The role of stage at diagnosis in colorectal cancer racial/ethnic - PowerPoint PPT Presentation

The role of stage at diagnosis in colorectal cancer racial/ethnic survival disparities - A causal inference perspective Linda Valeri Psychiatric Biostatistics Laboratory Harvard Medical School / McLean Hospital June 27th, 2016

Acknowledgments My collaborators at the Harvard T.H. Chan School of Public Health - Biostatistics Department Brent Coull Tyler VanderWeele - Epidemiology Department Xabier Garcia-Albeniz - Social and Behavioral Sciences Department Jarvis Chen Nancy Krieger

Background ¡ ◮ The identification and elimination of disparities in cancer-related outcomes remain among NCI’s highest priorities. ◮ Research in clinical populations and cohort studies have documented that such disparities exist across the cancer continuum. ◮ However, gaps in knowledge remain as to the extent of cancer health disparities in the population as a whole and the causes of these disparities.

¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ Two challenges: - Formalize relevant questions about mechanism leading to disparities in cancer outcomes as well as about interventions to eliminate such disparities. - Inference using big cancer registries and EMR data accounting for heterogeneities, confounding, and selection bias.

Racial Disparities in CRC Survival ◮ Colorectal cancer (CRC) is the third most common cancer in the United States, with more than 136,830 new CRC cases and 50,310 CRC deaths in 2014 in the US alone. ◮ CRC is also one cancer that demonstrates widening mortality disparities between Whites and Blacks. ◮ From the American Cancer Society website: ”African Americans have the highest colorectal cancer incidence and mortality rates of all racial groups in the United States. The reasons for this are not yet understood.”

Racial Disparities in CRC Survival Figure : Trends in Colorectal Cancer Incidence and Mortality Rates by Race/Ethnicity and Gender, 1975-2010 (Source: American Cancer Society, Surveillance Research, 2014).

Racial Disparities in Stage at CRC Diagnosis ◮ Although the determinants are multifactorial, previous studies report that differences in stage at diagnosis may explain up to 60% of the survival disparity (Grubbs et al., JCO, 2013). ◮ Higher risk of being diagnosed of advanced CRC for Black individuals is likely due to differences in screening and follow-up rates, which indicates that stage might be a manipulable factor. Figure : Colorectal Cancer Stage Distribution (%) by Race/Ethnicity, 2003-2009 (Source: American Cancer Society, Surveillance Research, 2014).

Traditional Approaches Previous studies on mechanisms leading to racial disparities in cancer survival are either flawed or problematic in interpretation. ◮ Difference method 1 to assess the importance of mediating factors have been used extensively but is usually inappropriate. ◮ Micro-simulation 2 studies might lack causal interpretations and might not allow the assessment for particular patients subpopulations. ◮ Causal mediation analysis 3 is problematic because assumes an intervention on racial/ethnic status. 1 Baron and Kenny, Psychological Methods, 1986. 2 Lansdorp-Vogelaar et al., Cancer Epidemiol Biomarkers Prev, 2012. 3 VanderWeele and Robinson, Epidemiology, 2014.

Motivation for a Causal Inference Perspective ◮ Potential outcome framework for causal inference comes to aid in: ◮ Clarifying the scientific questions of interest ◮ Formalizing the causal contrasts and conditions for their identifiability from observational data ◮ Statistical methods for causal inference come to aid in: ◮ Constructing robust estimators for the estimands of interest ◮ Accounting for potential biases due to the violation of identifiability assumptions

Question of Interest To assess the public health relevance of the disparities in stage at diagnosis we propose to estimate To what extent would racial differences in cancer survival be reduced had the distribution of the stage at diagnosis for Black individuals been equal to that of the White individuals. ¡ Figure : Intervention: shift of cancer stage at diagnosis distribution among black patients to be the same as in white patients.

Notation Let - T denote survival time and Y = min ( T , τ ), where τ is a pre-specified time point set at month 60 since diagnosis, - R denote race/ethnicity indicator taking value 0 if the individual is Non-Hispanic White and 1 if the individual is Non-Hispanic Black. - M denote a categorical mediator, stage at diagnosis in our case. - X denote additional covariates. - H x (0) denote a random draw of the mediator in the white population for a fixed level of the covariates X = x . - Y m denote the counterfactual outcome for a patient had his/her mediator been set at level m . - Y H x (0) denote the counterfactual outcome for a patient had his/her mediator been randomly sampled from the distribution of the mediator in the white population.

