social and policy challenges specifically at the intersection of the neurosciences and biomedical ethics.

Further reading: Brief E, Mackie J, Illes J. Incidental Findings in Genetic Research: A Vexing Challenge for Community Consent. Minnesota Journal of Law, Science & Technology.

2012; 13(2):541-558.

July-August 2012

Sharing and Caring There’s a right way and a wrong way for researchers to work with American Indian communities. Interview with Francine Gachupin

Francine C. Gachupin, PhD, MPH, CIP, has worked with American Indian tribal communities on chronic disease surveillance, public health practice, and epidemiology. She has been co-Chair of the National Indian Health Services Institutional Review Board and Chair of the Portland Area IHS IRB and the Southwest Tribal IRB. GeneWatch: How does tribal sovereignty complicate things for researchers?

Francine Gapuchin: Just as you would if you were going to do research in any other country, you need to have permission to be in those boundaries, to be speaking with that population. In the United States, tribes are their own entities, so there needs to be very clear approval granted from the tribe in order to conduct

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this kind of research. I think some researchers understand that, but most don’t, and so they end up doing things in a roundabout way and not getting the level of clearance and understanding that should have been there from the onset.

I think the Navajo Nation is a good example of a tribe that has been really firm in setting its boundaries and saying, “If you’re going to do research with us, you will abide by our rules.” These rules are extensive, and researchers coming in must agree to every single point—including that the data being collected belongs to the Navajo Nation and it will be given to the Navajo Nation at the conclusion of the study. Most tribes have not established such extensive rules, but researchers still need to understand what the expectations of the community are—especially when it comes to biological specimens.

Why is it that researchers have such interest in studying American Indian communities in the first place?

Depending on who you ask, some people will say there is a lot of research being done on American Indians, and others will say there is very little. One reason some researchers want to study American Indians is that there is so much variation between tribes, and it’s something we still don’t have a good grasp of.

I think scientists are interested to know the extent of that variability, and to study populations that are potentially unique.

You have noted before that despite this variation between tribes, some studies have used samples from just one or two tribes and tried to generalize the results to cover “American

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Indians” as a whole. Is this something that continues to happen?

It happens in a lot of different realms—these extrapolations happen where they shouldn’t, or where they should be footnoted to say where the data came from and that the generalizability might be limited.

Do you find it’s true that many tribes tend to be suspicious when they are approached by researchers, or begin with the assumption that the research might do more harm than good?

It’s very community specific. For tribes, as they’re doing their day to day living, when somebody comes in who is not from the community, you know. When researchers show up, it is very obvious to the community. So when someone comes in for the sole purpose of answering a research question, without trying to get to know the community, without spending time trying to understand the community’s values—if you don’t take a personal interest in the group of people that you are studying, you start off on the wrong foot to begin with. Researchers need to realize that a community will know: “If you really cared about us, you would have gotten to know us at least a little bit.”

Researchers often don’t have the time or luxury to do this, so they have to think about how much they can really invest in order to do research in this community. I think it’s a rare researcher who really does invest the time and energy necessary, but in the long run, they’re the ones who end up with the best research.

Communities are often suspicious when a researcher comes in, because they know that in order 20 GeneWatch

for someone to really serve their best interest, it’s going to take a lot of time. How the researcher comes in really does dictate how the community receives them, because they can see very quickly from the beginning how much give and take there is going to be. The majority of researchers come in, do their research, and leave, without every really getting to know the people. When that happens, it leaves an impression that makes it more difficult for other researchers— they’ll have more to prove than the ones who messed things up to begin with. Tribal communities are small and connected, so even though one community may not have had that experience, they may know of someone who did in another community.

Right now, the Havasupai experience is the example that most southwestern tribes are looking to, which makes them not want to participate in any studies—which is really unfortunate, because they could also be turning away beneficial research.

Does this give researchers extra incentive, then, to make sure they are doing things to benefit their subjects, like returning their research results?

I’m hoping this is in the minds of all researchers, not just when they are doing research specific to tribes. One of the basic tenants of the ethical principles that guide human subjects research is that you are trying to do good and not harm, and that if there is harm you are doing everything in your power to minimize it. So I don’t think it’s exclusive to tribes, and I hope it’s a basic tenant that all researchers hold.

So one of the places this may be different for tribes, then, is when researchers don’t understand that something which might not be

considered a harm in other situations—like not being able to give back tissue samples—could be considered a harm in a tribal context.

