DRAFT VERSION DO NOT CITE WITHOUT AUTHORIAL PERMISSION (C) CHRIS GROVES AND RICHARD TUTTON 2012

Walking the tightrope: expectations and standards in personal genomics

Dr Christopher Groves* The ESRC Centre for Economic and Social Aspects of Genomics (Cesagen) School of Social Sciences Cardiff University 6 Museum Place Cardiff, UK CF10 3BG Bio: Dr Groves work focuses on how people and institutions negotiate and deal with an intrinsically uncertain future. He specialises in the governance of risk and uncertainty and the ethics and social impact of new technologies. Email: grovesc1@cf.ac.uk Telephone: (029 208 77438)

Dr Richard Tutton The ESRC Centre for Economic and Social Aspects of Genomics (Cesagen) Lancaster University, Faculty of Arts and Social Studies FASS Building D10 Lancaster, UK LA1 4YD Bio: Dr Tuttons work centres on the governance of new medical technologies, changing forms of citizenship, patient participation, and identity practices in relation to genetic knowledge, biopolitics, and, more recently personalized medicine and the role of expectations in science and technology Email: r.tutton@lancaster.ac.uk * Corresponding author Abstract The sociology of expectations has examined how future expectations shape how technological options are selected and stabilised. Personal genomic susceptibility testing (PGST) is introduced as an example of a technology where expectations serve a crucial role, thanks to the inherently future-oriented nature of testing for genetic susceptibility to future health conditions. Nonetheless, expectations may increase rather than decrease scientific, regulatory and commercial uncertainties surrounding a technology. Technology promoters may therefore enact particular strategies to prove that technologies are not in need of stringent, technology-specific regulation. With the aid of an extensive historical analysis of company websites, together with semi-structured interviews with company representatives, it is shown how four PGST companies based in the USA have used discourses of responsible innovation and efforts towards collaborative standardisation as ways of stabilising and

2 legitimating PGST in an often hostile environment. We explore how these strategies make use of expectations, and how they centre on the promotion of new regulatory objects in an effort to influence regulatory agendas. While processes of standardisation in the PGST industry have stalled, we suggest that they nonetheless represent successful engagement with regulators, insofar as they have succeeded in shaping regulatory agendas and staving off new regulation. Keywords Direct-to-consumer genetic testing, personal genomics, personalised medicine, regulation, sociology of expectations, standardisation Word count (without references) 9828 words.

DRAFT VERSION DO NOT CITE WITHOUT AUTHORIAL PERMISSION (C) CHRIS GROVES AND RICHARD TUTTON 2012

Introduction The extent to which emerging technologies, particularly in the sphere of health, are shaped by interactions between fact and value, truth and hope has been a key theme within the sociology of expectations. Technological expectations have been defined as real-time representations of future technological situations and capabilities (Borup et al. 2006). Researchers in this field have explored the extent to which expectations can be performative representations, helping to shape and stabilize the direction of technological evolution by drawing in funding and by enabling the formation of social networks and coalitions. They contend that to explain how technologies evolve, it is necessary to include among the selection pressures invoked by analysts the dynamics of expectations that flow around and intersect with economic and broad social-structural constraints and potentials. Expectations are dynamic because they reflect often-complex interactions between fact and value, truth and hope (Brown 2005). In one sense, patterns of representation that centre on truth and those which centre on hope exhibit conflicting logics and are thus contradictory regimes (Moreira and Palladino 2005). The drive for truth and certainty minimizes the space in which valid judgements about the promise of a technology can be made. The invocation of hope, by contrast, maximizes the space in which potentiating judgements can be made. Nonetheless, the two regimes often turn out to be closely linked. The future cannot be articulated except in relation to the past. A body of scientific knowledge, which has been established by a multitude of acts of knowledge-production, acts as the basis for more or less plausible propositions about the future its application may bring about. Past evidence serves as the basis for separating more credible from less credible promised futures, for winnowing out relative certainty from uncertainty. At the same time, uncertainty is itself constitutive of the hope for, and drive toward, future truths (Brown 2005). Hope may thrive in the spaces left by truth, and may serve as the basis for going beyond the limits of the present, and liberating from congealed matters of fact the unrealised, virtual potential that expresses the present reality of the future (Adam and Groves 2007). It has been suggested that the relationship between hope and truth which plays out in the context of the dynamic course taken by changing expectations about a technology is a product of iterated interactions between technological enactors and selectors (Garud and Ahlstrom 1997). Enactors are those (like scientists or businesses) who are on the inside of innovation processes, while selectors (such as regulators, insurers, venture capitalists or users of technologies) who possess some degree of power to exert selection pressures on the course of a technologys development. Interactions between enactors and selectors often take place within arenas of expectations (Bakker et al. 2011), such as conferences, special issues of journals, and meetings. In these arenas, expectations are tested for plausibility and credibility within the context of the scientific, commercial and regulatory uncertainties that may surround an emerging technology. The process of testing and selection of expectations may help to stabilise a technology, marginalising expectations that become classified as unattainable and securing support for technology options that are built around other more realistic visions. Classifying some expectations as unrealistic and/or unattainable may be done on the basis of the gap between regimes of truth and hope. On the other hand, this may happen as a result of a contest between different hopes, in which judgements about commercial viability, social acceptability and other factors play a significant role. However the selection process plays out, the sociology of expectations suggests that the consolidation of some future visions at the expense of others loops back into the present, helping to create decision points and emergent pathways for technological evolution.

A perhaps neglected topic in relation to the role of technological expectations is their role in regulation, and particularly voluntary regulation. There is arguably a strong link, for example, between standards and standardization, and technological expectations. This link rests on several considerations. First, standards primary purpose is to create filters which allow only some products to qualify for market entry (Busch 2011). Second, standards are not simply read off some given technological reality, but are constructed through negotiation between enactors and selectors. To promote standardization in emerging technologies may enhance the autonomy of some early entrants, such as large companies with strong links to regulators and heavy investments in R&D, at the expense of other, smaller actors, as those with greater R&D capacity and influence may shape the content of standards which are finally adopted. As well as promoting improvements in products and processes, standardization also therefore promotes exclusion (Busch 2011). As standardization is a form of soft regulation often preferred by regulators who may face information deficits when confronted by novel technologies, it can also enable enactors to influence how regulation affects technology selection by shaping regulation itself. This can occur via the feeding back of scientific results from industrial research into the construction of new regulatory objects (Lezaun 2006) to fit an emerging technology, such as in the shift from minimum lethal dose to median lethal dose in drug regulation (Porter 1995). Such moves may help to resolve regulatory ambiguities by defining what matters about products or services from a regulatory point of view. At the same time, because defining what matters is reliant on evidence presented by those with dogs in the fight, the construction of new regulatory objects may represent a further strategic intervention by enactors aimed at securing the dominance of some technological options over others. These features of standards and standardization in general should be placed against the specifically anticipatory function they may fulfil in relation to emerging technologies (Rashba and Gamota 2003). Standards can act as change agents and guide the market (ISO 2007) - consolidating the dominance of some future visions of the technology at the expense of others. Moving the regulatory focus to standardization may also favour enactors in the sense that efforts at standardization may channel selection pressures bearing down on technological expectations into more orderly arenas of expectations where enactors may have opportunities to exert more influence. The arenas through which standardization is performed (such as regular meetings of standards committees, and the writing of working papers and draft standards) may become more important than (for example) debates in academic journals, professional conferences, and so on. Also, representatives of a range of communities of selectors, such as health professionals, insurers and patient groups, may be invited to participate in committees etc. Standardization may thus be attractive to enactors as a means of creating trust and legitimacy. In this paper, we examine some aspects of the role played by expectations in the evolution since 2007 of personal genomics, or more specifically personal genomic susceptibility testing (PGST). We show how expectations have shaped companies strategic responses to an unstable regulatory environment by focusing their energies on the development of voluntary standards as markers of credibility and legitimacy. At the same time, we show how these efforts have influenced the wider regulatory context itself. In addition to being a means by which selection pressures are exerted by selectors on emerging technologies, enactors expectations may also help make space for particular technological options. As a way of stimulating efforts at self-regulation, expectations may re-shape regulators views of how regulatory ambiguities can be resolved and what aspects of a technology are appropriate

