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• W2175752811 abstract "Personalized MedicineVol. 12, No. 6 EditorialFree AccessEvidence-based and precision medicine: the quest for pragmatic balance in autismStelios Georgiades & Peter SzatmariStelios Georgiades*Author for correspondence: E-mail Address: georgis@mcmaster.ca Offord Centre for Child Studies, McMaster University, 1280 Main St W MIP 201A, Hamilton, ON, L8S 4K1, CanadaSearch for more papers by this author & Peter Szatmari The Hospital for Sick Children, Centre for Addiction & Mental Health, University of Toronto, Toronto, ON, CanadaSearch for more papers by this authorPublished Online:3 Nov 2015https://doi.org/10.2217/pme.15.35AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: autism spectrum disorder • evidence-based medicine • precision medicineDuring the past year, two major events occupied much of our thinking and discussions as clinicians and scientists: on 20 January 2015, US President Barack Obama launched the precision medicine initiative; on 13 May 2015, Dr David Sackett, the ‘father’ of evidence-based medicine (EBM) passed away after a long and fruitful career.Simply put, precision medicine is a paradigm based on the idea that medical treatment should be tailored to the characteristics of subgroups of patients [1]; it has its origin in the evidence that better treatment for cancer is possible if one takes into account the genomic signature of the disease. EBM is a paradigm emphasizing that decisions about treatment should be based on a combination of evidence from well-designed, conducted and preferably replicated research, as well as from the clinical skills of the healthcare professional, and the patient's hopes, values and particular situation [2].In this editorial, we argue that based on the state of knowledge in autism spectrum disorder (ASD), at least for now, precision medicine sounds more like an ambitious idea rather than a feasible approach. At the same time, recognizing that the ASD field will be influenced by the precision medicine initiative, we propose that the two paradigms – evidence-based and precision medicine – can be more beneficial if they can ‘learn to exist’ in a symbiotic rather than a competitive relationship. And to achieve that we will have to strike a pragmatic balance between them!Although both, evidence-based and precision medicine, share a similar overarching objective – to improve treatment of disorder – the ‘research maps’ we are drawing to get to these largely unknown destinations might be ‘positioning’ them further apart than they should be. In fact, unless we try to first envision the bridge that links the two paradigms together, we might end up with incompatible outputs that cannot be integrated to address the health needs they originally set out to address.A reasonable lay stereotype is that precision medicine is born in a wet-lab while EBM is raised in a clinic. This simple stereotype serves as a reminder that the two paradigms might in fact be separated by the ‘valley of death’, a metaphoric representation of the systematic and vast translation gap between basic science research and clinical practice [3]. In the case of ASD, despite the fact that it is considered a disorder with strong genetic basis, this gap has been historically too big. For example, the breathtaking advances in genetics, neuroimaging and animal models in the field of ASD have yet to be followed by major advances in clinical treatments informed from these discoveries.At the moment, perhaps the biggest barrier to developing and implementing effective treatments in ASD is its clinical and biological heterogeneity. As a result, a given treatment may work for some subgroups of ASD patients but not for others [4]. Precision medicine seems uniquely poised to solve that problem as it proposes that by identifying subgroups with more homogeneous characteristics, more ‘precise’ treatments can be developed. The problem is that we cannot yet identify those characteristics in ASD the way we often can in cancer. In ASD, we do not have biomarkers that reflect pathogenesis and that can provide a target for more effective treatment than ‘treatment as usual’ (TAU). In other words, characteristics that identify variation in response to treatment have not been systematically studied in ASD intervention research [5]. What we have instead are clinical characteristics (or specifiers; see DSM-5; [6]) that may function as proxy biomarkers for treatment response: IQ, language ability, comorbid psychopathology, among others. [4]. Presumably, these characteristics (or specifiers) reflect variation at a biological level that may (or may not) reflect variation in pathogenesis corresponding to variation in treatment response. But these are important questions that will have to be tested empirically.So, according to the EBM paradigm, to change clinical practice one would have to ideally conduct