Right, which is why it is so important that researchers do their homework and learn about the people they will be working with.

Do you have any examples of researchers who have really done it the right way?

One example is a study that looked at metabolic syndrome and diabetes in children. When the initial project started to happen, they realized in their interviewing of the children that there was a lot of mention of depression. One of the requirements of the initial research agreement was that the team needed to go back to the tribal council every quarter with preliminary data, and this was something the project team took very seriously. So they reported these incidental findings about depression, and the tribal council became very interested—there had been some suicides, and this was data that could show them how much of a problem it was for their community. The council told the research team this was something they were interested in, and they asked if the research team could look into it further. And the team did work on it, even though it was not their original focus. Additional funding was sought and additional assessments were done. The researchers were studying something that was a priority to the community, and by reporting back to the community they didn’t just say “this is interesting”— they followed up on it. To me, this is an example of really good research.

They showed a commitment not only to their research question, but to the group they were studying. nnn

July-August 2012

Returning Research Results: Unresolved Issues Which information should be returned to research participants—and who makes that decision? By Karen Maschke In recent years, several new biobanks and some specific genetic studies have been designed so that some research results can be returned to participants. Yet many important issues must still be addressed. Many researchers, experts in research ethics, and others contend that only “actionable” genetic information should be returned to research participants.

“Actionable” is defined here to mean that some action can be taken by the individual and/or her physician to prevent a genetic-related disease or disorder from occurring, or to alter in some way its natural progression. Actionable genetic information can also guide physicians’ decisions about the type of drug or dose to give their patients. For example, some genetic variants are associated with how individuals respond to warfarin, a drug commonly used to prevent blood clots. If a patient has one of the variants, a physician may alter the standard dose of warfarin for that patient based on her genotype.

Some commentators object to the gatekeeper approach to returning genetic research results and contend that researchers should give research participants all of the genetic information generated from analyses of their DNA, not just actionable information. And many potential and actual research participants say they want access to all of their genetic information generated in research studies, even if the clinical utility of the information is uncertain. In fact, many genetic research participants say they were motivated to enroll in biobanks or specific studies so they could get access to their genetic Volume 25 Number 4

information. Surveys with research participants also indicate that even when individuals discover they have genetic variants associated with serious conditions for which no preventive or treatment interventions are available – e.g., the APOE genotype for risk of Alzheimer’s disease – they do not necessarily have high levels of distress from learning this information. Whether people will continue to give their biospecimens to a biobank or enroll in a genetic study if they can only have access to some of their genetic research results remains to be seen.

Another unresolved issue involves the “right not to know.” What if a research participant says she does not want any of her genetic information, yet analysis of her DNA reveals she has a genetic variant that is linked to sudden cardiac arrest? Researchers, biobanks, and genetic counselors may object to withholding this information from the research participant. Yet respecting individuals’ autonomous decision to reject medical information is a core principle of medical ethics. On the other hand, it is unclear whether the failure to inform individuals about potentially

life-threatening information – even against their wishes – raises issues of legal liability for researchers and biobanks. It is also unclear whether researchers have an obligation to inform a research participant’s biological relatives about the participant’s genetic information that may have implications for their own health.

What if the genetic information is generated from analysis of DNA samples after the biospecimen contributors have died? Do family members have a right to the genetic information post-mortem?

Some of these issues are not unique to the research setting, and many remain unresolved when genetic testing is conducted in the clinical context. Nonetheless, researchers and biobanks that plan to return genetic results to research participants must develop thoughtful and defensible approaches to these complex ethical issues that have implications for individual research participants, and that may have implications for family members as well. nnn Karen Maschke, PhD, is a research scholar at the Hastings Center and Editor of IRB: Ethics & Human Research.

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Topic update: Gene Patents

U.S. Appeals Court Reaffirms Ruling in Favor of Myriad’s Gene Patents A U.S. federal appeals court has once again affirmed the right of Myriad Genetics, Inc. to patent two genes linked to breast and ovarian cancer, after the U.S. Supreme Court ordered it to take another look at the high profile case.

Earlier this spring, the US Supreme Court had set aside the Federal Circuit’s July 2011 decision favoring Myriad and directed that court to review the case again in light of its unanimous ruling in Mayo v.