5 regulatory objects. Standards regimes are typically seen, in a Foucauldian fashion (Loconto & Busch, 2010), as mechanisms of truth, ways of determining whether a given technology option measures up to norms of safety and reliability. According to some commentators PGST companies have tried to enforce a tight demarcation between facts and values, and specifically, to sever their product[s] from questions of clinical utility (Curnutte and Testa 2012). The actuality, we suggest, has been quite the opposite: the case of PGST shows how debating what standards should cover can also be a way of reinforcing hope by creating broader commitment to the potential of a technology among enactors and selectors, and opening up rather than closing down the future. Background There are now a host of companies in the USA and elsewhere (from the UK to Singapore) involved in selling PGST services, some of which sell testing services direct-to-consumer (DTC) over the internet, whereas others require tests to be ordered by a clinician. PGST companies have exploited several specific socio-technical developments. These include conceptual shifts in how connections between genotype and phenotype are studied (moving from single-gene linkage to multi-gene association), increases in sequencing efficiency and computing power (enabling association studies to cover the entire genome and to cover larger populations) and the building of genomic databases such as public biobanks. These have helped produce a new research methodology: the genome-wide association study (GWAS). The tests sold by personal genomics companies typically involve submitting a tissue sample (typically taken from a cheekswab or spit tube sent through the post) to a genetic assay. The genotype of the individual is compared to databases of variations at specific points on the genome (single-nucleotide polymorphisms or SNPs) that have been found by GWAS to be associated with specific phenotypical traits and which capture significant degrees of genetic variation between different ethnicities. The products typically sold by PGST companies focus on these two aspects of genetic association. On the one hand, there are tests for genetic susceptibility to multigenic common and/or chronic health conditions (such as heart disease and diabetes, but perhaps also including Alzheimers), for susceptibility to adverse reactions to certain drug treatments, and with some companies, tests for carrier status for monogenic genetic conditions like Tay-Sachs or cystic fibrosis. On the other, there are ancestry tests, which purport to assess the proportions of ones genome from different ethnic groups, based on analysis of mitochondrial and autosomal DNA. It is chiefly because companies have sought to develop a market in health-related susceptibility testing services that their tests have, since 2007, provoked significant debate regarding their benefits and risks. Whereas tests for monogenic conditions have been marketed since the 1990s, the genomic model of health and pharmacogenomic susceptibility testing where multiple genes across the whole genome are involved has brought new ambiguities, with the result that regulators and other stakeholders have assigned PGST to a class of its own (SACGHS 2010). The genomic model has recently been further complicated by the findings of the ENCODE project, in which the complex interaction of multiple regions of the genome in producing phentypical characteristics has been confirmed (Souza 2012). Positive expectations regarding the future social value of PGST latch on to all four of the Ps in 4P medicine (participation, prediction, prevention and personalisation) which has increasingly been promoted as a new model for public health in the years since the completion of the Human Genome Project in 2003. In relation to both health conditions and drug reactions, companies such as 23andMe, Navigenics, deCODEme (a venture of the Icelandic deCODE Genetics) and Pathway Genomics have proposed that assessing genetic

6 contributions to the risk of contracting serious common conditions will enable earlier primary and secondary prevention by individuals and their physicians, particularly by providing a strong motivation for individuals to participate in their own healthcare by de-risking lifestyles. PGST will enable more personalised prevention and treatment plans, based on individual genotypes, as well as helping physicians to avoid adverse drug reactions and optimise prescriptions.1 A representative sketch of the contribution some outside the industry hope that PGST may make to a personalised medicine future is given by Feero, Guttmacher, and Collins (2008) from the National Human Genome Research Institute (NHGRI), who describe personalized medicine in 2020 as a healthcare system founded on perfect vision, in which early PGS testing enables clinician-led lifetime monitoring and timely interventions to prevent common serious diseases. The overarching object of hope here is how PGST might reduce increasing future healthcare costs, caused by the chronic common conditions anticipated to accompany extended lifespans, as well as reducing individual burdens of disease and ill-health. However, the relationship between hope and truth in the case of personal genomics becomes strained at this point. If this future vision for PGST is to be realized, then the clinical validity of tests the extent to which the presence of a particular genetic variation is reliably associated with the development of a disease must be demonstrated. Showing that the tests are clinically valid is problematic for two reasons. First, the methods by which PGST companies, on the one hand, create databases of genetic associations documented by GWAS and, on the other, calculate genetic contributions to disease risk are recent innovations. Second, the knowledge they produce is future-oriented by its very nature: predictions remain to be verified, until they eventuate. Third, the value of GWAS as predictive of future incidence of a trait in a given population remains something of an open question. Given that associations are retrospective by nature, and established in relation to specific reference populations, scepticism as to whether this past knowledge is an appropriate guide to the future of test consumers, from potentially different populations, is inevitable (Offit 2008, also cf. Adam and Groves 2007, p. 114). Scepticism from selectors such as some geneticists, health professionals and public health researchers has focused on scientific uncertainties surrounding clinical validity. As an example of an emerging technology, PGST is thus no exception to the observation that key tests of the expectations produced by enactors are typically levelled at the regime of truth to which they are connected and upon which they stake some of their credibility (Garud and Ahlstrom 1997). The predictive power of tests has been the subject of criticism (Liu and Song 2010, Hall et al. 2010). It has been suggested that the promise of PGST might be overstated because the heredity of common conditions may have been overestimated (Richards 2010), or that next to phenotype data (relating to lifestyle etc.), genomic data will prove a statistically insignificant predictor of disease (Paynter et al. 2010). Others contest enactors expectations at a more fundamental level. Some genomics researchers question whether the common variants approach to mapping susceptibility under GWAS is superior to methods which examine rare variants; whether the complexity of gene-gene or gene-environment interactions will create significant obstacles (McCarthy et al. 2008), or that the phenomenon of missing heredity surrounds GWAS studies with a significant and unquantifiable amount of uncertainty (Tomasson 2009, Zuk et al. 2012).

