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Introducing the Endotype Concept to Address the Challenge of Disease

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Introducing the Endotype Concept to Address the Challenge of Disease Diabetes Care 1 Manuela Battaglia,1 Simi Ahmed,2 Introducing the Endotype Concept Mark S. Anderson,3 Mark A. Atkinson,4 Dorothy Becker,5 Polly J. Bingley,6 to Address the Challenge of Emanuele Bosi,1,7 Todd M. Brusko,4 Linda A. DiMeglio,8 PERSPECTIVES IN CARE Disease Heterogeneity in Carmella Evans-Molina,9 Stephen E. Gitelman,10 Type 1 Diabetes Carla J. Greenbaum,11 Peter A. Gottlieb,12 13 14 https://doi.org/10.2337/dc19-0880 Kevan C. Herold, Martin J. Hessner, Mikael Knip,15 Laura Jacobsen,16 Jeffrey P. Krischer,17 S. Alice Long,11 Markus Lundgren,18 Eoin F. McKinney,19 Noel G. Morgan,20,21 Richard A. Oram,22,23,24 Tomi Pastinen,25 Michael C. Peters,26 Alessandra Petrelli,1 Xiaoning Qian,27 Maria J. Redondo,28 Bart O. Roep,29,30 Desmond Schatz,16 David Skibinski,11 and Mark Peakman31,32 The clinical diagnosis of new onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable hetero- geneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrierbothtodecipheringpathogenesisandtothetranslational effortofdesigning, conducting, and interpreting clinical trials of disease-modifying agents. This re- alization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the “single disease” approach appears untenable, as does the notion of individualizing each single 1San Raffaele Diabetes Research Institute, IRCCS patient’s care, obliging us to conceptualize type 1 diabetes less in terms of San Raffaele Hospital, Milano, Italy phenotypes (observable characteristics) and more in terms of disease endotypes 2JDRF, New York, NY 3 (underlying biological mechanisms). Here, we provide our view on an approach to Diabetes Center, University of California, San Francisco, San Francisco, CA dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the 4Department of Pathology, Immunology, and data gathered to date, we aim to delineate a roadmap through which the field can Laboratory Medicine, University of Florida, Gain- incorporate the endotype concept into laboratory and clinical practice. We predict esville, FL 5 that such an effort will accelerate the implementation of precision medicine and has Division of Endocrinology and Diabetes, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA the potential for impact on our approach to translational research, trial design, and 6Translational Health Sciences, Bristol Medical clinical management. School, University of Bristol, Bristol, U.K. 7Vita-Salute San Raffaele University, Milan, Italy, and Department of Internal Medicine, IRCCS San Describing aspects of biology as “heterogeneous” often has a negative connotation. It Raffaele Hospital, Milan, Italy is a term that is used when we do not understand a measured or observed aspect of 8Division of Pediatric Endocrinology/Diabetology disease or when we need to explain data that are not consistent. However, it is evident and Wells Center for Pediatric Research, Depart- that recognizing that there are “different kinds” of cells, genes, types of response, and ment of Pediatrics, Indiana University School of Medicine, IN severity of disease could offer a set of opportunities for therapies to work and 9Herman B Wells Center for Pediatric Diabetes biomarkerstobemeaningful. Thus,itmaybetimetoexploitheterogeneityratherthan Research, Indiana University School of Medicine, curse it and to use the opportunity to carve out endotypes of type 1 diabetes that Indianapolis, IN 10 have traction both in the clinic and in the laboratory. Division of Pediatric Endocrinology and Diabe- “ ” tes, University of California, San Francisco, San The introduction of the term endotype can largely be attributed to developments Francisco, CA in the field of asthma (1) when it became apparent in the late 1990s that differ- 11Diabetes Program, Benaroya Research Insti- ent pathogenic mechanisms induce a similar symptom cluster and manifest as a tute, Seattle, WA Diabetes Care Publish Ahead of Print, published online November 21, 2019 2 An Approach to Heterogeneity in Type 1 Diabetes Diabetes Care phenotype; the implications being 1) that scope of this article, and therefore some insufficiently addressed in the design of there are multiple pathways to disease key examples are highlighted in Table 1, type 1 diabetes clinical trials, which typ- and 2) that pathway-specific therapeutic and others are expanded in ENDOTYPE DEF- ically adopt very basic and standard in- strategies will appear to have limited INITION LED BY OBSERVATIONS AND HYPOTHESES. clusion criteria (e.g., short time from success if applied to a population of Examples include continuous as well as disease onset, wide age range, single subjects in which the pathway is only qualitative variables and