The Use of Preliminary Scientific Evidence in Public Health: a Case Study of XMRV

Policy Forum The Use of Preliminary Scientific Evidence in Public Health: A Case Study of XMRV

Kumanan Wilson1,2*, Katherine Atkinson2, Jennifer Keelan3 1 Departments of Medicine and of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada, 2 Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada, 3 Dalla Lana School of Public Health, University of Toronto, Toronto, Canada

The xenotropic murine leukaemia virus-related virus (XMRV) controversy Summary Points has made evident novel challenges related to integrating scientific evidence into N The rapid response to XMRV as a novel pathogen has highlighted some policy making that concerns the safety of challenges pertaining to policy making and editorial responsibilities in a policy blood products and public health in environment influenced by the precautionary principle. general. The initial publication of an N Once published, preliminary scientific evidence can result in rapid changes in article in the journal Science postulating policy and can undergo widespread dissemination via both the Internet and that XMRV was a causative agent for social media. chronic fatigue syndrome (CFS) set N The impact on policy and the propagation of the initial scientific information forward a cascade of decisions that may not cease if the evidence is disproven and retracted from peer-reviewed resulted in the implementation of blood journals. donor deferral policies targeting individ- N Regulators should consider the use of frameworks to guide the use of the uals with any history of CFS [1]. Despite precautionary principle and a separate, more flexible policy stream for the subsequent failure to replicate the precautionary policies. study and the ultimate retraction of the N Editors should continue to develop strategies to place preliminary scientific original paper, many of these policies evidence of potential public health relevance in context for the public and for have not been reversed [1]. The XMRV policy makers. saga highlights new dilemmas pertaining to the publication of preliminary scientific evidence in matters of public health research article in Science reported that the point, all initial research publications concern. These challenges have been virus had been identified in 68% of showing a positive association between created by the current precautionary patients with CFS versus only 4% of XMRV and pathogenesis have been policy-making paradigm, and the impact healthy controls [8]. This publication retracted, with or without the agreement of the Internet and social media as a raised immediate concerns that XMRV of the authors [9–11]. mechanism for the rapid transmission of could be the biological cause of CFS and health information. could be transmitted through blood trans- Blood Donor Policies fusion. After months of scientific investi- XMRV as a Potential gation into possible transfusion transmissi- The theory that individuals with CFS Transfusion-Transmissible bility and the potential links to both CFS might harbor XMRV and that the Infection and prostate cancer, a consensus emerged virus could be transfusion transmissible that XMRV was a laboratory artifact, and prompted some blood operators to take The story of how XMRV was first not a threat to blood recipients [6]. At this a precautionary approach and implement identified as a potential transfusion-transmissible infection and the subsequent rejection of this hypothesis has been well documented [1–6]. Briefly, the first evi- Citation: Wilson K, Atkinson K, Keelan J (2014) The Use of Preliminary Scientific Evidence in Public Health: A dence that XMRV might be a disease- Case Study of XMRV. PLoS Med 11(4): e1001623. doi:10.1371/journal.pmed.1001623 causing agent was reported in 2006 when Published April 8, 2014 XMRV genome sequences were detected Copyright: ß 2014 Wilson et al. This is an open-access article distributed under the terms of the Creative in a cohort of American men with Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, localized prostate cancer undergoing rad- provided the original author and source are credited. ical prostatectomy [7]. Concern over the Funding: This work was supported by the Canadian Institute of Health Research (Grant # MOP-119492). The threat of XMRV escalated in 2009 when a funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: KW is an unpaid member of Canadian Blood Services Scientific Advisory Board. The Policy Forum articles provide a platform for health authors have no other conflicts of interest to report. policy makers from around the world to discuss the Abbreviations: CFS, chronic fatigue syndrome; XMRV, xenotropic murine leukaemia virus-related virus. challenges and opportunities in improving health care to their constituencies. * E-mail: [email protected] Provenance: Not commissioned; externally peer reviewed.