Some question whether this idea of personalized medicine is even coherent. See for example Busch 2011, p. 317 n. 16.

7 Still other sceptical voices focus directly upon the regime of hope created around PGST, and the credibility of future visions concerning the uses to which testing may be put. The clinical utility of PGST whether test results can provide information that improves clinical decisions remains uncertain (FEAM 2012). Vulnerable individuals, it has been suggested, may suffer anxiety at test results that indicate raised risk. People may have difficulties understanding their results and may overestimate their significance. They may be falsely reassured by reports of reduced genetic risk and alter their behaviour, thus increasing their environmental risk (Lippi et al. 2011). Others point to potentially negative unintended consequences of the commercial exploitation of personal genetic information (PGI), such as lost or stolen data leading to blackmail and discrimination in e.g. insurance markets on the basis of test results (Khan 2011). Finally, the broader social utility of PGST has been questioned. Health economic studies of the expected social utility of genetic testing for common conditions have not been uniformly positive (Cornel et al. 2011, S23-S24). Some have suggested that growing markets for PGST may in fact lead to rising public healthcare costs, by encouraging unnecessary testing (McGuire and Burke 2008), though there is evidence that this may not be the case (Reid et al. 2012). These sceptical viewpoints and the uncertainties on which they focus have fuelled regulators concerns. In addition, PGST is subject to significant regulatory ambiguity. From a regulatory point of view, it does not fit squarely into any existing regulatory paradigm (Gould 2010), a problem which is not limited to the USA. In the USA, products legally classified as medical devices require pre-market approval from the Food and Drug Administration (FDA), based on a formal assessment of the safety and efficacy of a product. A medical device is legally defined as a product intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease or is intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body (Federal Food, Drug, and Cosmetic Act, Section 201[h]). Genetic tests are only classified as medical devices if they are manufactured as a separate product and then sold on to a testing laboratory. Most genetic tests, however, fall within the category of laboratory-developed tests (LDTs), produced by clinical laboratories for their own use. In the USA, clinical laboratories are subject to standards for test quality established in the Clinical Laboratory Improvement Amendments of 1988 (CLIA). However, there is no provision under CLIA to assess claims about the clinical validity or utility of tests as part of a pre-market process. Although LDTs have, legally speaking, been within the jurisdiction of the FDA since the 1970s, it has chosen not to subject them to additional pre-market tests a position which remains under review at the time of writing. If regulators were concerned, and some researchers and health professionals actively hostile, still other selectors maintained a supportive mien while setting out areas where significance obstacles remained. Such an attitude characterises Feero, Guttmacher and Collins paper, cited above, in which the feasibility of perfect vision in 2020 is proclaimed along with the need for complex, groundbreaking, and multidisciplinary research before the potential becomes actual. These authors, as noted above, were affiliated with the NHGRI at the National Institutes of Health (NIH), a major source of commentary on genetics in the public health sphere as well as being part of an institution responsible for the allocation of both financial and research resources. Hope, for such selectors, has to be tempered by attention to weaknesses in PGSTs regime of truth. The dynamic of expectations around PGST quickly

8 developed to the point where selectors invited companies to develop ways to establish the credibility of the visions they articulated. As we shall see, these efforts involved organisations like the Personalized Medicine Coalition (PMC), the NIH and Centres for Disease Control (CDC) as well as the FDA. Companies were invited to suggest how to formulate standards in the sense of values against which objects are measured for the industry, and how to bring about standardization in the sense of making diverse objects fit with standards (cf. Loconto & Busch, 2010, p. 526) both in order to resolve tensions between hope and truth, and to resolve regulatory ambiguities.

The evolution of PGST 2007-2011 Methodology Our study of the relationship between dynamics of expectation and standardization was based on a corpus of 245 documents in the public domain, covering four companies (23andMe, deCODEme, Navigenics, and Pathway Genomics), with 23andMe being the most represented (80 items). These included an extensive sample of company webpages, interviews with staff, articles by staff, and public documents such as testimony to Congressional committees and journal articles. To provide a more comprehensive historical view, we used the Internet Archive (internetarchive.org) to index versions of the companies websites at quarterly intervals (where available), and constructed a timeline of documents relating to PGST produced by regulators and other federal agencies (see Table 1). In addition, semi-structured interviews were conducted with senior staff from two of the four companies. All documents (including new interviews we conducted) were coded using NVivo 8 in order to map changing views of companies regarding the purpose, focus and limitations of voluntary standards related to those aspects of PGST which, based on regulatory documents, can be viewed as the most salient from a regulatory point of view that is, tests for susceptibility to health conditions and drug response.2 In this section, we provide a narrative account of how the dynamics of technological expectations within the industry have shaped efforts to create standards. As we shall show, these dynamics unfold upon a background of regulatory selection pressures, whilst also being folded back into the regulatory environment itself, leading to the production of new regulatory objects: clinical usefulness and personal utility.3 Initial selection pressures The situation of PGST companies has been characterised as walking a tightrope (Vorhaus 2011) between alternative strategies that risk regulatory sanctions on the one hand and, on the other, commercial failure. Companies may be tempted to make strong claims about the clinical value of their tests. Such claims may invite regulators to test the regime of truth behind these claims by closing down regulatory ambiguities e.g. by re-classifying PGS tests as medical devices requiring pre-market approval. On the other hand, companies might seek to avoid regulatory action by downplaying claims about their products, representing them as
2

Some limitations of our approach should be noted. The Internet Archive does not preserve webpages from Navigenics.com, as the company website is configured to prevent bots (automated software applications used for tasks like indexing webpages) from indexing its content. Nonetheless, the company archives its press releases online, and a number of past interviews with senior staff, together with the interviews undertaken as part of this project, were also available. 23andMe and deCODEme were unavailable for interview, citing time pressures. 3 References to webpages are given below in the text in the form (site, page title, date range), where the date range indicates the dates of the earliest and the most recent instances of the quoted text we found.

2007
March Selectors of Health (regulators, Department Services and Human federal (HHS) launched the Personalized Health agencies, Care integrate genomic etc.) techs into general
health care

2008
April
Secretarys Advisory Committee on Genetics, Health, and Society (SACGHS) publishes report on regulatory gaps relevant to AV, CV, CU

2009
August:
Publication of report on Dec 2008 NIH/CDC seminar, plus papers by Grosse et al (2009) and Foster et al (2009).

