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O  =nFA workshop introducing doubly robust estimation of treatment effectsGG$ cJConflict of Interest Statement+Macro development funded by the Agency for Healthcare Research and Quality via a supplemental award to the UNC CERTs (U18 HS10397-07S1) Additional support from the UNC/GSK Center for Excellence in Pharmacoepidemiology and Public Health. No potential conflicts of interest with respect to this work.,Z,o <Regression models assume that& (The parametric form is correct. Should we use logistic regression, or log- binomial? We have included correct predictors. Should we really include age in this model? Those predictors have been specified correctly. Should age be coded continuously or in 10 year categories? Is there an interaction with race? What about higher order terms? Etc&  Z7Z%Z-Z0ZZ 7f%-f0  fWhat if the model is wrong?~Lunceford & Davidian, Stat Med, 2004 Omit a true confounder (extreme example) True relationships known (simulated data) Vary associations between Risk factor  outcome Confounder  exposure 6,,$ "ML outcome regression: false model##  ADoubly robust (DR) estimator: false model for outcome regressionBB  !ML outcome regression: true model""  :DR: true models for propensity score & outcome regression;;  "ML outcome regression: false model##  IDR: true model for propensity score & false model for outcome regressionJJ  /Doubly robust (DR) estimation from 30,000 feet00(Robins & colleagues recognized the doubly robust property in mid-90 s Combines standardization (or reweighting) with regression Part of the family of methods that includes propensity scores and inverse probability weightingZE5Conceptual description$Doubly robust (DR) estimation uses two models: Propensity score model for the confounder - exposure (or treatment) relationship Outcome regression model for the confounder  outcome relationship, under each exposure condition These two stages can use: different subsets of covariates, and different parametric forms. If either model is correct, then the DR estimate of treatment effect is unbiased./PPPPPPEPPRPP/EQ0* Two stages Causal effect of interestComparing counterfactual scenarios E(Y1): Whole population treated (exposed) vs. E(Y0): Whole population untreated (unexposed) Average causal effect of treatment E(Y1)  E(Y0) : difference E(Y1) / E(Y0) : ratio In non-randomizes studies, the unexposed may not fairly reflect what would have happened to the exposed had they been unexposed (confounding)$Z]Z$Z1ZZ$ . *$     F6Doubly robust estimatorY: outcome Z: binary treatment (exposure) X: baseline covariates (confounders plus other prognostic factors) e(X,): model for the true propensity score m0(X,0) and m1(X,1): regression models for true relationship between covariates and the outcome within each strata of treatment Causal effect of interest (deltaDR): difference in mean response if everyone in the population received treatment versus everyone receiving no treatment; E(Y1)-E(Y0). Z C%o#z  ,o`Doubly robust estimator afAverage population response with treatment (1,DR)*4.( ((-  )True PS model; false regression model (I)**  b*True PS model; false regression model (II)++  )False PS model; true regression model (I)**  *False PS model; true regression model (II)++  h VDR = [E(Y1) + junk] - [E(Y0) + junk],Px   +Standard errors4Option 1: Sandwich estimator Option 2: BootstrapSimulation findingsBang & Robins 2005 N=500, 1000 iterations False propensity score model 1 of 4 true predictors of tx 1  noise variable, independent of tx False outcome regression model Omit one risk factor, an higher order term and an interaction term jGZCZZCZZGCC,a$dBias under false modelsVariance under false models#Recapping L&D simulationsCompare performance of propensity score analysis, IPW, outcome regression (OR) and DR Omit a true confounder (extreme example) True relationships known (simulated data) Vary associations between Risk factor  outcome Confounder  exposure Vary sample size <,,.If all models are true& (LBias <3% for