THE ETHICS OF BIG DATA IN GENOMICS: THE INSTRUCTIVE ICELANDIC SAGA OF THE INCIDENTALOME.

• Author: Gitter, Donna M.

1. INTRODUCTION 354 II. THE EXPLOSION OF GENOMIC DATA GIVES RISE TO THE INCIDENTALOME 357 III. THE HISTORY OF GENETIC RESEARCH IN ICELAND 358 IV. THE ICELANDIC DEBATE REGARDING THE RETURN OF GENETIC INCIDENTAL FINDINGS 363 V. GENOMIC RESEARCH AND THE RIGHT NOT TO KNOW UNDER NATIONAL AND INTERNATIONAL REGULATIONS AND NORMS 365 VI. THE THREE POSSIBLE APPROACHES TO THE RELEASE OF IMPUTED GENETIC DATA CONSIDERED BY THE ICELANDIC 368 GOVERNMENT A. Arguments Against Returning Incidental Findings 368 B. Arguments in Favor of Making It Publicly Known That Imputed Genetic Information Is Available and Inviting Individuals to Request Information Themselves 374 C. Arguments in Favor of Contacting Affected Individuals Directly to Inform Them That Researchers Possess Information Relevant to Their Health 381 VII. AN EXAMPLE OF MANDATORY REVELATION OF HEALTH RISK INFORMATION: HIV/AIDS 382 VIII. A WAY FORWARD FOR CONTRIBUTED AND Imputed Data 383 IX. Conclusion 389 "Medical science has made such tremendous progress that there is hardly a healthy human left." --Aldous Huxley, 1894-1963 I. INTRODUCTION

   DeCODE Genetics, Inc., a pioneering Icelandic biotech firm, recently introduced a free website that permits Icelanders to learn whether they carry mutations in the BRCA2 gene that are known to increase cancer risk, even if these citizens have never participated in genetic testing. Approximately 5,000 citizens have elected thus far to receive their status. (1) This is made possible by the consanguinity of Icelandic citizens, who number fewer than 350,000, (2) and their detailed genealogical records dating back centuries, a set of circumstances that presents a unique opportunity to study genetic mutations and the medical disorders associated with them. (3) Dr. Kari Stefansson, the founder and CEO of deCODE, has been able, by combining the genomic data deCODE has gathered and using genealogical records, to impute the genotypes of not only the Icelanders who have participated in its genetic research, but even those who have not, including individuals who are deceased. (4) Stefansson asserts the ability to "impute [genetic] variants with a frequency down to .05%, so basically everything except extremely rare familial or de novo mutations." (5)

   This ability to impute individuals' genotypes without having gathered bio-specimens or medical information directly from them calls into question researchers' duty to inform individuals about their health risks, and the individuals' right not to know ("RNTK"), defined as the idea that people ought to be able to control their receipt of genetic information about themselves. (6) Noting that the affected women have an 82% probability of developing a fatal cancer and have a life expectancy twelve years shorter than other women, Stefansson requested from the Icelandic government permission to inform these women. (7) The Icelandic Parliament responded by charging the Ministry of Health with developing guidelines for informing Icelandic citizens of their potential genetic vulnerability. (8) Stefansson participated as a committee member, but resigned before the group reached its conclusion. Ultimately, the Ministry of Health committee issued an opinion declining to permit deCODE to contact affected Icelanders, and that same day deCODE established its website. (9)

   This emergence of unanticipated and yet highly significant genetic findings is referred to as the "incidentalome." (10) Similarly, commentators use the phrase "incidental findings" (which will be employed and shortened to "IFs" throughout this article) to refer to medically significant information that arises from research but is unrelated to the goals of that research. (11)

   This Article will analyze the return of IFs to individuals whose genotypic data has been imputed, and who therefore have not explicitly indicated their consent to receive such information. While Iceland is at the forefront of this issue first due to its small, homogeneous population and detailed genealogical records, other nations increasingly encounter the same debate. As noted by Myles Axton, Chief Editor of the journal Nature Genetics, a large enough U.S. database could also be used to make similar inferences. (12) This fact, combined with the trend toward global networking of biobanks, (13) demonstrates that the RNTK imputed genetic data impacts communities around the world and therefore is of international significance.