2010
April
Letters sent by FDA to Pathway and then to 23andMe, deCODEme, Navigenics, indicating that the tests might be considered medical devices that require pre-market review Direct-to-Consumer Genetic Testing Report of the SACGHS (SACGHS 2010)

2011
JanuaryFebruary:
Consultation on PGST by FDA Medical Devices Advisory Committee FDA expected to heed advice to allow testing only with physician involvement. Part of remit of FDA panel is to consider parameters of standardisation

June:
Californias Department of Public Health sends cease and desist letters to 23andMe, deCODEme and Navigenics

July
FDA reviews regulation of laboratory-developed tests, moving towards risk-based approach. US Congress Committee on Energy and Commerce hearing.

December:
Seminar convened by CDC and NIH on personal genomics discuss standards, nature of personal utility

Enactors (industry)

November 6:
Navigenics official launch, but no products available

April:
Navigenics launches $2500 (plus $250 annual fee) direct-to-consumer service, together with proposal for standards. Announces intention to integrate product into package reimbursable via medical insurance

June:
Publication of paper from 23andMe promoting personal utility (Hsu, Avey et al. 2009)

January
Decode Genetics Inc sold to Saga Investments CEO states privacy and data policies remain the same Navigenics withdraws direct-to-consumer products

November 16:
deCODEme launch

July:
Pathway launches with split product (medical test vs. ancestry/recreational test)

November 19:
23andMe launch

July:
23andMe, Navigenics, deCODE Genetics and DNA Direct, began discussions on voluntary standards with the Personalized Medicine Coalition (PMC)

May:
Pathway announces it will sell testing kits in Walgreens

November 15: 23andMe splits

$399 scan into two (health/ ancestry) options

July
Pathway withdraws testing kits after being told they are regulatable medical devices & not lab tests

November 17: December

Document detailing process of discussion on standards published on PMC website. deCODEme files for bankruptcy protection in US

Table 1: Timeline of significant events

10 e.g. merely recreational or educational products. This would, however, fail to demarcate the new health-related tests being offered by companies from previous generations of tests (e.g. nutrigenomic tests). The first wave of PGST companies (including the four in our study), began as small start-ups, faced with a situation in which a market for their products had to be built by promoting health-related tests to both consumers and health insurance companies in the absence of actuarial data regarding clinical validity and utility (Navigenics interview). The story of how companies have promoted the need for standards is also therefore one of how they have pursued standardization as a strategy for negotiating commercial and regulatory selection pressures. On the regulatory side, companies have, in the face of the commercial uncertainties surrounding their products, been sensitive to regulatory responses to previous generations of genetic and genomic testing and screening technologies. In the mid-to-late 2000s, several reports attempted to chart a path for regulatory agencies to follow on genetic testing in general, identifying PGST in the process as an area of particular concern. In 2006, the Government Accountability Office (GAO) Report on Nutrigenetic Testing suggested that companies selling a previous generation of susceptibility tests which purported to provide customers with nutritional advice based on genetic profiling were likely to mislead consumers by making predictions that are medically unproven (Kutz 2006). This report also pointed to certain ambiguities in the intended purpose of the tests. It noted that companies included disclaimers in their promotional materials indicating that the tests we purchased do not diagnose disease, but that the test results received predicted that our fictitious consumers were at risk of developing a myriad of medical conditions (p. 7). As well as the GAO report discussed above, a report by the Secretarys Advisory Committee on Genetics, Health, and Society (SACGHS) was published in April 2008. This report noted the pervasive lack of data on the clinical validity of genetic tests (including for genetic susceptibility), and that this was compounded by the future-oriented nature of predictive tests, where data confirming or refuting validity and clinical utility would not be forthcoming for some time (SACGHS 2008). To address this problem, the Committee suggested that the FDA be more consistent in its registration and regulation of LDTs, and commit resources to assessing the clinical validity of all such tests. The SACGHS also suggested that multi-stakeholder groups, with industry representation, be convened by the Department of Health and Human Services (HHS) to stratify different families of tests according to the degree of risk of negative psychological effects which might be associated with them (SACGHS 2008), and to establish standards of evidence according to which their clinical utility could be assessed (SACGHS 2008). Regulators saw their task, at this stage, as to support the application of genomics to healthcare by developing criteria for consistently distinguishing credible tests from invalid and/or fraudulent ones. Standardization was identified by a variety of external stakeholders who were generally supportive of genomics in healthcare as a necessary part of any such enterprise, as in the American Society for Human Genetics (ASHG) call in 2007 for companies to be transparent in reporting to potential consumers on tests current predictive value, any associated risks, the certification status of test laboratories, and privacy policies. Standards were widely seen as essential to help establish the clinical validity and utility of tests, to stop companies from misrepresenting their products, and to ensure that customers had access to resources such as genetic counselling to help them understand their results (Hudson et al. 2007). At this stage, standards were therefore seen by a variety of selectors as engines of truth, enabling the promises made for tests to be identified as either credible or not.

11

Like earlier companies who had marketed nutrigenetic tests, PGST companies stressed from the outset that the future social value of their products would derive specifically from the unique significance of the personal genetic information (PGI) they provided. Their key expectation was that genetic information would have a special impact on behaviour, which would then lead to reductions in health risks and in healthcare costs. Each company added its own particular inflection to this future vision. 23andMe emphasized that the usefulness of this information lay, first and foremost, in how it would affect consumers own attitudes to their health, both independently from and in consultation with physicians: it would inspire [consumers] to take more responsibility for their own health and well-being (23andMe.com, Open Letter to Physicians, 13/11/08). Navigenics and deCODEme, on the other hand, represented the usefulness of tests results as primarily a stimulus to consultation with medical professionals (Goetz 2007). For these companies, test results were presented as health information that potentially had clinical utility in a strict sense i.e. it might help improve clinical diagnoses and treatment recommendations in a regulated setting. For all companies, however, the real potential value of test results lay in the future, thanks to a growing evidence base that would include dozens and perhaps hundreds of conditions as scientific and medical research continues to identify the genetic basis for a wide variety of health conditions (Navigenics, Press Release, 08/04/08). At the same time, companies also included small print disclaimers at the bottom of webpages (and elsewhere, such as in consent documents) to the effect that test results, by themselves, were informational or educational in nature, and by themselves did not constitute a diagnosis, given that a diagnosis by definition had to take into account family history, current physical condition, and other factors (23andme.com, FAQs 13/11/08 17/05/11). This strategy was similar to that undertaken by companies selling earlier nutrigenetic tests (GAO 2006, pp. 7-8). The combination of messages regarding expectations of future value and (somewhat deprecated) caveats concerning limitations created ambiguities which some argued would affect how promotional language would be received and acted upon. It was suggested that the use of disclaimers juxtaposed to unambiguous headline claims on webpages about how tests can motivate individuals to act on risk information (Umbehr 2008), could seriously worsen the consumers position, by creating confusion instead of assurance (Tamir 2010, p. 231, n. 50). By 2009, some evidence of such confusion had been found among potential PGST users on Facebook by McGuire and colleagues (2009). In this regulatory climate, then, questions of scientific validity and the credibility of expectations were framed as being of crucial importance, along with how the expected value and limitations of tests were communicated. We explore in the next section how issues concerning the scientific basis for PGST and the credibility of its regime of hope were addressed by companies in the period 2008-2010, by invoking the need for standards. With respect to technical standards for risk modelling and database curation, companies sought to stabilise an already existing regime of truth, and to minimize the space in which claims about the validity of tests could be made (Moreira and Palladino 2005). In relation to the PGST regime of hope, however, companies used expectations, as we shall, to question existing regimes of truth insofar as they set out ways of assessing the social value of medical tests, including strict clinical utility. 2008-early 2010: from technical standards to new regulatory objects While their business models differed, Navigenics and deCODEme both emphasized strongly the clinical role that their products could play in the hands of clinicians practising the art of