all methods except for PS analysis using strata (due to residual confounding) Variance similar in general VarOR < VarDR (slightly) if confounder-exp relationship is strong VarDR < VarIPW If OR model is right, most efficient. But we have no way of knowing whether or not it s right.tZBZZQZ_ZBQ_fZ5`JIf outcome regression model is false& &&$jBias DR always <1%; OR biased by 10-20% in most scenarios Efficiency DR nearly as efficient as correct model except when conf-exp relationship strong DR always more efficient than IPW Confidence interval coverage DR coverage nominal ML coverage poor Adding risk factors to PS model improves precision If both are nearly right (only a little wrong), bias is smallP5oP PsoPP%oPqP&5& &s&&%&q&{ DiscussionIf method offers some protection against model misspecification, why isn t it being used by pharmacoepidemiologists?\SAS macro for DR estimationObjectives Facilitate wider use of DR estimation Improve performance by implementing sandwich estimator for SEs Enhance usability by following SAS conventions Provide user with relevant diagnostic details &  l`  iRunning the DR macroBy design, the DR macro uses common SAS syntax for specifying the source dataset, variables for modeling, and additional options: %dr(%str(options data=SAS-data-set descending; wtmodel exposure = x y z / method=dr dist=bin showcurves; model outcome = x y z / dist=n ; ) ); $ Z ,P# -jRunning the DR macro%dr(%str(options data=SAS-data-set descending; wtmodel exposure = x y z / method=dr dist=bin showcurves; model outcome = x y z / dist=n; ) ); )P  (kRunning the DR macro%dr(%str(options data=SAS-data-set descending; wtmodel exposure = x y z / method=dr dist=bin showcurves; model outcome = x y z / dist=n; ) ); )P  (lRunning the DR macro%dr(%str(options data=SAS-data-set descending; wtmodel exposure = x y z / method=dr dist=bin showcurves; model outcome = x y z / dist=n; ) );  )P  )mDR macro: output nDR macro: output oExample analysisCVD Outcomes Continuous: CVD score (i.e. LDL) Binary: acute MI Exposure (treatment): statin use (yes/no) 50% of population exposed 10 covariates (5 continuous, 5 binary) Data are simulated, so true relationships among exposure, covariates & outcome are knownj 2* 2*UpExample analysis qTPropensity scores from  showcurves option"+*  .       rResults from sample analysis"$$  sValidation: simulation methodsDraw random sample (n) from simulated population Vary n from 100 to 5000 Estimate doubly robust effect of treatment and standard error Repeat 1000 timesZ1PPtContinuous outcome uContinuous outcome vContinuous outcome wDichotomous outcome xDichotomous outcome yDichotomous outcome ]FCaveatsSEs conservative when sample size is small; bootstrapping may be used in this case to get more appropriate SEs Macro only provides difference estimates (not RR or OR) for now Exposure must be dichotomous; outcome must be continuous or dichotomous (time-to-event analysis not supported) Some SAS conventions not recognized within the macro code where and class statements not recognized interaction terms and higher order polynomials must be created in a prior data step PP:P~PPP:o6h52Practical considerationsHow to choose which covariates to include? Good question. Based on simulations from PS literature Include all risk factors for outcome May omit predictors of tx that do not affect outcome:+7Z+7ZPractical considerations  Practical considerationsWhat sort of diagnostics should be checked? Potentially influential obs with extreme PS values  common_support option in SAS macro Distribution of PS scores stratified by treatment / exposure group  showcurves option in SAS macrob,3%C!,3%C! >DZ Checking PS distribution Checking PS distribution Checking PS distribution | LimitationsDR estimation is not a panacea for unmeasured confounding. Recall-  junk only reduces to 0 with assumption of no unmeasured confounders One of the models must be correct for the estimator to be unbiased Bang & Robins suggest that it will be minimally biased if both models are nearly right& Standard errors