PLOS Medicine | www.plosmedicine.org 1 April 2014 | Volume 11 | Issue 4 | e1001623 additional donor deferral strategies to XMRV, donor deferral policies still exist disseminated. One of the legacies of the protect against this threat (Table 1). that target individuals with any past or transfusion transmission of HIV and At present, no countries are screening present diagnosis of CFS. In many of hepatitis C was the adoption of precau- for XMRV or have banned individuals these jurisdictions, these retained policies tion as a guiding principle in blood who test positive for XMRV from donat- are likely a consequence of governance safety decisions and in public health in ing blood, organs, or other tissues. or regulatory processes that make it general [14]. The precautionary principle However, since it remains possible that difficult to reverse policy. Nevertheless, advocates for the introduction of safety CFS is caused by a retroviral agent, they highlight challenges related to the measures based on preliminary scientific several countries adopted strong precau- elimination of policies that were intro- evidence [15]. Such an approach was tionary approaches [12] by introducing duced on a precautionary basis. By found to be successful for managing the indefinite or permanent deferrals for themselves, the CFS deferral policies risk of transfusion transmission of variant blood donation from donors with any are not likely to have a significant impact Creutzfeldt-Jakob disease [16]. However, history of CFS diagnosis (e.g., Canadian on the supply of blood products as only a this approach carries potential dangers as Blood Services, Australia, United King- very small portion of blood donors are made evident by the XMRV experience. dom). Other jurisdictions (e.g., European affected. However, failing to revisit Traditionally, scientific journals published Union, He´ma-Que´bec) chose to wait for precautionary decisions once new evi- provocative hypothesis-generating evi- more evidence to accumulate before dence becomes available could result in dence, which passed peer review with an making a decision regarding the threat the accumulation of scientifically unjus- expectation that other researchers would of XMRV. tified policies. This could contribute to seek to replicate the results and ultimately Unlike other cases where high-risk blood shortages by unnecessarily defer- confirm the validity of the findings. In the groups protested being the target of donor ring groups of potential blood donors era of precautionary decision making in deferral, the CFS community embraced and could lead to self-deferral by poten- public health, preliminary evidence may the restriction. Rather than stigmatizing tial donors due to the ambiguity of be acted upon before confirmatory evi- CFS sufferers, the identification of a existing policies. dence is available. possible infectious basis was seen as Further complicating matters, prelimi- validation for a disease often characterized Science, Social Media, and the nary scientific evidence may be rapidly as a type of psychological disorder. The Precautionary Principle disseminated via the Internet and, in CFS community advocated for the imple- particular, social media. The Internet mentation of these additional donor de- XMRV highlights a new dilemma and social media have been invaluable in ferral policies as well as for donor relating to the publication of preliminary allowing individuals to access information education and self-deferrals within their evidence in matters of public health about health, and as a means for scientific communities [13]. concern. This dilemma has been created evidence to be disseminated. However, Three years later, despite a thorough because of a change in the way public this is a double-edged sword. Stakeholder evaluation of risk and a series of health decisions are being made and how groups may disseminate and distort scien- publications discrediting the threat of preliminary scientific information is being tific evidence and the meme may persist

Table 1. Countries and their past and present deferral policies relating to CFS and the effects of XMRV on deferral policies.

Country Previous Deferral Policy Change Date Current Deferral Policy Reason

Australia Those with active diagnosis April 28, 2010 Indefinite for any history of Safety of blood products, of CFS deferred until diagnosis of CFS low supply impact. Will symptoms resolve revisit in two years’ time [25] Canada (Canadian Blood Those with active or April 7, 2010 Indefinite for any history of Safety of blood products, Services) symptomatic diagnoses of diagnosis of CFS low supply impact, pressure CFS deferred from recipient groups [26] Canada (He´ma-Que´bec) Those with active or None None Formal risk evaluation symptomatic diagnoses of conducted CFS deferred United Kingdom Those with CFS deferred November 1, 2010 Permanent for any history of Protect blood donor health until recovered diagnosis of CFS [27] United States No previous guidance December, 2010 AABB Bulletin: Active Protect blood donor health discouragement from and recipients [28] donating for any history of CFS diagnosis Europe (European Centre No previous guidance Risk assessment completed None Awaiting more evidence [29] for Disease Prevention and July 2011, no change to Control) policy New Zealand Those with current diagnosis April 21, 2010 Permanent for any history of Align with international or who have been diagnosed diagnosis of CFS policy change [30] with CFS within past two years deferred

