Workshop on Flexible Models for Longitudinal and Survival Data with Applications in Biostatistics Warwick, 27-29 July 2015 Missing data and net survival analysis Bernard Rachet
General context Population-based, routine data Cancer registry data Clinical data tumour, treatment, comorbidity Cancer survival and roles played by patient, tumour and healthcare factors (very) large data sets, but incomplete information, which we have handled using multiple imputation procedure with Rubin s rules
Preliminary results of on-going work
Multiple imputation procedure Under Missing At Random (MAR) assumption 1. Impute the missing data from f data sets Y M Y O to give K complete 2. Fit the substantive model to each of the K data sets, to obtain K estimates of the parameters and estimates of their variance 3. Combine them using Rubin s rules
Multiple imputation steps Imputation Analysis Pooling Incomplete data Final results K completed data sets K analysis results
Pooling K estimates Rubin s rules Given K completed data sets, there are: K estimates with variance ˆk,k 2 ˆ k 1,...,K,k 1,...,K Pooled estimate Total variance ˆ ˆ V MI MI Wˆ 1 ˆ K 1 k within-imputation variance between-imputation variance K (1 k 1 K )Bˆ Wˆ Bˆ 1 K 1 K -1 K k 1 K k 1 2 k ( ˆ ˆ k MI 2 )
Multiple imputation procedure Congeniality 1. Imputation model congenial with substantive model 2. Given the substantive model from f Y X, f Y X g X is a congenial imputation model if both f and g are correctly specified 3. Valid inference (under MAR) if f Y X g X (approximately) represents data structure and substantive model
Concepts and measures of interest Aims Concepts Prognosis of a cancer and impact at population level Excess hazard Excess hazard ratio Net survival Crude probabilities of death from cancer and other causes Relative survival data setting Population-based data Expected mortality hazard from life tables By single year age and sex, and calendar year, geography, deprivation
Nur et al, 2009 - Settings Population-based cohort of colorectal cancer patients Complete information on age, sex, follow-up time, vital status, deprivation, comorbidity, surgical treatment Tumour stage, morphology and grade: 45% incomplete data Relative survival data setting λ x = λ P x + exp xβ Substantive model: generalised linear model (Dickman et al, Stat Med 2005) Link function log μ j d Pj = log y j + xβ d j ~Poisson μ j ; μ j = λ j y j ; y j person-time at risk d Pj expected number of deaths life tables Excess hazard ratio (+ Ederer-2 relative survival) Offset
Data description Variable Stage Patients Category No. % 29 563 100.0 I 2 193 12.3 II 7 326 41.0 III 7 726 43.2 IV 643 3.6 Missing 11 684 (39.5) Missing information associated with: Older ages More deprived categories Less treatment with curative intent Higher probability of death Morphology Adenocarcinoma 23 693 90.7 Mucinous and serous 2 314 8.9 Other 128 0.5 Neoplasm, NOS 1 3 428 (11.6) Grade I 3 212 14.5 II 16 047 72.4 III/IV 2 907 13.1 Missing 7 397 (25.0)
Missing information in several variables Multiple imputation using Full Conditional Specification (chained equations van Buuren, 1999) Same basic assumptions than in multiple imputation Assumes a joint (multivariate) distribution exists without specifying its form f Y, Y,..., Y f Y Y,..., Y i,1 i,2 i, p i, p i,1 i, p 1 f Y Y,..., Y... f Y Y f Y i, p 1 i,1 i, p 2 i,2 i,1 i,1 Imputation model (joint model for the data) Gibbs sampler to: 1. Estimate the parameters in the joint imputation model 2. Impute the missing data Y ~ N β, Ω Multivariate problem split into a series of univariate problems
Imputation models Outcomes Ordinal regression for stage and grade Polytomous regression for morphology Covariables Other two covariables with incomplete information Sex, age, deprivation, comorbidity, treatment, cancer site Vital status Follow-up time (years): piecewise function (0, 0.5, 1, 2, 3, 4, 5, 5+) Time-dependent effects (categorical) for deprivation and age Substantive (excess hazard) model includes all these variables (binary) time-dependent effects