Prometheus. In that case the Court had found invalid Prometheus Labs’ patents on methods of evaluating patients’ drug responses, finding that they were not permitted to patent observations about natural phenomena. Myriad, alternatively, revolves around product patents and the “products of nature” doctrine—a different legal theory, though based on quite similar arguments. Indeed the American Civil Liberties Union, which brought the case against Myriad, made that very argument: that Prometheus reaffirmed the Court’s well established precedent of finding laws of nature and natural phenomena not patentable.

However, the Federal Circuit was not persuaded to change its ruling and ruled in favor of Myriad again 2-1. The language of its current ruling changed little from its prior one.

Writing for the majority, Judge Alan Lourie said: “Everything and everyone comes from nature, following its laws, but the compositions here are not natural products. They are the products of man, albeit following, as all materials do, laws of nature.”

Judge Moore agreed, finding that invalidating such patents would 22 GeneWatch

cause irreparable harm to industry: “(W)e must be particularly wary of expanding the judicial exception to patentable subject matter where both settled expectations and extensive property rights are involved.”

However, in his dissent Judge Bryson said: Just as a patent involving a law of nature must have an “inventive concept” that does “significantly more than simply describe natural relations,” a patent involving a product of nature should have an inventive concept that involves more than merely incidental changes to the naturally occurring product. In cases such as this one, in which the applicant claims a composition of matter

that is nearly identical to a product of nature, it is appropriate to ask whether the applicant has done “enough” to distinguish his alleged invention from the similar product of nature. Has the applicant made an “inventive” contribution to the product of nature?

Does the claimed composition involve more than “well-understood, routine, conventional” elements? Here, the answer to those questions is no.

What’s next? The Myriad case is likely far from over. There is a strong possibility of either an en banc rehearing by the full 12-member Federal Circuit Court, a grant of certiorari by the US Supreme Court, or both. Stay tuned. nnn

July-August 2012

A Problematic Reading of the Genetic History of the Jews Diana Muir Appelbaum and Paul S. Appelbaum review Harry Ostrer’s book Legacy: A Genetic History of the Jewish People.

Legacy: A Genetic History of the Jewish People by Harry Ostrer. (Oxford University Press, 2012)

Harry Ostrer is a distinguished medical geneticist at Albert Einstein College of Medicine whose new book, Legacy: A Genetic History of the Jewish People, is not nearly as good as it could—or should—have been.

Part of the difficulty arises from Ostrer’s tendency to make un-nuanced assertions. The book opens with the statement: “In June 2010, I published a scientific article that demonstrated a biological basis for Jewishness.”

Ostrer is referring to the findings of his 2010 study, “Abraham’s Children in the Genome Era: Major Jewish Diaspora Populations Comprise Distinct Genetic Clusters with Shared Middle Eastern Ancestry,”1 which appeared within a month of a study by an Israeli group led by Doron Behar, “The Genome-wide Structure of the Jewish People.”2 Both studies compared DNA microarray analyses of Jews whose recent ancestors lived in a variety of Jewish communities scattered across several continents.

The data for these Jewish communities, all of which had strong traditions of endogamy, were compared with existing data on West Eurasian populations.

The Behar et al. study looked at a wider assortment of Jewish communities, while Ostrer et al. sampled a larger number of individuals, but the two came to remarkably similar conclusions. Most of the communities Volume 25 Number 4

of the diaspora, and all of the largest communities, are more closely related to one another than they are to the populations of the countries in which they have lived for centuries or millennia. This despite the fact that they were spread from Lithuania to Yemen, ranged from short and swarthy to tall and blue-eyed, and in many cases had limited opportunities for contact with one another for the better part of two millennia.

The non-Jewish population to which Jews can at present be shown to be most closely related is the Samaritans, an ethno-religious group that most people associate with the New Testament parable of the “good

Samaritan.” Samaritans are understood as originating in an ancient (first millennium BCE) schism within the Jewish community in Palestine.

The group, which follows the law of the Torah but not rabbinic Judaism and never left the land of Israel, practices endogamy and has shrunk over the millennia to a mere handful of families. Genetic mapping also shows high overlap between Jews and Druze, another indigenous, endogamous Levantine ethno-religious group, and with Cypriots. Jews and Palestinians are less closely related, not only because Jews mixed with other populations during the long diaspora, but also because Palestinian GeneWatch 23

Muslims have substantial non-Levantine ancestry.

There is interesting work still to be done. It would be interesting to compare Jewish markers with those of more populations historians regard as most likely to have continuously resided in the Levant, such as Palestinian Christians, Maronites, and Aramaic-speaking Christians.