tend to be slightly larger compared to a single correctly specified regression model Explaining DR estimation in your methods section could be interesting& ~;PPNPPCPPXPPPP;NCX>/ ApplicationsDR estimation potentially valuable for comparative effectiveness studies, and in particular for head-to-head comparisons of treatment effectiveness or adverse events from observational data when RCTs can t or won t be done... for ethical reasons, for economic reasons, for reasons of rare or late-effect outcomes, or for reasons of the need to conduct faster analyses of possible sentinel events>0Z0ZZ ExtensionsiMissing data Incomplete follow-up in RCTs Longitudinal marginal structural models Goodness of fit test? 6 @ @%AB3SummaryObservational studies of treatment effects depend on statistical models to disentangle causal effects from confounding We can never be certain that the statistical model we have chosen is correct DR estimate unbiased if at least one of the two component models is right and therefore provides some protection against model misspecification The  price of double robustness is slightly larger standard errors than a single correctly specified regression model Assumption of no unmeasured confounders requiredPZA2 References* Bang, H. & J.M. Robins: Doubly-robust estimation in missing data and causal inference models. Biometrics 2005, 61, 962 973. Lunceford, J. K. and Davidian, M. (2004). Stratification and weighting via the propensity score in estimation of causal treatment effects: A comparative study. Statistics in Medicine 23, 2937 2960. Robins, J. M. (2000). Robust estimation in sequentially ignorable missing data and causal inference models. Proceedings of the American Statistical Association Section on Bayesian Statistical Science, 6 10. Robins, J. M., Rotnitzky, A., and Zhao L. P. (1994). Estimation of regression coefficients when some regressors are not always observed. Journal of the American Statistical Association 89, 846 866. Rotnitzky, A., Robins, J. M., and Scharfstein, D. O. (1998). Semiparametric regression for repeated outcomes with nonignorable nonresponse. Journal of the American Statistical Association 93, 1321 1339. Scharfstein, D. O., Rotnitzky, A., and Robins, J. M. (1999). Adjusting for nonignorable drop-out using semiparametric nonresponse models. Journal of the American Statistical Association 94, 1096 1120 (with Rejoinder, 1135 1146). Van der Laan, M. J. and Robins, J. M. (2003). Unified Methods for Censored Longitudinal Data and Causality. New York: Springer-Verlag. Z:}   M X  '  B  /  is;-Acknowledgements/Chris Wiesen, PhD, Odum Institute for Research in Social Science, University of North Carolina, Chapel Hill, NC Daniel Westreich, MSPH, Department of Epidemiology, University of North Carolina, Chapel Hill, NC Marie Davidian, PhD, Department of Statistics, North Carolina State University, Raleigh, NCl0PZ#\I GPa XO}Acknowledgements (II)ZAgency for Healthcare Research and Quality Supplemental Award to the UNC CERTs (U18 HS10397-07S1) UNC/GSK Center for Excellence in Pharmacoepidemiology and Public Health Kevin Anstrom, Lesley Curtis, Brad Hammill, and Rex Edwards from the Duke CERTs team for valuable feedback on the alpha version. Thanks to students from UNC s EPID 369/730, a causal modeling course, for valuable feedback on the beta version. Presented in memory of Harry Guess, MD, PhD, 1940-2006, who co-authored the initial proposal to develop a SAS macro for doubly robust estimation..PP.bIb JI9Contact InformationMichele Jonsson Funk, PhD Research Assistant Professor Department of Epidemiology University of North Carolina Chapel Hill NC 27599-7521 mfunk@unc.edu 919-966-8431 (ph) 919-843-3120 (fax) http://www.harryguess.unc.edu F(" d, 0~Questions & Discussion0 /1C ^"#$%&'()*+,-./01235679;<=?