doi:10.1371/journal.pmed.1001623.t001

PLOS Medicine | www.plosmedicine.org 2 April 2014 | Volume 11 | Issue 4 | e1001623 even after the refutation of the original dence. Policies implemented under pre- challenges related to the publication of evidence. Perhaps the most infamous caution are essential to maintaining early evidence in areas of public health illustration was the publication of the since public health safety as well as public concern. The primary responsibility for withdrawn article postulating a link be- confidence in the system [16]. In an ideal addressing this challenge lies with the tween the MMR vaccine and autism [17]. world this would be a prudent approach regulatory process. However, scientific Despite numerous studies refuting the under the following conditions: policies journals publishing basic research need association, the rumor continues to exist, are revisited in the face of new scientific to take into consideration the dual impact largely disseminated by the Internet, and evidence, regulatory policies could be of the dissemination of information via has had a very tangible impact on rapidly changed, and the initial impact of the Internet/social media by advocacy childhood vaccination rates, which has revoked policies could be combated groups and the precautionary principle subsequently contributed to measles out- through effective risk communication. policy-making paradigm in public health breaks [18]. The suspected and since Unfortunately, these conditions often do (Figure 1). rejected link between thimerosal and not exist. In many instances policies are autism has also been similarly problematic not revisited in a timely manner. Even The Regulatory Process [19]. The Institute of Medicine (IOM) when they are, the regulatory process The use of frameworks to guide the invoked the precautionary principle when can be lengthy and there also may be a initial and ongoing use of the precaution- arguing for a removal of the preservative reluctance to withdraw policies in the ary principle by policy makers is a useful [20]. This fueled antivaccination senti- face of new evidence for fear of creating firststeptoaddressthischallenge ment and, despite the absence of studies the perception that the public is being [12,15,21]. These can help clarify wheth- supporting the association and a subse- putatrisk. er an emerging threat is suitable for a quent statement from the IOM articulat- precautionary approach depending on ing that the link did not exist, the impact Recommendations the severity of the threat and the of the original precautionary statement has consequences of taking action to remove persisted. The experience with XMRV, like the the threat. If a framework had been used, The XMRV story illustrates challeng- past experiences with vaccines and au- XMRV may not have warranted precau- es with acting on early scientific evi- tism, illustrates some of the emerging tionary action as the condition was not fatal, had arguably limited morbidity, and the virus was potentially not widespread. Frameworks can also be useful to guide the transitioning of precautionary policies when new evidence becomes available. A fundamental component of the European Union’s communication on the precautionary principle is that the policy be ‘‘subject to review, in the light of new scientific data’’ [15]. However, the amount of evidence needed to remove the policy is often much greater than the amount of evidence of risk needed to introduce the policy in the first instance. The length of time to change policies related to donation of blood from men having sex with men in many jurisdictions is illustrative of this dilemma [22,23]. To overcome this obstacle, we recommend that threats that qualify for the use of precaution are brought through a separate policy process from policy decisions made on more definitive evidence. A distinctive policy process could funnel decisions through a less onerous process in order to be changed when new evidence becomes available. For example, in the instance of XMRV, the American Associ- ation of Blood Banks (AABB) chose to issue an advisory to its members recommending that they defer blood donations from individuals with any history of CFS. This approach facilitated the process of revis- ing and ultimately removing the recom- Figure 1. Recommendations for policy makers and journal editors. mendation as more evidence became doi:10.1371/journal.pmed.1001623.g001 available. We further recommend that