But we may be able to get even closer to knowing what the ancient Jewish gene pool looked like by examining DNA from Jewish burials in the Roman catacombs or graveyards in Palestine such as Beit She’arim.

These fine-grained details would be interesting to see, but the debate over whether Jews can claim significant Middle Eastern descent is settled. DNA evidence of Jewish peoplehood and Near Eastern origins corroborates the evidence of Jewish unity and cultural continuity in the linguistic, historical and archaeological record. Less than twenty years ago almost all historians assumed that while Jews shared a unique cultural heritage traceable to origins in the hill country of Judea, they shared most of their ancestry with the peoples among whom they lived. These assumptions have been overturned by the work of Ostrer and others demonstrating that Jews from every continent share genetic markers with surprising frequency.

Racists, of course, always suspected something of the sort.

None of this, however, suggests that there is a biological basis for “Jewishness,” whatever that vague entity might be. As the genetic data and the historical record make clear, no small number of non-Jews has joined the Jewish people over the last several millennia. Ruth, the Moabite ancestor of King David, may have been the most widely publicized convert, but she was by no means the last. Debates over whether Jews 24 GeneWatch

are best understood as constituting a religion or a nation may continue forever, but neither category has a biological basis.

Ostrer also exhibits a disappointing proclivity for overreading the import of his findings for contemporary geopolitical dilemmas. This is why readers will be troubled by Ostrer’s assertion that “the stakes in genetic analysis are high,” because genetic evidence lies at “the heart of Zionist claims for a Jewish homeland in Israel.”

This is a problematic assertion for several reasons, of which the simplest is that Ostrer conflates the claim to a national homeland made by pre-state Jewish nationalists and the right to sovereignty on the part of an exist-

Some of Ostrer’s misstatements will make Jewishly knowledgeable readers smile; his assertion that Sephardic Jews spoke “Latino” has real charm. ing nation state. More troubling is Ostrer’s assertion that investigation of where one’s ancestors lived upwards of 2000 years ago is relevant to the rights of nations—a standard that would leave few contemporary nation states on firm footing. Ostrer “can imagine future disputes about exactly how large the shared Middle Eastern ancestry of Jewish groups has to be to justify Zionist claims.”

It doesn’t require much imagination.

One only has to look at the emerging use of genetic information for similarly dubious purposes, for example the Hungarian Member of Parliament from the Jobbik party who hired a genetic testing laboratory to

certify that he is free of Jewish and Roma (Gypsy) genetic markers.3 The Zionist claim was not based on genetics; it was based on the liberal political principle that sovereignty resides in the people. The claim that Israel is the territory in which Jews are entitled to have a sovereign state was based on the demonstrable cultural continuity of the Jewish people since ancient times, on the argument that Israel was the “cradle” of the Jewish nation, and the fact that the Jewish nation has historically been a sovereign nation on this land before.

But the claim to sovereignty itself is based on the right of a people to selfdetermination, not on genetic data or ancestry.4 Some of Ostrer’s misstatements will make Jewishly knowledgeable readers smile; his assertion that Sephardic Jews spoke “Latino” has real charm. (They spoke a Judeo-Spanish language called Ladino.) Other statements, like the false precision of asserting that “27,290 members of the kingdom of Israel” were deported by Assyria in 722 BCE, make it clear that Ostrer has no idea how to judge the reliability of historical sources. And no one familiar with European Jewish history or geography could describe a world in which Warsaw lies east of Kiev. Indeed, the proofreading of the book as a whole is abysmal.

Beyond unfamiliarity with the details of Jewish history, there is a quirkiness to the topics Ostrer chooses to discuss. He is, for example, fascinated by a minor early twentieth- century Jewish medical researcher named Maurice Fishberg who “proved” that Jews are not a race by the assiduous measurement of Jewish crania. But Ostrer fails to provide the context of the fin de siècle investigation of race and eugenics in which Jews figured in a minor way. He might have been better off with a coauthor better versed July-August 2012

Race and the Genetic Revolution

Science, Myth, and Culture

Edited by Sheldon Krimsky and Kathleen Sloan

“I can hardly wait for this book to begin circulation. It should be read and taught as widely as possible.” —Adolph Reed, Jr., University of Pennsylvania Divided into six major categories, the collection begins with the historical origins and current uses of the concept of “race” in science. It follows with an analysis of the role of race in DNA databanks and its reflection of racial disparities in the criminal justice system. Essays then consider the rise of recreational genetics in the form of for-profit testing of genetic ancestry and the introduction of racialized medicine, specifically through an FDA-approved heart drug called BiDil, marketed to African American men.