large randomized clinical trials that compare the ‘new treatment’, now delivered to a subgroup, to TAU delivered to the heterogeneous ASD population. But if within the exciting new framework of precision medicine most ‘new treatments’ are the outcome of biological/genetic research, any attempt to compare the ‘old’ and the ‘new’ would look like trying to compare apples and oranges unless we design complex randomized controlled trials (RCTs) that incorporate both screening and treatment. In other words, to test whether a new treatment developed using the precision medicine initiative is more effective than TAU, the EBM paradigm would urge us to conduct RCTs in which the two arms would be: screening for markers that predict differential response to treatment and then providing that treatment versus TAU. Of course some of those participants in the screening arm will screen negative and also receive TAU so the size of the experimental arm will have to be large enough to be able to detect statistically significant and clinically meaningful differences in outcome [7].Ultimately, to achieve improved outcomes based on precision medicine, researchers will not only have to make new discoveries (e.g., through genomic and biotechnology advances) but would also need to conduct large follow-up studies including randomized trials, something that is at the core of EBM [8].The question that arises from the aforementioned is whether the field of ASD (and neurodevelopmental disorders more generally) is ready for the ambitious idea of precision medicine. As noted earlier, there is no doubt that ASD is characterized by remarkable heterogeneity both at the clinical/behavioral and biological level [9]. But do we really know enough about what that heterogeneity means to be able to use it as ‘informative variance’ to classify patients with ASD into meaningful and valid subgroups (or subtypes) that could benefit from tailored therapeutics? These authors’ ‘gut response’ to that question is ‘not yet’.So before we rush to jump on the precision medicine wagon, perhaps a more timely (and potentially useful) question we should be focusing on could be “What are the barriers (and how those can be removed or avoided) to bridging the gap between basic science research and clinical practice in ASD”. That of course is not a new question but it is a question that is becoming more and more ‘endangered’, threatened to be extinguished by the attractive idea of medicine that is both ‘precise’ and ‘cheap’ as the price of biotechnology products keeps dropping. Answering that question will be the first step toward a carefully researched, beneficial, pragmatic balance between evidence-based and precision medicine in ASD.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Collins FS, Varmus H. A new initiative on precision medicine. N. Engl. J. Med. 372(9), 793–795 (2015).Crossref, Medline, CAS, Google Scholar2 Sackett DL, Rosenberg WM, Gray JA et al. Evidence based medicine: what it is and what it isn't. BMJ 312(7023), 71–72 (1996).Crossref, Medline, CAS, Google Scholar3 Szatmari P, Charman T, Constantino JN. Into, and out of, the “valley of death”: research in autism spectrum disorders. J. Am. Acad. Child. Adolesc. Psychiatry 51(11), 1108–1112 (2012).Crossref, Medline, Google Scholar4 Anagnostou E, Zwaigenbaum L, Szatmari P et al. Autism spectrum disorder: advances in evidence-based practice. CMAJ 186(7), 509–519 (2014).Crossref, Medline, Google Scholar5 Warren Z, McPheeters ML, Sathe N et al. A systematic review of early intensive intervention for autism spectrum disorders. Pediatrics 127(5), e1303–e1311 (2011).Crossref, Medline, Google Scholar6 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th Edition). American Psychiatric Publishing, Arlington, VA, USA (2013).Crossref, Google Scholar7 Ruberg SJ, Chen L, Wang Y. The mean does not mean as much anymore: finding sub-groups for tailored therapeutics. Clin. Trials 7(5), 574–583 (2010).Crossref, Medline, Google Scholar8 Khoury MJ, Evans JP. A public health perspective on a national precision medicine cohort: balancing long-term knowledge generation with early health benefit. JAMA 313(21), 2117–2118 (2015).Crossref, Medline, CAS, Google Scholar9 Georgiades S, Szatmari P, Boyle M. Importance of studying heterogeneity in autism. Neuropsychiatry 3(2), 123–125 (2013).Crossref, Google ScholarFiguresReferencesRelatedDetailsCited ByPrecision Medicine Informatics: Principles, Prospects, and ChallengesIEEE Access, Vol. 8Public health and precision medicine share a goal30 May 2017 | Journal of Evidence-Based Medicine, Vol. 10, No. 2 Vol. 12, No. 6 STAY CONNECTED Metrics History Published online 3 November 2015 Published in print November 2015 Information© Future Medicine LtdKeywordsautism spectrum disorder • evidence-based medicine • precision medicineFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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