@ABDEGHOPRSTVWY[_`a bcdefghi j$m.n/o0p2  0` fff33` 3KI3ff` 33ff` /p` 3%*3|` Jy3fff3f` 3ff3̙` 33ff33` DDyq3f` ̙3n` w3ff` }ff>?" dd@,?nKd@ P nA@F`d n?" dd@   @@``PR"   @ ` `2p>> V N  (    T!e!e #" ``   J* 0    T!e!e #" `` `  J* 0  TZ X # "X  # l !e!ed#" `P *   Tؿ!e!ed#" `U (   <Ó!e!e"UY 6"0   <|Ǔ!e!e"YW 6"0    <˓!e!e"YU 6"0    <lΓ!e!e" 6"0    <ғ!e!e#" `SV (    <Փ!e!e"Y 6"0    <Hٓ!e!e"X 6"0   T ܓ!e!e #" `  `  T Click to edit Master title style! !B  Nޓ!e!e " `p  RClick to edit Master text styles Second level Third level Fourth level Fifth level!     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JOR @` t <?   JPS @` t <? p P0.00 @`  t <?  D @`  t <?   P0.86 @`  t <? 0p P0.92 @`  t <\? p Q-0.09 @`  t <P? p P0.00 @` t < ?> p HDR @` t <? 0  @ @` t <DK?   Q-1.56 @` t <x K?  P0.00 @` t <K?>   HOR @` t <K?0  @ @` t <T#K?   D @` t <,K?  R-0.01  @` t <h5K?>  HPS @` t <h7K? 0 S False Model   @` t <@GK?  w True Model(s) @` t <AK?> UAnalysis Method @``B t 0o ?>0ZB t s *1 ?> 0 ZB t s *1 ?> 0 `B t 0o ?>p0p`B t 0o ?>>pZB t s *1 ?pZB  t s *1 ?  p`B !t 0o ?00pZB "t s *1 ?>0ZB #t s *1 ?  pZB $t s *1 ?pZB %t s *1 ? 0 &t B4UKT b&H Bang & JM Robins, Biometrics (2005). '0 '# H t 0޽h ? }ff___PPT10i..+D=' ^= @B + a 0 `%&|6(  |x | c $>K  `  K  >@p |# #"&>@p K | <gK?@ JBoth @` | <oK?,  HOR @` | <xK? ,  HPS @` | <K? , p P0.08 @`  | <K? ,  D @`  | < p HDR @` | <K? @  @ @` | <K?,   P0.07 @` | <K?   P0.07 @` | <K?>   HOR @` | <K?@  @ @` | <XK?,   D @` | <K?  Q0.21  @` | <lK?>  HPS @` | <L? @ S False Model   @` | < L?  P True Model   @` | <L?> NAnalysis   @``B | 0o ?>@ZB | s *1 ?> @ ZB | s *1 ?> @ `B | 0o ?>p@p`B | 0o ?>>pZB | s *1 ?pZB  | s *1 ?  p`B !| 0o ?@@pZB "| s *1 ?>@ZB #| s *1 ?, , pZB $| s *1 ?pZB %| s *1 ? @ &| BL0\ b&H Bang & JM Robins, Biometrics (2005). 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    s On-screen Showu AA ITimes New RomanArial Wingdings Arial Black Courier NewSAS MonospacePixelMicrosoft Graph ChartGA workshop introducing doubly robust estimation of treatment effectsConflict of Interest Statement!Regression models assume that…What if the model is wrong?#ML outcome regression: false modelBDoubly robust (DR) estimator: false model for outcome regression"ML outcome regression: true model;DR: true models for propensity score & outcome regression#ML outcome regression: false modelJDR: true model for propensity score & false model for outcome regression0Doubly robust (DR) estimation from 30,000 feetConceptual description Two stagesCausal effect of interestDoubly robust estimatorDoubly robust estimator5Average population response with treatment (μ1,DR)*True PS model; false regression model (I)+True PS model; false regression model (II)*False PS model; true regression model (I)+False PS model; true regression model (II) Slide 22Standard errorsSimulation findingsBias under false modelsVariance under false modelsRecapping L&D simulationsIf all models are true…(If outcome regression model is false… DiscussionSAS macro for DR estimation Slide 32Running the DR macroRunning the DR macroRunning the DR macroRunning the DR macroDR macro: outputDR macro: outputExample analysisExample analysis/Propensity scores from ‘showcurves’ optionResults from sample analysisValidation: simulation methodsContinuous outcomeContinuous outcomeContinuous outcomeDichotomous outcomeDichotomous outcomeDichotomous outcomeCaveatsPractical considerationsPractical considerationsPractical considerationsChecking PS distributionChecking PS distributionChecking PS distribution Limitations Applications ExtensionsSummary ReferencesAcknowledgementsAcknowledgements (II)Contact InformationQuestions & Discussion  Fonts UsedDesign TemplateEmbedded OLE Servers Slide TitlesA 8@ _PID_HLINKSA86/http://www4.stat.ncsu.edu/~davidian/double.pdf/http://www4.stat.ncsu.edu/~davidian/double.pdf/http://www4.stat.ncsu.edu/~davidian/double.pdf/http://www4.stat.ncsu.edu/~davidian/double.pdf/http://www4.stat.ncsu.edu/~davidian/double.pdf/http://www4.stat.ncsu.edu/~davidian/double.pdf/http://www4.stat.ncsu.edu/~davidian/double.pdf/http://www4.stat.ncsu.edu/~davidian/double.pdf/http://www4.stat.ncsu.edu/~davidian/double.pdf,_f0Michele Jonsson FunkMichele Jonsson Funk  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      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