12 medicine by tak[ing] daily input from multiple sources and giv[ing] a recommendation to patients (Navigenics interview). Navigenics initially offered its product direct-to-consumer, although after subsequent regulatory interventions (particularly by the State of New York) turned to offering it largely through a customers physician only (Ray, Turna 2010). Nonetheless, a key feature of Navigenics business model from the beginning was that they would work with health insurers in order to be able to offer tests as part of a standard medical insurance package (Warburton 2008). It was important, in particular, to provide an evidence base strong enough to persuade health insurers to reimburse the costs of PGS tests, as this would remove a major obstacle to commercial viability. Articulating a regime of truth to support such claims was therefore of high importance. DeCODEme also took this tack. It saw the guarantee of progress towards personalized medicine through personal genomics firmly lay in the past and present, in the regime of truth created by the Icelandic parent company deCODE, which had via GWAS identified major inherited risk factors for diseases including type 2 diabetes, heart attack, stroke, breast cancer, prostate cancer, glaucoma (deCODEme, Front Page, 13/02/08). Its initial offering, for $985, was a genome scan that drew on the complete body of this research, and was also advertised as granting access to the parent companys expertise in other areas, such as in safeguarding genetic data, and genetic counselling. If deCODEmes regime of truth focused on its parent companys achievements, Navigenics claims invoked, in addition to expectations of incremental scientific progress, the alreadyregulated clinical settings in which they expected customers genetic information would be disclosed and acted upon. The company represented its more expensive Health Compass scan ($2500 plus a $250 annual subscription for risk updates) as a tool that would only provide information about SNPs related to medical conditions (no ancestry or other recreational product was offered) deemed clinically actionable (Warburton 2008, Umbehr 2008, Mesko 2009) would be disclosed. Non-treatable or non-preventable conditions would not be reported on. The social value of PGST was therefore positioned as dependent on the involvement of clinical gatekeepers who determined whether, on the basis of established medical practice, test results might have clinical value and thus should be made available. In this way, Navigenics model rested on a regime of truth that, it was claimed, was rooted in the practices of trusted social institutions. 23andMes business model stood in stark contrast to both these companies, consisting largely in simply making genetic information available to those interested in it. 22andMes vision of a personalized medicine future around was one in which the PGST industry provided PGI to increasing numbers of enthusiastic consumers who used this information to form new communities of interest and research advocacy coalitions around particular healthcare conditions and ancestries. Social value would be generated from the bottom up rather than through the intervention of medical professionals, which would represent, according to 23andMe, a democratizing (Singer 2008) of genomics. At the same time, recognised that it was also a gatekeeper, concerned not only with freeing PGI but also with helping individuals understand their own genetic information (23andMe.com, press release, 19/11/07). Although it emphasised future promises in a way other companies did not, the company had a strong need to articulate a regime of truth adequate to support its role as interpreter of PGI. Pressure was applied from a range of sources to the regimes of truth articulated by PGST companies during the spring and summer of 2008. Californias Department of Public Health

13 sent cease-and-desist letters to the three companies (and to others) in June, asking them to account for their products (Wadman 2008). Academics made criticisms of the methods companies were using to curate databases of GWAS (Janssens et al. 2008). Later, journalists reported divergences between the risk scores returned by different companies for the same test sample (Fleming 2008). Directly after Californias intervention, the companies announced in July that they would be collaborating to standardize methods for validating genetic tests and guaranteeing accuracy and quality as well as addressing wider issues, such as consumer privacy and transparency and encouraging companies to be up-front about the limitations of genetic-risk information (Lynch 2008). Concerns about clinical validity, i.e. about the interpretation of PGI, and specifically about how databases were curated and risks modelled why there were always different SNPs and different disease-specific panels used within each companys tests were of foremost concern (Navigenics interview). The framework initially used was one published by Navigenics in April 2008 (Press Release, 8/04/08). This covered areas of concern similar to those set out in the ASHGs 2007 paper. At the same time, this framework included priorities that were part of Navigenics vision of RI. For example, the framework called for the inclusion of only clinically actionable conditions in test reports, as well as for the provision of (post-test) genetic counselling. Neither of the other companies made clinical actionability a criterion of responsibility, nor provided (at this stage) genetic counselling for PGST. Despite this, cooperative efforts began, consisting of a series of meetings together with one other company (DNA Direct) and the Personalized Medicine Coalition (PMC) on a set of voluntary standards designed to promote integrity among their competitors. The proposed standards would be presented to the PMCs conference in December 2008. When the statement appeared in December, instead of setting out standards, or even proposing next steps the standardization process could take, the document staked out a minimal consensus position on what technical aspects of PGST services should be treated as benchmarking priorities. This agree to disagree position was necessitated by fundamental divergences between the basic assumptions on which the companies respective approaches to risk modelling and database curation were based. The only firm commitment in the document was to transparency on the part of each in disclosing their individual methodologies and assumptions, via websites and other media. Navigenics later represented the outcome of the 2008 discussions in stark terms: we just couldnt get the three companies to agree on [...] whats real and whats science (Navigenics interview). Simultaneously, the companies were developing a distinct and separate position on standards. This gradually became apparent in the promotional content of websites, and particularly in the ways customer testimonies and blogs were used by companies to point to the personal utility and wider clinical value of tests, independently of criteria of strict clinical utility. The positive effects of genetic testing on an individuals sense of identity and agency, particularly their sense of being able to influence their future, were extensively discussed. As responsible gatekeepers, companies could provide personalized guidance on steps to lessen the chances of negative health impact (Navigenics, Press Release, 9/10/08); confronted with risk information, people can live their lives in fear or they can embrace it (deCODEme, Fighting Coronary Heart Disease - Pamela Ayers, 04/11/08-07/06/11); decision making on risk can bring families closer together, and genetic information strengthen intergenerational bonds (Mountain 2008). Rhetorical themes of individual empowerment were emphasized more heavily. More personal perspectives on test value were included, in the hope of using different epistemological resources (individual testimony, clinician experiences) to increase