span the differ- autoantibody) to assure consistency, en- active in a subgroup. From this new ent stages of disease. Of note, traits are able cross-trial analysis and, at a prac- thinking, the term “endotype” was coined; often linked (e.g., age and HLA-specific tical level, to facilitate recruitment. Yet, in this case, the term reflects a subtype autoimmunity)insuchawaythatsuggests one can imagine that factors such as of type 1 diabetes that can be defined associations that could be built into dis- disease severity, age, and underlying by a distinct functional or pathobiological tinct pathobiological entities (endotypes). genetic predisposition could each influ- mechanism (that is also tractable ther- ence trial outcomes and treatment re- apeutically). THE IMPACT OF TYPE 1 DIABETES sponsiveness (“theratypes”) (5). These Here, we focus on gaining a better HETEROGENEITY ON CLINICAL are rarely, if ever, used as stratifiers understanding of heterogeneity in type TRIALS AND RESEARCH andwhenprespecified as covariates 1 diabetes and how the endotype concept An overarching goal of type 1 diabetes their utility is often limited by insuffi- might be introduced to the field in order research has been to bring forward cient statistical power. In practice, to bring about a sea change in clinical disease-modifying therapies that pre- whether a trial succeeds or fails in meet- practice and research activity. As the serve b-cell function (2). This has ing its primary objective(s), there are number of targeted immunotherapy been allied with progress made in often subgroups of subjects who appear treatments under development continue the design and conduct of interven- to benefit from the therapy. One such togrowandassociatedclinicaltrialactivity tion (stage 3) and prevention (stages example is monoclonal anti-CD3 anti- proceeds unabated, this is a propitious 1 and 2) trials. Despite some successes body (2). Despite promising results in moment in which to evaluate whether, and considerable knowledge gain, no phase II trials, a phase III trial with this and how, a strategic approach to disease agent has progressed beyond phase III agent did not meet its primary composite heterogeneity could unlock the power of clinical trials and into clinical practice, outcome of insulin use (,0.5 units/kg disease-modifying drugs designed to ar- and as such, type 1 diabetes remains an per day) and glycated hemoglobin A1c rest b-cell decline. Since the existence of outlier among the autoimmune dis- (,6.5%) at 1 year. However, some pa- heterogeneity in disease traits is a critical eases. Numerous factors account for tients appear to have responded rather component of the rationale for studying this, but it is our contention that disease well (i.e., younger subjects with higher endotypes, it is valuable to begin by heterogeneity contributes to this im- C-peptide at study entry and patients reflecting on the nature of type 1 diabetes passe in the field (3,4). from North America and Europe) diversity. Cataloguing all reported aspects Hitherto, the potential confound- (6). More recently, this approach has of heterogeneity in detail is beyond the ing effect of heterogeneity has been shown efficacy in prevention of diabetes 12Barbara Davis Center for Childhood Diabetes, 23NIHR Exeter Clinical Research Facility, Univer- Corresponding authors: Manuela Battaglia, University of Colorado School of Medicine, Au- sity of Exeter Medical School, Exeter, U.K. [email protected], and rora, CO 24Academic Renal Unit, Royal Devon and Exeter 13 Mark Peakman, [email protected] Department of Immunobiology, Yale Univer- NHS Foundation Trust, Exeter, U.K. sity, New Haven, CT 25 Received 2 May 2019 and accepted 14 October 14 Center for Pediatric Genomic Medicine, Child- Department of Pediatrics, Medical College of ren’s Mercy Kansas City, Kansas City, MO 2019 Wisconsin, Milwaukee, WI 26Division of Pulmonary and Critical Care Med- This article contains Supplementary Data online at 15 ’ Children s Hospital, University of Helsinki, Re- icine, Department of Medicine, and Cardiovas- http://care.diabetesjournals.org/lookup/suppl/ search Program for Clinical and Molecular Me- cular Research Institute, University of California, doi:10.2337/dc19-0880/-/DC1. tabolism, Helsinki University Hospital, Helsinki, San Francisco, San Francisco, CA S.A., M.S.A., M.A.A., D.B., P.J.B., E.B., T.M.B., L.A. Finland 27Department of Electrical and Computer Engi- 16Department of Pediatrics, University of Florida, D.M., C.E.-M., S.E.G., C.J.G., P.A.G., K.C.H., M.J.H., neering, TEES-AgriLife Center for Bioinformatics M.K., L.J., J.P.K., S.A.L., M.L., E.F.M., N.G.M., R.A. Gainesville, FL and Genomic Systems Engineering, Texas A&M 17HealthInformaticsInstitute,MorsaniCollegeof O., T.P., M.C.P., A.P., X.Q., M.J.R., B.O.R., D.Sc., University, College Station, TX and D.Sk.
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