PLOS Medicine | www.plosmedicine.org 3 April 2014 | Volume 11 | Issue 4 | e1001623 precautionary-based decisions have an publication comments on their websites, as structured manner, these could state expiry/stop date at which the evidence well as issuing expressions of concern and where on the scale of scientific certainty is reviewed and the decision be made retractions through these media. The this research falls, which findings are into a permanent policy, removed com- National Library of Medicine has similarly preliminary and require more evidence pletely, or continued for another set enabled authors to comment and discuss and which findings are substantive enough period. Such an approach would guard publications through the creation of to warrant action, and what future re- against the accumulation of measures PubMed Commons. To supplement these, search is required to clarify any uncertain- with limited scientific basis. we would also suggest some further ty. This is particularly important because initiatives at and prior to publication for standard methods for evaluating evidence Academic Journals articles of potentially high policy impact would likely not apply as the evidence on What steps can scientific journals take to and public interest. High policy impact which precautionary decisions are being navigate the current public health policy- publications include those that present made is often based on a basic science making environment? Even if the regula- findings relevant to the environment or study, a case report, or a case series. tory process is changed to be more public health, domains influenced by the responsive to new evidence that negates precautionary principle. High public in- Conclusion existing precautionary policies, there is still terest articles that may be rapidly dissem- the risk that the communication of pre- inated among advocacy groups include The potential transfusion transmission liminary evidence may have a lasting those that concern areas where the public of XMRV has highlighted novel challeng- impact, particularly where there are ad- perception of risk associated with the topic es pertaining to policy making and the vocacy groups that support and dissemi- is high, i.e., those addressing risks of an publication of preliminary scientific evi- nate the evidence. These new realities, involuntary or catastrophic nature [24]. dence on matters of public health. In however, should not discourage the pub- Some journals commission editorials and particular, it demonstrates challenges in an lication of provocative novel findings. commentaries to contextualize research era in which decision making concerning Journals have already taken several findings that might cause alarm. We public health is increasingly influenced by steps to correct or clarify scientific evi- recommend wider uptake of this practice. the precautionary principle, and where dence. Some of these steps have included These editorials could clarify both the scientific findings linked to areas of public encouraging authors to add balanced scientific context of the article’s findings interest are rapidly disseminated via the information to papers, permitting post- and the policy context of the research. In a Internet and social media.