14 the credibility of promises by re-articulating the regime of truth behind PGST as seen, most obviously, in deCODEme.coms Customer Stories series, with its cast of visionary physicians and informed, persistent patients. Rather than simply demonstrating unanimity on the benchmarks tests would have to reach in order to be valid, this strategy linked promise to testimony in order to draw attention to dimensions of the social value of tests to which established assessment criteria (e.g. for clinical utility) could not be sensitive. In addition, efforts to develop standard ways of assessing the strict clinical utility of tests proved as problematic as developing standards for clinical validity, with the result that ideas about what could constitute clinical value began to change. Such criteria could only be developed on the back of actual clinical use. At the same time, uptake in the clinic depended on a demonstration of tests clinical utility. To render hopes of clinical value credible, Navigenics sought to find surrogate markers of clinical efficacy (Navigenics interview) such as behaviour change or an increase in drug treatment compliance among customers taking tests. The fact that expectations of future clinical value were so central to the case companies made for the social benefits of their tests meant, therefore, that definitions of clinical value began to take on different emphases. The content of any standards designed to differentiate useful from useless or fraudulent tests would have to reflect more sensitively the regime of hope constructed for PGST. This case was made at a seminar in December 2008 convened by the NIH and Centre for Disease Control (CDC) that served as an arena of expectations where assumptions about the requirements of the regime of truth applicable to PGST were subjected to scrutiny from a future-oriented perspective of hope. Invitees included medical academics, geneticists, representatives from the HHS and other federal bodies, the PMC, public health institutions, along with 23andMe, deCODEme and Navigenics. A report from this seminar (Khoury et al. 2009) and additional report detailing the proceedings (Fraker and Mazza 2011) show how central to the event were debates about the restrictiveness of the existing regime of truth to which PGST was expected to measure up, and how these debates advanced by interrogating companies expectations about PGST. Discussions about the best way to establish and measure clinical utility noted that clinical usefulness might be a better concept (Fraker and Mazza p. 6), that evidentiary bars should not be set so high as to discourage innovation (p. 14), that test utility for some conditions should be assessed under less stringent criteria (p. 18), and that there was no reason to assume genetic exceptionalism by subjecting PGST to tighter criteria than other medical tools (p. 40). These elements of the discussion were also presented in the final report, where the personal utility of tests was identified as a largely overlooked dimension of benefit, and one that would need to be related to an expanded conception of CU. A position emerged among several participants that acknowledged that the claims for clinical value made by companies were not currently sustainable. Nonetheless, their products might stimulate further innovation, drive translational progress and thus contribute to expanding the evidence base on which CV and CU could be assessed. The final reports promotion of new objects of concern for regulators and researchers expanded clinical usefulness and personal utility confirmed this recognition. Standards for assessing the clinical value of this emerging, inherently future-oriented technology would have to be constructed from the point of view of the future, of hope, as well as taking into account existing and established assumptions about how the truth of claims made by companies should be assessed. Following the publication in June 2009 of a paper from 23andMe in the American Journal of Bioethics promoting the importance of personal utility (Hsu, Avey et al. 2009), August saw

15 the publication of the final report on the December 2008 seminar in Genetics in Medicine, accompanied by papers examining the potential usefulness of personal utility as a regulatory object. Grosse et al (2009) note that measuring personal utility would be of use to regulators, in helping create qualifying standards for allowing tests onto the market (p. 576). Foster et al (2009) argue that even with traditional monogenic tests, clinical utility is a complex, composite and often ambiguous metric. As a result, an expansive measure of clinical utility would be appropriate for PGST, to include the information value of PGI for changing risk behaviours. In addition, personal utility (the benefits of PGI to a consumers sense of identity, responsibility and agency, its impact on family dynamics, coping strategies and so on) should be included so as to ensure that PGST results can be integrated with clinical practice rather than being excluded as lacking strict medical value (p. 571). The category of empowerment benefits emphasized by companies encompasses precisely these kinds of considerations, as we have seen above. Communication problems: 2009-2011 We have explored how companies sought to advance standards relating to two areas of concern the clinical validity and clinical utility of tests. In April 2008, Navigenics had identified how companies communicate with customers as a third area of concern, one that, as we have seen, was interpreted as such by the ASHG, and federal agencies including regulators. However, this area saw no sustained standardization efforts by companies. Disclaimers, which as we have seen, were used by all three of the companies we have examined so far, represented a direct continuation of an ad hoc strategy used by earlier nutrigenetics companies. There was no explicit collaborative effort on standards around customer communication beyond the acknowledgement in the December 2008 document produced the PMC-sponsored standards working group that transparency about methodological differences was important. As 2009 went on, PGST companies began to include within the lists of conditions tested for an increasing number of clinical conditions (e.g. for Tay-Sachs and cystic fibrosis). In such cases, the alleles that are tested for have the added significance of indicating that a testees children may inherit a condition for which the testee has the relevant allele(s). This meant that including such conditions would potentially, from a regulators point of view, place the test into a different regulatory risk category, namely that occupied by existing genetic tests for monogenic conditions. Regulators therefore began to take a more active interest, once again, in the expectations companies had begun to articulate about the clinical usefulness of their tests, having decided that, increasingly, the claims [PGST companies] are making are medical claims (Carmichael 2010). Overclaiming and how companies communicated the limitations of their tests would subsequently become central regulatory issues. In July 2009, the launch of Pathway Genomics intensified regulatory concerns. Pathway initially sold its tests direct-to-consumer, but its promotional rhetoric was less sensitive to the tensions between truth and hope than that of the other companies we studied. On its website, it depicted personalized medicine as a reality here and now, describing PGI as information that can save your life by providing a crystal ball to see into your hearts future (Pathway.com, front page, 09/06/09). The differences between strict clinical utility, clinical usefulness and personal utility were not acknowledged either. For example, the privacy policy stated that tests may assist you (emphasis added) in identifying medications or treatments (Pathway.com, Privacy Policy, 09/06/09). The websites front page suggested you can take the necessary steps to control or prevent the disease (emphasis added). Yet