Results Variable Stage Patients Data after imputation Category No. % % 29 563 100.0 I 2 193 12.3 10.1 II 7 326 41.0 36.1 III 7 726 43.2 47.4 IV 643 3.6 6.2 Missing 11 684 (39.5) Missing information associated with: Older ages More deprived categories Less treatment with curative intent Higher probability of death Morphology Adenocarcinoma 23 693 90.7 90.5 Mucinous and serous 2 314 8.9 8.9 Other 128 0.5 0.5 Neoplasm, NOS 1 3 428 (11.6) Grade I 3 212 14.5 13.6 II 16 047 72.4 72.0 III/IV 2 907 13.1 14.4 Missing 7 397 (25.0)
Results Complete-case analysis (16 223 cases) Five years** First year Second to fifth years Period since diagnosis over which EHR was estimated Multiple imputation (29 563 cases) Five years** First year Second to fifth years EHR 95% CI EHR 95% CI EHR 95% CI EHR 95% CI EHR 95% CI EHR 95% CI I 1.0 - - 1.0 - - II 3.6 2.7 4.7 2.6 2.2 3.0 III 10.2 7.7 13.5 7.0 5.9 8.4 IV 26.4 19.6 35.5 16.5 13.8 19.8 Missing 15 to 44 1.0 - - 1.0 - - 1.0 - - 1.0 - - 45 to 54 1.1 0.8 1.5 1.3 1.0 1.6 1.3 1.0 1.6 1.3 1.1 1.5 55 to 64 1.4 1.0 1.9 1.2 1.0 1.5 1.7 1.4 2.1 1.3 1.1 1.5 65 to 74 2.0 1.5 2.7 1.2 1.0 1.5 2.4 2.0 2.9 1.3 1.1 1.6 75 to 84 2.7 2.0 3.7 1.1 0.9 1.4 3.6 2.9 4.3 1.4 1.2 1.6 85 to 99 4.0 2.9 5.5 0.9 0.7 1.3 5.4 4.4 6.6 1.5 1.2 1.9 Other results Indicator approach Systematically underestimates variance of EHRs Overestimates EHRs for tumour morphology Underestimates EHRs for age and deprivation Does not identify time-dependent effects
Stage-specific survival Before imputation 100 100 After imputation 80 80 60 40 Relative survival (%) 60 40 20 20 0 I II III IV missing 0 1 2 3 4 5 Years since diagnosis 0 I II III IV 0 1 2 3 4 5 Years since diagnosis
Limitations Tutorial paper no systematic evaluation Relatively simple substantive model piecewise model categorical variables Further recent methodological developments in: multiple imputation net survival, flexible modelling More systematic evaluation simulations
Concepts and measures of interest Excess hazard λ E t = λ O t λ P t λ O t dt = dnw t ; λ Y W t P t dt = i=1 n Net survival S E t = e 0 Crude mortality F C t = 0 W t = 1 S Pi t t λe u du t S O u λ E u du Yi W t λpi t Y W t Expected probability of surviving up to t
Modelling approach Flexible multivariable excess hazard model Excess hazard Time-dependent and non-linear effects (splines) Variables affecting both mortality processes (cancer and other causes of death) included in the model Net survival is the mean of individual net survival functions predicted by the model
Multiple imputation procedure Congeniality 1. Imputation model congenial with substantive model 2. Given the substantive model from f Y X, f Y X g X is a congenial imputation model if both f and g are correctly specified 3. Valid inference (under MAR) if f Y X g X (approximately) represents data structure and substantive model 4. Problematic within net survival setting and with nonlinear and time-dependent effects
Falcaro et al, 2015 Study settings Data 44,461 men diagnosed with a colorectal cancer in 1998-2006, followed up to 2009 Age at diagnosis (continuous), tumour stage (4 categories), deprivation (5 categories) Missing stage: 30% MCAR logit Pr MAR on X logit Pr MAR logit Pr R i = 1 Z i = δ 0 R i = 1 Z i = α 0 + α 1 (age i 60) R i = 1 Z i = γ 0 + γ 1 (age i 60) + γ 2 T i + γ 3 D i R = 1 if stage missing 100 simulated data sets per scenario
Distribution on fully observed data and empirical expected distribution in remaining complete records
Substantive model Flexible log cumulative excess hazard model ln Λ E t x i = s 1 ln t ; γ 1, k 1 + β x i + s 2 age i ; γ 2, k 2 Flexible functions: restricted cubic splines Baseline excess hazard: 5 df, 4 internal knots and 2 boundary knots Age (continuous): 3 df, 2 internal knots Covariables: deprivation and stage Aims: estimate effect of stage (log EHR) and stage-specific net survival at 1, 5 and 10 years since diagnosis