References 1. Kakisi OK, Robinson MJ, Tettmar KI, Tedder 11. Lo SC, Pripuzova N, Li B, Komaroff AL, Hung Board on Health Promotion and Disease Preven- RS (2013) The rise and fall of XMRV. Transfus GC, et al. (2012) Retraction for Lo et al., tion: 2. Med 23: 142–151. Detection of MLV-related virus gene sequences 21. Weir E, Schabas R, Wilson K, Mackie C (2010) A 2. Erlwein O, Kaye S, McClure MO, Weber J, Wills in blood of patients with chronic fatigue syn- Canadian framework for applying the precau- G, et al. (2010) Failure to detect the novel drome and healthy blood donors. Proc Natl Acad tionary principle to public health issues. retrovirus XMRV in chronic fatigue syndrome. Sci U S A 109: 346. Can J Public Health 101: 396–398. PLoS ONE 5: e8519. 12. Wilson K (2011) A framework for applying the 22. Wainberg MA, Shuldiner T, Dahl K, Gilmore N 3. van Kuppeveld FJ, van der Meer JW (2012) precautionary principal to transfusion safety. (2010) Reconsidering the lifetime deferral of XMRV and CFS–the sad end of a story. Lancet Transfus Med Rev 25: 177–183. blood donation by men who have sex with men. 379: e27–28. 13. Dodd RY (2011) XMRV and blood safety: a case CMAJ 182: 1321–1324. 4. Karafin MS, Stramer SL (2012) The scientific study of science and public pressure. ISBT Sci Ser 23. Wilson K, Atkinson K, Keelan J (2014) method at work: xenotropic murine leukemia 6: 446–448. Three decades of MSM donor deferral policies. virus-related virus is neither a cause of chronic 14. Martuzzi M (2004) The precautionary principle What have we learned? Int J Infect Dis 18 1– fatigue syndrome nor a threat to the blood supply. protecting public health, the environment and the 3. Transfusion 52: 222–225. future of our children. World Health Organiza- 24. Slovic P (1987) Perception of risk. Science 236: 280–285. 5. Dodd RY (2011) Chronic fatigue syndrome, tion, Regional Office for Europe. 25. Australian Red Cross Blood Service (2010) Blood XMRV and blood safety. Future Microbiol 6: 15. Commission of the European Communities Service updates CFS donor policy. Available: 385–389. (2000) Communication from the commission on http://www.donateblood.com.au/media-centre/ 6. Dodd RY, Hackett J Jr, Linnen JM, Dorsey K, the precautionary principle. COM(2000) 1 (Brus- latest-national-news/blood-service-updates-cfs- Wu Y, et al. (2012) Xenotropic murine sels: 2 February 2000). Available: http://ec. donor-policy. Accessed 25 March 2013. leukemia virus-related virus does not pose a risk europa.eu/dgs/health_consumer/library/pub/ to blood recipient safety. Transfusion 52: 298– pub07_en.pdf. Accessed 2 March 2014. 26. Canadian Blood Services (2010) Indefinite defer- 306. 16. Wilson K, Ricketts MN (2004) The success of ral for history of chronic fatigue syndrome. 7. Urisman A, Molinaro RJ, Fischer N, Plummer SJ, precaution? Managing the risk of transfusion Available: http://www.blood.ca/centreapps/internet/ Casey G, et al. (2006) Identification of a novel transmission of variant Creutzfeldt-Jakob disease. uw_v502_mainengine.nsf/page/Indefinite_Deferral_ gammaretrovirus in prostate tumors of patients Transfusion 44: 1475–1478. for_History_of_Chronic_Fatigue_Syndrome?Open homozygous for R462Q RNASEL variant. PLoS 17. Wakefield AJ, Murch SH, Anthony A, Linnell J, Document. Accessed 14 March 2013. Pathog 2: e25. Casson DM, et al. (1998) Ileal-lymphoid-nodular 27. NHSBT (2010) ME/CFS sufferers permanently 8. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost hyperplasia, non-specific colitis, and pervasive deferred from giving blood. MA, Hagen KS, et al. (2009) Detection of an developmental disorder in children. Lancet 351: 28. AABB (2010) Recomendations on chronic fatigue infectious retrovirus, XMRV, in blood cells of 637–641. syndrome and blood donation. patients with chronic fatigue syndrome. Science 18. (2011) Increased transmission and outbreaks of 29. European Centre for Disease Prevention and 326: 585–589. measles, European Region, 2011. Wkly Epide- Control (2011) Risk assesssment on xenotropic 9. Alberts B (2011) Retraction. Science 334: 1636. miol Rec 86: 559–564. murine leukemia virus-related virus (XMRV) 10. Silverman RH, Das Gupta J, Lombardi VC, 19. Baker JP (2008) Mercury, vaccines, and autism: and its implications for blood donation. Stock- Ruscetti FW, Pfost MA, et al. (2011) Partial one controversy, three histories. Am J Public holm. retraction. Detection of an infectious retrovirus, Health 98: 244–253. 30. New Zealand Blood Service (2010) XMRV – A XMRV, in blood cells of patients with chronic 20. Stratton K, Gable A, Shetty P, McCormick M new transfusion transmitted infection? Blood fatigue syndrome. Science 334: 176. (2001) Immunization safety review. Committee, Issues, Issue 24.

PLOS Medicine | www.plosmedicine.org 4 April 2014 | Volume 11 | Issue 4 | e1001623