16 Pathway also followed a disclaimer-based approach to communicating the limitations of its tests: its terms of service and consent form stressed that Pathways tests were for research and educational use only, and that consumers should consult a clinician before making any behavioural changes (Pathway.com, Terms of Service, 09/06/09). With its launch, Pathway stepped out upon the tightrope other companies had been walking. In addition to how it represented its services to potential customers, Pathway took a comparatively unusual approach to modelling risk and to communicating it to present customers. As well as using PGI, it used phenotypic data obtained via health questionnaires, presenting its test results as going beyond genetics in a vacuum (Pathway interview). It claimed that it used a unique algorithm developed by Pathway to combine risk scores from genetic health, lifestyle and family history data (Mesko 2009). Thanks to its incorporation of more personal data, this move away from simply interpreting PGI could be interpreted as moving closer to providing a diagnosis. At the same time, Pathways health risk reports used qualitative risk bands rather than hard numbers, i.e. absolute or relative risk scores, stating that the company just [didnt] think that theres clinical evidence to support that (Pathway interview). Pathways approach suggested that any clinical validity standards would have to go far beyond the approach taken by dominant PGST companies, and that producing such standards would have consequences for how risk should be communicated, placing a much heavier responsibility on PGST companies to look at the significance of the scientific uncertainties that surrounded their tests. This seemed to suggest another way in which PGSTs regime of hope should reshape its regime of truth: to personalize medicine, a fuller accounting of risk factors would be required, going beyond personal genomics, and requiring a more ambitious research programme than GWAS-based research alone. In May 2010, Pathways balance on the tightrope was shaken. Its decision to sell susceptibility tests in the Walgreens pharmacy chain led the FDA to announce that the tests were regulatable medical devices. The company subsequently withdrew them, stopped retail sales through its website, and shifted its business model completely away from DTC. Subsequently, it required a physician to order all tests. Around the same time, the SACGHS produced a report on PGST (SACGHS 2010) that made observations about companies communication strategies, denouncing the disclaimers that typically appeared as small print on their websites as misleading (p. 19). The report also implicitly supported a position similar to Pathways position on what would be needed to provide adequate standards for the clinical validity and value of tests. There was a need for environmental and phenotype data to be included in risk profiles, so as to provide a full accounting of susceptibility risk (p. 24). The problem of the utility of tests was discussed explicitly in terms of the validity of a wider definition of clinical usefulness (including motivation to act on health recommendations) and, in addition, of the validity of concepts of personal utility. However, in both cases, the report noted that adverse consequences could be expected if information provided by companies proved inaccurate or hard to understand (p. 25). The problem of overclaiming, i.e. of representing expectations too unanchored in a regime of truth, and miscommunication was thus moved back to the forefront of the regulatory agenda, together with the lack of relevant standards. Following the Pathway controversy, the FDA sent letters to 23andMe, Navigenics, and deCODE, advising them that their tests might also be regulatable medical devices, and requesting that they provide information on their tests to enable their regulatory status to be established. The first few months of 2010 thus set the stage for hearings on DTC testing to take place on 22-23 July before the House of Representatives Committee on Energy and

17 Commerce, where a comparative report from the GAO on the services provided by different companies would be presented. 23andMe, Navigenics, and Pathway were invited to give evidence. At the hearing, the GAO testimony (Kutz 2010) drew attention to the persistence of divergences between companies in their interpretations of PGI from the same customers. In addition, the report drew attention to examples of interactions between investigators posing as customers and customer service staff that, it said, were evidence of fraudulent claims. Testimony by representatives of 23andMe, Navigenics and Pathway pointed to the instability and fragility of PGST in the present. Navigenics suggested that there was a lack of clarity in the FDAs process of decision making on how to regulate PGST (Vanier 2010) and that an outside advisory committee should be set up to advise the agency on how to make progress on standards relating to the scientific basis for PGI interpretation. 23andMe and Pathway asked for assistance for the industry from the NIH and FDA on standards relating to clinical validity, with Pathway adding caveats regarding the need for a full accounting of risk before the promise of PGST could be realised. Despite acknowledging the persistent gaps in PGSTs regime of truth, testimony from all three companies folded concerns about truth back into articulations of hope, widening the scope of expectations in the process in ways that reflected their contributions to regulatory debates in 2008-09. Companies acknowledged the presence of knowledge gaps. At the same time, they presented testimonial evidence of individual cases where, they claimed, tests had demonstrated clinical usefulness (thanks mainly to the persistence of informed customers), or personal utility in modifying behaviour. Pathway (Becker 2010) cited the 2009 Boston University REVEAL study on the clinical and personal utility of genetic testing in relation to Alzheimers as support for positive expectations regarding the personal utility of widespread testing in the future. In their testimony, all three companies also sought to expand their visions of the future benefits of PGST-supported personalized medicine to include, for example, its impact on economic growth and on medical research. Navigenics and Pathway both sought to portray PGST (despite the demonstrably small size of the industry) as a source of high-paying jobs and even as a channel for resurgent economic growth after the 2007-08 financial crisis. 23andMe described the future promise of its 23andWe customer-based research model as a way of transforming genomic research through crowdsourced GWAS research (Gould 2010). While the need for scientific standards received considerable attention within companies evidence to the committee, issues around communication were relatively deprecated. Pathway mentioned the need for standardized labelling and website disclosures (Becker 2010) around the limitations of susceptibility risk reporting. 23andMe provided more extensive coverage of communication, offering its standard disclosure practices relating to the incomplete nature of GWAS research, to the influence of environmental factors over whether any health condition might actually eventuate, and to the possibility of unforeseen consequences being attendant on receiving risk reports, as examples of how companies could proceed. Nonetheless, the need for standards in this area was not made an explicit theme of discussions. No further regulatory steps followed upon the July 2010 hearings until early 2011. In March 2011, the FDAs expert advisory panel on Molecular Genetics met to consider priorities for standardization. Its (non-binding) recommendations repeated many of the same points made by earlier reviews, adding that a full accounting of risk (including environmental factors) was the only way to move towards an adequate informational standard for judging the credibility of PGS tests. To date, the FDA has not moved on any of the panels recommendations.

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In this phase of the evolution of PGST, the first wave of influential companies was joined by new entrants, such as Pathway, who used the same language of standardisation in describing their preferred model of regulation. At the same time, Pathway sought to differentiate its products from its rivals in ways that proved commercially risky, employing business models that fell foul of the FDA and also by adopting stances on risk communication that had already been questioned during regulatory engagement with nutrigenomics companies in 2005-06. They regained their balance on the tightrope by striking the same notes in their testimony to the E&C Committee as their rivals, underlining the need for an expansive view of the utility of tests, one based on hope, which could shift the epistemological focus of PGSTs regime of truth towards clinical usefulness and personal utility. Discussion Standardization has been promoted by all actors as a vital part of a viable regulatory approach for PGST. We have examined how attempts at standardization have been funnelled through arenas (such as the PMC process, NIH/CDC seminar, and July 2010 hearings) in which expectations are tested and selected, feeding back into the evolution of technologies and the selection pressures exerted upon them, including those exerted by regulators. The shifts we have traced in how companies talk about standards reveal, we suggest, how they have articulated a regime of hope in such a way as to reshape the regime of truth on which credible claims about PGST are taken to depend. The uncertainties surrounding multigenic susceptibility testing which were central to the regulatory agenda in 2007 have been supplemented and to an extent displaced by other uncertainties, tied to the promises of clinical usefulness and personal utility. Figure 1 summarizes the relationships between stages in the testing process involved in PGST, different regulatory objects, existing standards and arenas of expectation. It indicates, among other things, where in the testing process different regulatory objects become relevant, where existing standards apply, and which stages of the testing process were the foci of particular arenas of expectation. Curnutte and Testa (2012) have argued that PGST companies have pursued a standardization strategy in which they have sought to close down debates over standards by focusing on technical standards concerning analytical and clinical validity. We have shown that this is not the case, and that the four companies in our study (including 23andMe and Navigenics, studied by Curnutte and Testa) have actually taken a quite different tack on standards that can be explained by looking at the dynamics of expectations within the industry. In the early stages of standardization efforts, companies sought to respond to concerns regarding the established regime of truth on which their application of GWAS results rested, and to standardise certain technical procedures upon which the analytical and clinical validity of tests was held to depend. These aspects were ones that could, in principle, be subjected to criteria dependent solely on quantitative parameters. Later on, after difficulties with this process had been encountered, companies sought to promote the value of regulatory objects that represented much harder-to-quantify variables (clinical usefulness and personal utility) and which related to the social value of their tests (an area which Curnutte and Testas paper claims companies expressly avoided). At the same time, companies continued to invest little explicit effort in seeking to standardise softer aspects of their services, such as how they communicated the value and limitations of tests, or risk profiles, areas which had been prominent in the outline of priorities produced by Navigenics in 2008.