Concluding sections discuss the contradictions between our scientific and cultural understandings of race and the continuing significance of race in educational and criminal justice policy, not to mention the ongoing project of a society that has no use for racial stereotypes.

SHELDON KRIMSKY is professor of urban and environmental policy and planning and adjunct professor of public health and community medicine at Tufts University. He is the author of Science in the Private Interest: Has the Lure of Profit Corrupted Biomedical Research?

KATHLEEN SLOAN is a human rights advocate specializing in global feminism. She has run nonprofit organizations for more than twenty years and has directed communications and public relations functions for multinational corporations and nonprofits.

CO LU M B I A U NIVE R S ITY PRE S S Tel: 800-343-4499 Fax: 800-351-5073 cup.columbia.edu

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“Novel and forward thinking, this book will be a valuable addition to a literature that needs to be brought up to speed.” —David Rosner, Columbia University and Mailman School of Public Health

ORDER ONLINE AND SAVE 30% To order online: www.cup.columbia.edu Enter Code: RACKR for 30% discount Race and the Genetic Revolution Edited by Krimsky Sloan (304 pages) paper ISBN 978-0-231-15697-4 regular price $35.00, now $24.50 Regular shipping and handling costs apply.

in Jewish and intellectual history.

A thornier problem is that Ostrer, like many research physicians, takes genetic data to be more scientific, and therefore more definitive, than they are. Genetically described populations reflect probabilistic clusters of markers inscribed in our DNA. They are not a concretization of race.

Moreover, many of the conclusions that can be drawn from genetic evidence are reliant on the quality of accompanying historical data. For example, the Cohen modal haplotype is a cluster of distinctive genetic markers shared by a high percentage of contemporary Jewish Cohanim (the priestly clan that traces its ancestry back to Moses’ brother Aaron). The idea that the ancestry that these men share can be traced to the ancient Israelite priesthood makes sense to almost everyone who views these data, but it is not inherent in the data.

The data show only that these men share common ancestors who lived a specified number of generations ago.

Estimating when those ancestors lived depends on an educated guess about the length of an average generation during the last 3000 years or so. But the idea that those ancestors were Cohanim is derived from our knowledge of Jewish history, it is not inscribed in the genetic markers.

Determining who does and who does not bear West Asian genetic markers is even more fraught. We do not have the genomes of the ancient Israelites, Phoenicians, Philistines or any of the other ancient peoples of the Near East. All that we have are genetic data on the peoples who live in the region today, and even these are not as refined as data for some other populations. We do know that there have been significant in-migrations, depopulation events, population bottlenecks, and constant contact with other peoples. What we do not know is the relative significance 26 GeneWatch

of these factors in producing modern Middle Eastern populations. The ongoing work on the genetic roots of the British, in which the influence of waves of conquest is beginning to be limned, is a possible model for the kind of investigation that could be done on the ancestral origins of the peoples of the Middle East.

Meanwhile, Ostrer necessarily used a cruder tool, comparing his Jewish samples to modern populations of Druze, Bedouin and Palestinian Arabs. Although his findings show enough similarity to make shared origins for some ancestors among these four groups clear, there is work yet to be done.

This is important because there has been more than a little over-interpretation of the findings. For example, studies of the Y-haplotypes passed from father to son show that a remarkably high percentage of the male founders of Jewish communities in almost all parts of the diaspora were almost certainly descended from Near Eastern ancestors. This naturally roused curiosity about the mitochondrial DNA passed on by the founding mothers of diaspora communities; the findings support longstanding assumptions by historians that diaspora communities were often founded at least in part by Jewish men who reared Jewish families with local women who had not been born Jewish. A 2006 study of the mitochondrial DNA of Ashkenazi Jews excited particular interest because it demonstrated that as many as 70% of Ashkenazi (Eastern European) Jews descend from four women who lived about 2000 years ago.5 The authors of the study argue that “Near Eastern origin” of these four ancestors was “likely.” Ostrer agrees that evidence shows “four common types of mitochondrial genomes… suggesting four founder females… (who) originated in the Middle East

and their descendants migrated to Europe by way of the Rhineland.” But the data do not trace a route along the Rhine—this is an assumption borrowed from historical evidence.

