title: A framework for the analysis of heterogeneity of treatment effect in patient-centered outcomes research.
abstract: Individuals vary in their response to a treatment. Understanding this heterogeneity of treatment effect is critical for evaluating how well a treatment can be expected to work for an individual or a subgroup of individuals. An overemphasis on hypothesis testing has resulted in a dichotomy of all heterogeneity of treatment effect analyses into confirmatory (hypothesis testing) and exploratory (hypothesis finding) analyses. This limited view of heterogeneity of treatment effect is inadequate for creating evidence that is useful for informing patient-centered decisions. An expanded framework for heterogeneity of treatment effect assessment is proposed. It recognizes four distinct goals of heterogeneity of treatment effect analyses: hypothesis testing, hypothesis finding, reporting subgroup effects for meta-analysis, and individual-level prediction. Accordingly, two new types of heterogeneity of treatment effect analyses are proposed: descriptive and predictive. Descriptive heterogeneity of treatment effect analyses report treatment effects for prespecified subgroups in accordance with prospectively specified analytic strategy. They need not be powered to detect heterogeneity of treatment effect. They emphasize estimation and reporting of subgroup effects rather than hypothesis testing. Sampling properties (e.g., standard error) of descriptive analysis can be characterized, thus facilitating meta-analysis of subgroup effects. Predictive heterogeneity of treatment effect analyses estimate probabilities of beneficial and adverse responses of individuals to treatments and facilitates optimal treatment decisions for different types of individuals. Procedures are also suggested to improve reliability of heterogeneity of treatment effect assessment from observational studies. Heterogeneity of treatment effect analysis should be identified as confirmatory, descriptive, exploratory, or predictive analysis. Evidence should be interpreted in a manner consistent with the analytic goal.
authors: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. rvaradhan@jhmi.edu
authors: Ravi
authors: R
authors: Varadhan
authors: Jodi B
authors: JB
authors: Segal
authors: Cynthia M
authors: CM
authors: Boyd
authors: Albert W
authors: AW
authors: Wu
authors: Carlos O
authors: CO
authors: Weiss
mesh_terms: D057186:Comparative Effectiveness Research / Q000379:methods*; D003627:Data Interpretation, Statistical; D006801:Humans; D015201:Meta-Analysis as Topic; D017063:Outcome Assessment, Health Care / Q000379:methods*; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results
references: Clin Trials. 2005;2(4):276-81; discussion 364-78
references: 16281425
references: Health Serv Res. 2010 Feb;45(1):283-301
references: 19929962
references: N Engl J Med. 2011 Oct 13;365(15):e31
references: 21992473
references: N Engl J Med. 1996 Jul 25;335(4):217-25
references: 8657237
references: N Engl J Med. 2001 Dec 6;345(23):1667-75
references: 11759645
references: Stat Med. 2012 Sep 28;31(22):2552-64
references: 21976358
references: JAMA. 1991 Jul 3;266(1):93-8
references: 2046134
references: BMJ. 2010 Mar 30;340:c117
references: 20354011
references: J Natl Cancer Inst. 2000 Oct 4;92(19):1561
references: 11018090
references: Stat Med. 1985 Jul-Sep;4(3):255-63
references: 4059716
references: Lancet. 2005 Jan 8-14;365(9454):176-86
references: 15639301
references: N Engl J Med. 2008 Oct 23;359(17):1757-65
references: 18946061
references: J Gen Intern Med. 2011 Jul;26(7):783-90
references: 21286840
references: Biostatistics. 2011 Apr;12(2):270-82
references: 20876663
references: Trials. 2010 Aug 12;11:85
references: 20704705
references: Am J Manag Care. 2010 May 01;16(5):e131-3
references: 20455639
references: Biometrics. 1980 Jun;36(2):337-42
references: 7407321
references: BMJ. 2011 Oct 03;343:d5888
references: 21968126
references: N Engl J Med. 2007 Nov 22;357(21):2189-94
references: 18032770
references: J Am Coll Cardiol. 2012 Feb 7;59(6):572-82
references: 22300691