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Figure 1: Relationship between PGST testing/reporting process, regulatory objects, standards and arenas of expectations

20 Early concerns with analytical and clinical validity meshed with pre-existing concerns about genetic testing registered by regulators and by the 2006 enquiry into nutrigenomic testing. If regulatory agencies, public health research organisations like NHGRI, and advisory bodies like the SACGHS expressed (in their role as technology selectors) concern about the credibility of company expectations, they also maintained a generally supportive posture in relation to the broad promise of genomics for personalized medicine. The second track on standards taken by companies focused on building consensus about the promise of PGST among federal advisory agencies and more widely by promoting the clinical usefulness and personal utility of tests regulatory objects which blurred the boundaries between clinical and personal value. At the same time as the failure of the PMC process created negative uncertainty for the industry, discussions over social value in arenas like the NIH/CDC seminar in 2009 and changing patterns in how companies represented the future social value of PGST more widely arguably created positive uncertainty. The lack of standards for analytical validity and clinical validity failed to close down existing regulatory ambiguities, which were exposed again when regulators began to register renewed concern over how companies were communicating the value of their tests. However, by opening up a second front on standardization, companies drew attention to other ambiguities that affected how the future value of their tests could be assessed. By doing so, their representations of hope (which drew on personal testimonials, blogs exploring different dimensions of value, and academic discussions around personal utility and less strict definitions of clinical utility) began to shift the territory on which the credibility of expectations would be sought. Indeed, the growing weight given to ideas of clinical usefulness and personal utility as tools for thinking about the social value of PGST meant that, increasingly, the purpose of regulatory criteria appeared to shift from selecting between credible and non-credible products to safeguarding and legitimizing a stable regime of hope for the PGST industry, as the NIH/CDC seminar report from Khoury et al (2009) demonstrates. Navigenics statement on standardization priorities in early 2008 employed standards in an anticipatory mode recognisable from the literature (e.g. ISO 2007): it sought to guide the emerging market for PGST shape by promoting key aspects of its own business model as central to realizing the future social value of PGST in general. As time went on, the shifting of debate to cover new regulatory objects in late 2008 and throughout 2009 presented a new anticipatory focus for standards. The regime of hope built on clinical usefulness and personal utility by company rhetoric and within arenas of expectations displaced the centrality of the regime of truth around analytical validity, clinical validity and strict clinical utility. Rather than uncertainties around the social value of PGST focusing solely on established regulatory terms of reference (e.g. the calls from the SACGHS for common technical standards to establish criteria for validity, and clinical trials to establish utility), they had moved to encompass the lack of standard definitions and models for assessing expanded clinical utility and personal utility. During the period examined in this study, evidence began to emerge that PGST seemed neither to harm consumers, nor to have any large positive effect on behaviour (Bloss et al. 2011, McGowan et al. 2010). Consequently, the terms of debate about PGSTs social value remain very much open. Conclusions The research on which this paper draws has legitimated the application of results from the sociology of expectations to PGST, and has documented the role of dynamics of expectations in shaping agendas in standardization within the industry. In doing this, it has also shown

21 that, as well as being part of a set of contemporary tools for producing truth, they may also help to sustain and produce hope. The dynamics of expectations in our study may be seen as an instance of how uncertainty has strategic significance for knowledge and action (McGoey 2012). We have described how discourses around PGST standardization have sought to redefine what kinds of known unknowns are relevant to assessments of the social value of PGST, and demand, as a result, responses from particular actors. The regulatory uncertainties which surrounded the industry in 2007-08 demanded more research on clinical validity and utility to establish evidentiary standards according to which companies claims about the social value of their tests could be judged credible or not. Here, the responsibility was primarily on companies to provide evidence. Although by 2011 this demand remained unfulfilled, the focus had shifted from the known unknowns of clinical validity and strict clinical utility to encompass the new regulatory objects of clinical usefulness and personal utility. Responsibilities relating to these known unknowns were wider in scope, touching on the responsibilities of regulators, federal agencies, academic researchers and others to grapple with the problem of how to model and assess these less traditional sources of credibility. Whether this reframing of uncertainty can be said to have resulted from a deliberate, strategic attempt to manufacture uncertainty (Michaels 2008) or should best be understood as a result of the internal logic of iterative attempts to represent the promise of PGST remains an open question. The temporal structure of susceptibility testing its credibility depends on its predictive power, to be demonstrated in the future (and, one might recall, demonstrating its predictive power will, conversely, depend on it accruing credibility enough to encourage wide uptake and trialling) means that discussions about how best to buttress the development of genomics-based technologies in such a way as to create genuine social value, have a particular character. On the one hand, the scope for making promises is extremely large. On the other, there is a need to find criteria for determining how plausible these promises might be that do not close off the possibility that the social value of these technologies may need to be assessed in ways quite other than those with which medical professionals are familiar. Moreover, the uncertainties which come to the fore in such discussions are perhaps inherently of a disorderly character. Rather than simply requiring more research on PGS tests to light up the darkness which surrounds their clinical validity, the prospect of a full accounting of risk (SACGHS 2010, p. 24) as the only regime of truth adequate to fully support PGSTs regime of hope will require whole new research paradigms, and huge progress concurrently in epigenetics, genomic interpretation, risk modelling, psychological research and so on. The hope invested in PGST points towards larger demands on regulators and indeed society more generally, and towards the need for a capacity to go beyond the common assumption that uncertainty is an epistemological effect of our current state of knowledge, and to acknowledge that it may be a less remediable condition (Groves 2009).

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Acknowledgements The authors would like to thank Dr Andrew Bartlett, Professor Lawrence Busch, Dr Joan Haran and Professor Adam Hedgecoe for helpful comments on an earlier version of this paper.

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