Nor do the data make the ethnic or geographic origin of these four maternal ancestors of Ashkenazi Jews at all clear; merely, they raise the possibility, or arguably the probability, of a West Asian origin.

The greatest surprise has been the discovery of genetic evidence showing that Jews from the large communities of the diaspora—from Persia to Morocco, and from Basra to Vilna– are more closely related to one another in the male line than they are to the peoples among whom their ancestors lived for centuries. Harry Ostrer is surely correct when he writes, “To look over the genetics of Jewish groups and to see the history of the Diaspora woven in is truly a marvel.”

What we have with advances in population genetics are new and marvelous tools with which to explore the past. Together with what we know from linguistics, history and archaeology, they can widen our understanding of the course of history, including the history of peoples and nations. But let’s not get carried away, or carry our conclusions beyond the evidence. nnn Diana Muir Appelbaum is an author and historian. She is at work on a book tentatively entitled Nationhood: The Foundation of Democracy, and often writes on topics related to genetic history.

Paul S. Appelbaum, MD, is the Dollard Professor of Psychiatry, Medicine & Law at Columbia, where he conducts research on the ethical, legal and social implications of advances in genetics.

July-August 2012

Endnotes Jonathan S. Berg and James P. Evans, p. 4

Diana Muir Appelbaum and Paul S. Appelbaum, p. 23

1. Green ED, Guyer MS; National Human Genome Research Institute.

“Charting a course for genomic medicine from base pairs to bedside.”

Nature. 2011 Feb 10;470(7333):204-13.

2. Kohane IS, Hsing M, Kong SW. “Taxonomizing, sizing, and overcoming the incidentalome.” Genet Med. 2012 Apr;14(4):399-404.

3. Berg JS, Khoury MJ, Evans JP. “Deploying whole genome sequencing in clinical practice and public health: meeting the challenge one bin at a time.” Genet Med. 2011 Jun;13(6):499-504.

4. Berg JS, Adams M, Nassar N, Bizon C, Lee K, Schmitt CP, Wilhelmsen KC, and Evans JP. “An informatics approach to analyzing the incidentalome.” Genet Med. In press.

1. Atzmon G, Hao L, Pe’er I, Velez C, Pearlman A, Palamara PF, Morrow B, Friedman E, Oddoux C, Burns E, Ostrer H. “Abraham’s children in the genome era: major Jewish diaspora populations comprise distinct genetic clusters with shared Middle Eastern ancestry.” American Journal of Human Genetics 2010;86(6):850859, doi:10.1016/j.ajhg.2010.04.015.

2. Behar DM, Metspalu M, Metspalu E, Rosset S, Parik J, Rootsi S, Chaubey G, Kutuev I, Yudkovsky G, Khusnutdinova EK, Balanovsky O, Semino O, Pereira L, Comas D, Gurwitz D, Bonne-Tamir B, Parfitt T, Hammer MF, Skorecki K, Villems R. “The genome-wide structure of the Jewish people.” Nature 2010;466:238– 242, doi:10.1038/nature09103.

3. Abbot A. “Genome test slammed for

assessing ‘racial purity:’ Hungarian far-right politician certified as ‘free of Jewish and Roma’ genes.” Nature, 12 June 2012, http://www.nature. com/news/genome-test-slammedfor-assessing-racial-purity-1.10809.

4. Appelbaum DM, Appelbaum PS. “The gene wars: should science determine sovereignty?” Azure 2007;No.27:51-79, http://www. azure.org.il/article.php?id=30.

5. Behar DM, Metspalu E, Kivisild T, Achilli A, Hadid Y, Tzur S, Pereira L, Amorim A, Quintana-Murci L, Majamaa K, Herrnstadt C, Howell N, Balanovsky O, Kutuev I, Pshenichnov A, Gurwitz D, Bonne-Tamir B, Torroni A, Villems R, Skorecki K. “The matrilineal ancestry of Ashkenazi Jewry: portrait of a recent founder event.” American Journal of Human Genetics 2006;78(3):487– 497, doi:10.1086/500307.

GeneWatch Multimedia CRG is excited to announce that GeneWatch magazine has launched its new Youtube video channel: GeneWatch TV. Each new issue of GeneWatch magazine will have a video component highlighting the key people and hot topics in its pages.

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Volume 25 Number 4

GeneWatch 27

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