Imputation models Outcome (stage) Ordinal or multinomial logistic regression Covariables Survival time and log(survival time) or Nelson-Aalen estimate of the cumulative hazard Event indicator Age splines defined as in the substantive model Deprivation dummy variables 30 imputations Net survival: Rubin s rules applied on log log S E t to obtain approximate normality, then back-transformed
Multiple imputation strategy Multiple Imputation Strategy Functional Form How Survival Is Modeled in the Imputation MI_ologit_surv Ordinal logistic Survival time and log survival time MI_ologit_na Ordinal logistic Nelson-Aalen estimate of cumulative hazard MI_mlogit_surv Multinomial logistic Survival time and log survival time MI_mlogit_na Multinomial logistic Nelson-Aalen estimate of cumulative hazard
Results Bias in log excess hazard ratio estimates for stage (reference stage 1), 100 replications Poor results with ordered logit even under MCAR scenario
Stage-specific net survival at 1 year, 100 replications
Results Bias in stage-specific net survival estimates at 1 year, 100 replications
Comments Promising results despite that the parameter estimated in the substantive model (here excess hazard) does not correspond to the final outcome of interest (net survival) Limitations No time-dependent effects of stage Which joint model? Which variables in the imputation models? Vital status Nelson-Aalen estimates of cumulative hazard Interactions with time since diagnosis (age at diagnosis, deprivation ) Other relevant interactions (tumour stage, region ) other factors (treatment variables, co-morbidities, hospital volume, surgeon s experience )
Limitations and challenges: preliminary study Simulated data set colon cancer, 12,048 men followed up at least 5 years Baseline excess hazard: 5 df, 4 internal knots Covariables: stage, deprivation, age Time-dependent effects of stage: 2 df, 1 internal knot for each higher stage Non-linear effects of age: 3 df, 2 internal knots Substantive model ln Λ E t x i = s 1 ln t ; γ 1, k 1 + β x i + s 2 age i ; γ 2, k 2 + s 3j stage j t ; γ 3, k 3 Missing stage simulated as in previous example 100 data sets per scenario, with 30% missing stage Focus on MAR here
Limitations and challenges: preliminary study Time (year) Net Survival function Complete MAR Stage 1 1 0.95 0.99 5 0.91 0.99 2 1 0.90 0.97 5 0.78 0.90 3 1 0.77 0.86 5 0.46 0.59 Simulation of missingness mechanisms as in previous example Same imputation model was applied (multinomial, Nelson-Aalen) 4 1 0.32 0.41 5 0.06 0.09
Results Excess hazard ratios for stage 3.5 Tumour stage 2 (reference stage 1) 3 2.5 2 1.5 1.5 0 True EHR Complete-case EHRs Imputed EHRs 0 1 2 3 4 5 Time since diagnosis (years)
Results Excess hazard ratios for stage 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Tumour stage 3 (reference stage 1) True EHR Complete-case EHRs Imputed EHRs 0 1 2 3 4 5 Time since diagnosis (years)
Results Excess hazard ratios for stage 60 55 50 45 40 35 30 25 20 15 10 5 0 Tumour stage 4 (reference stage 1) True EHR Complete-case EHRs Imputed EHRs 0 1 2 3 4 5 Time since diagnosis (years)
Results Stage-specific net survival 1 Tumour stage 1.9.8.7.6.5.4.3.2.1 0 0 1 2 3 4 5 Time since diagnosis (years)
Results Stage-specific net survival 1 Tumour stage 2.9.8.7.6.5.4.3.2.1 0 0 1 2 3 4 5 Time since diagnosis (years)
Results Stage-specific net survival 1 Tumour stage 3.9.8.7.6.5.4.3.2.1 0 0 1 2 3 4 5 Time since diagnosis (years)
Results Stage-specific net survival 1 Tumour stage 4.9.8.7.6.5.4.3.2.1 0 0 1 2 3 4 5 Time since diagnosis (years)
Conclusion and development Why MI? Strength: clear division between imputation and analysis stages both efficiency and MAR plausibility increased Challenge: incompatibility between imputation and substantive models asymptotically biased estimates Define joint model for flexible excess hazard models Multiple imputation by fully conditional specification with substantive model compatible algorithm (SMC-FCS) Bartlett JW et al. Statistical Methods in Medical Research 2015
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