Estimands of Interest: - Disparity D = E ( Y | r = 1 , x ) − E ( Y | r = 0 , x ) - Residual Disparity D H x (0) = E ( Y H x (0) | r = 1 , x ) − E ( Y | r = 0 , x ) - Percent Disparity Reduction (% DR ) % DR = ( D − D H x (0) ) / D The residual disparity measure is identifiable from the observed data if: Assumption 1: Y m ⊥ M | R , X (No unmeasured confounding of stage-survival relationship). Assumption 2: Models for the stage and outcome are correctly specified.

Inference on disparity measure: a model-free approach ◮ Conditionally on x , we estimate the difference in restricted mean survival times 1.0 non−Hispanic White (RMST) truncated at 60/mo non−Hispanic Black of follow-up between racial 0.8 groups 5 . ◮ This quantity is estimated as Survival (Probability) 0.6 the difference in the areas under the Kaplan-Meier curve 0.4 for Blacks and Whites truncated at month 60. 0.2 ◮ The disparity measure in the overall population is then 0.0 obtained via random effect 0 50 100 150 200 meta-analysis across all Time (Months) confounder strata to allow for heterogeneous disparity measures in each stratum. 5 Uno et al., JCO, 2014.

Inference on residual disparity: a model-free approach ◮ We estimate for White and Black patients, for each confounder and stage levels, the RMST after 60 months of follow up. ◮ Probability of being diagnosed at a certain stage in the white population was also empirically estimated. ◮ The estimator for the residual disparity is given by the racial differences in the RMST, where for the black population the stage specific RMST’s are standardized over the probability of being diagnosed at that stage in the white population: � ˆ { � E ( Y | r = 1 , m , x ) − � D H x (0) = E ( Y | r = 0 , m , x ) } ˆ p ( m | r = 0 , x ) m ◮ The overall residual disparity measure was then obtained via random effect meta-analysis.

Population under Study and Data 4 ◮ Study population consists of a sample of n = 166 , 727 eligible adult White and Black CRC patients diagnosed between 1992 and 2005 and followed up to 2010 from SEER-9 cancer registries. ◮ We included patients diagnosed at stage I-IV according to the ¡ American Joint Committee on Cancer (AJCC) staging criteria. Figure : SEER Cancer Registries. 4 Surveillance, Epidemiology, and End Results (SEER) Program Research Data (1973-2010), National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013.

Disparities in CRC Survival: The questions of interest - Y : min ( T , τ = 60 / mo ) - R : Racial/Ethnic status indicator White vs Black - M : Stage at Diagnosis (I-IV) - X : Age and year at diagnosis, gender, grade of tumor differentiation, tumor site, state, and county median income 1) How much of the disparity in CRC cancer survival would be reduced had stage at diagnosis distribution for the Black had been equal to that of the White? 2) Does stage modify the difference in survival between the racial groups? 3) Is there gender heterogeneity in survival disparities as well as in the impact of the hypothetical shift in stage at diagnosis distribution?

Racial Disparities in CRC Survival: Results We find evidence of race-stage interaction. ˆ E ( Y | r = 1 , m ) E ( Y | r = 0 , m ) M D I 49.3 52.2 -2.9 (-4.3, -1.4) II 45 48.6 -3.6 (-5.0, -2.2) III 41.7 43.5 -1.8 (-3.2, -0.3) IV 15.9 18.3 -2.4 (-3.7, -1.1) Table : Estimates and 95% confidence intervals of RMST in months by race and stage diagnosis and racial differences in RMST ( D ) by stage at diagnosis.

Racial Disparities in CRC Survival: Results (count)/sum(count) 0.10 0.10 0.10 percent percent 0.05 0.05 0.05 0.00 0.00 0.00 20 20 20 30 30 30 40 40 40 50 50 50 RMST (Months) for Black RMST (Months) for Black RMST (Months) for Black 0.25 0.20 percent 0.15 0.10 0.05 0.00 20 30 40 50 RMST (Months) for White 0.15 0.10 percent 0.05 0.00 20 30 40 50 RMST (Months) for Black after hypothetical intervention Figure : Histograms of restricted mean survival time truncated at month 60 by age at diagnosis for White, Black, and Black after the hypothetical shift in stage at diagnosis distribution to match that of the White.