   Part II of this Article will consider the global rise of biobanks and the concomitant challenges posed to the management of the incidentalome and the RNTK. Part III considers how the incidentalome arises in Iceland, a country renowned for its genomic research, while Part IV examines the current debate in Iceland regarding the release of imputed genomic information to its citizens. International laws and norms regarding the RNTK are the subject of Part V. Part VI of this Article explores the legal and ethical arguments surrounding the three possible approaches considered in Iceland for the release of imputed BRCA2 genetic data: no return of the data; make it publicly known that the information is available and thus enable individuals to take the initiative to request that information for themselves; or contact the affected individuals directly to inform them that researchers possess information relevant to their health. Because similar legal and ethical questions arise when health care providers consider their duty to inform individuals exposed to HIV and AIDS, Part VII analyzes considerations surrounding the provision of this risk information. Finally, Part VIII of this Article proposes an approach for the future, emphasizing the need for a robust public service campaign that encourages individuals to access their imputed genetic data and, more broadly, for expanded governmental investment in and public access to genetic testing. Increasingly, direct access to such testing through a clinician will allow individuals to express explicitly their desire to receive or reject information about their genetic risk profiles, which is preferable to offering imputed genetic information without explicit consent.

2. THE EXPLOSION OF GENOMIC DATA GIVES RISE TO THE INCIDENTALOME

   Incidental findings have proliferated because cheaper and faster genome sequencing technologies have expanded the amount of genetic information available, and the "previously unimaginable goal of a $1,000 genome is now nearly obtainable." (14) As a result, genomic sequencing, already an important tool for researchers, is increasingly employed in clinical medicine as well. (15) At the level of individual consumers, the direct-to-consumer genetic industry is increasingly robust, and individuals voluntarily generate and share personal genetic information they obtain via direct-to-consumer tests. For example, the website patientslikeme.com offers a forum for patients to communicate with others who have similar diagnoses, and these individuals identify themselves through their social media accounts. (16)

   Along with the explosion of genetic information, another factor that renders the handling of IFs particularly challenging is the structure of the biobanks themselves. Biobanking, which began with small, university-based collections developed for the research needs of a specific project, has changed vastly in the last four decades. The taxonomy of biobanks now includes institutional and government-supported repositories; commercial biobanks; population-based collections; disease-specific biobanks; and, most recently, virtual biobanks. Population-wide biobanks have been established by several nations, including Canada, Denmark, Estonia, Iceland, Japan, Latvia, Singapore, South Korea, Sweden, the United Kingdom, and the United States, in order to collect and analyze genotypic and phenotypic information of their populations. (17) Global research networks have arisen through the establishment of virtual biobanks, which are electronic databases of biological specimens and other related information, designed to allow researchers worldwide to locate bio-specimens for testing and data mining from biobanks in dispersed locations. (18) Pooling of such data is considered vital in order to develop means of diagnosing and treating common medical disorders. (19) In addition to the increased complexity of the structure of biobanks, the data associated with stored bio-specimens is more detailed, including not only fundamental information such as dates of collection and diagnoses, but also demographic characteristics, information about the contributors' (20) phenotypes, and the like. (21)

   While biobanks are quite diverse in terms of the specimens and data they collect, they share certain characteristics that complicate the issue of whether to share IFs with individual contributors, a process referred to in Europe as "feedback." (22) Biobanks typically involve research settings where investigators are working mostly with anonymized (23) samples, and most contributors have signed consent forms stating that they will not be contacted. (24) This complicates the question of whether IFs should be returned to bio-specimen contributors, in the absence of their explicit consent to receive these results. This issue is further complicated in Iceland by the fact that genetic information can be imputed for individuals who did not even directly participate in genetic research. (25) Thus, genetic research in Iceland raises not just the typical issues relating to IFs but involves additional complexity in that the return of IFs must be considered when the contributor did not wittingly participate in research. This issue comes into sharper focus with an understanding of the history of genetic research in Iceland.

3. THE HISTORY OF GENETIC RESEARCH IN ICELAND

   Genetic research in Iceland began over two decades ago with the direct gathering of biomedical samples and associated data from individual citizens. Over time...