Published On: 10/19/2021
by Alex Breskin
Blog  One Model to Rule Them All: Using a Single Model to Control for Confounding and Informative Censoring
Introduction
Studies designs for estimating causal effects are numerous. Based on the design, it is often necessary to control or address several sources of bias, such as baseline and timevarying confounding, informative censoring, selection bias, and a whole host of others. Designs like the treatment decision design [1], new user design [2], and prevalent new user design [3] each address these biases in different ways and require seemingly different analytic approaches to yield unbiased estimates from their resulting data.
Recently, the ‘clonecensorweight’ approach [4–6] has become a popular way to estimate the effects of sustained or dynamic treatment regimens. However, this approach, and the way of thinking it entails (which involves conceptualizing a ‘target trial’ and adapting it to the observational setting [7]), is more general, and nearly all studies can be thought of in this way. Here, we show that a standard study of a point treatment can be thought of as a clonecensorweight design, and we show how confounding and informative censoring can be addressed with a single nuisance model.
The Setup
Consider a study of a binary baseline treatment, \(A\), on a timetoevent, \(T\). Patients may be censored prior to experiencing the event, and the time of censoring is \(C\). A patient’s observed followup time is \(\tilde{T}=min(T,C)\). In addition, a set of baseline covariates sufficient to control for confounding and informative censoring are collected, denoted \(W\). Finally, we define \(\Delta=C>\tilde{T}\), which is an indicator that a patient was not censored at their observed followup time (and therefore had the event). A subject’s observed data therefore consist of \(\{A, \tilde{T}, W, \Delta\}\).
One estimator for the counterfactual cumulative incidence of the outcome under treatment level \(A=a\) is [8]:
\[ \hat{Pr}(T(a)<t)=\frac{1}{n}\sum_{i=1}^n{\frac{\Delta_iI(\tilde{t}_i<t)I(A_i=a)}{\hat{Pr}(\Delta=1W_i,A_i,T_i)\hat{Pr}(A=aW_i)}}, \]
where \(T(a)\) is the time of the event had, possibly counter to fact, a subject received treatment level \(A=a\), \(n\) is the total population size, and each of the probabilities in the denominator are modeled appropriately, e.g., with a Cox proportional hazards model for the censoring model and logistic regression for the treatment model.
Data Generation
Here, we generate a simple dataset for demonstration.
expit < function(p){
exp(p)/(1+exp(p))
}
n < 10000
dat < tibble(
id = 1:n,
W = runif(n),
A = rbinom(n, 1, expit(W)),
T0 = rexp(n, rate = 0.5 + 2*W),
T1 = rexp(n, rate = 1 + 2*W),
T = A*T1 + (1A)*T0,
C = rexp(n, rate = .5 + .55*A + .5*W)
)
Note that our true causal risk difference is 11.93%.
Typical Study Design and Analysis
Using the causalRisk package, we can easily implement the estimator described above to get the unadjusted and adjusted cumulative incidence curves:
mod_unadj < specify_models(identify_treatment(A),
identify_outcome(T),
identify_censoring(C))
mod_adj < specify_models(identify_treatment(A, ~W),
identify_outcome(T),
identify_censoring(C, ~W))
fit_unadj < estimate_ipwrisk(dat, mod_unadj, times = seq(0, 0.5, by = 0.01), labels = "Unadjusted, Standard")
fit_adj < estimate_ipwrisk(dat, mod_adj, times = seq(0, 0.5, by = 0.01), labels = "Adjusted, Standard")
make_table1(fit_adj, side.by.side = T)
plot(fit_unadj, fit_adj)
make_table2(fit_unadj, fit_adj, risk_time = 0.5)
CloneCensorWeight Design with Single Model
While the previously described analysis seems to work fine, it is limited by the fact that treatment must occur at a single point in time. The clonecensorweight design relaxes this restriction by allowing for sustained treatments or dynamic treatment regimens. This is accomplished by a 3step process:
 ‘Clone’ each patient once for each treatment regimen of interest.
 ‘Censor’ each clone when their persontime is no longer consistent with the corresponding treatment regimen.
 ‘Weight’ the remaining persontime by the inverse probability of being censored.
This approach is quite general and can easily accommodate simple study designs like the one previously undertaken here. One complicating factor, however, is the need to handle baseline as well as timevarying treatment. The 3step process does not seem to have any way of dealing with baseline treatment, for instance using inverse probability of treatment weights. Doing so would require, within each set of ‘clones’, further dividing the clones by baseline treatment and applying both treatment and censoring weights.
It turns out that a single Cox proportional hazards model can be used to handle baseline and timevarying treatments. This is accomplished by ensuring that all patients contribute at least some persontime (so patients who are on the ‘wrong’ treatment at baseline are given some tiny amount of persontime) and specifying the censoring model flexibly enough to act as if it were in fact two separate models  one for treatment and one for censoring.
Here, we demonstrate how this works.
dat2_treat < dat %>%
group_by(id) %>%
mutate(C2 = ifelse(A == 0, runif(n, min = 1e8, max = 1e7), C)) %>%
slice(rep(1, 2)) %>%
mutate(t_ind = ifelse(row_number() == 1, 1, 0),
end = ifelse(row_number() == 1, 1e7, C2),
start = ifelse(row_number() == 1, 0, lag(end))) %>%
filter(start != end) %>%
mutate(treat = 1) %>%
mutate(del = ifelse(row_number() == n(), 1, 0)) %>%
mutate(end = ifelse(end > .5, .5, end),
del = ifelse(end >= .5, 0, del)) %>%
ungroup()
dat2_notreat < dat %>%
group_by(id) %>%
mutate(C2 = ifelse(A == 1, runif(n, min = 1e8, 1e7), C)) %>%
slice(rep(1, 2)) %>%
mutate(t_ind = ifelse(row_number() == 1, 1, 0),
end = ifelse(row_number() == 1, 1e7, C2),
start = ifelse(row_number() == 1, 0, lag(end))) %>%
filter(start != end) %>%
mutate(treat = 0) %>%
mutate(del = ifelse(row_number() == n(), 1, 0)) %>%
mutate(end = ifelse(end > .5, .5, end),
del = ifelse(end >= .5, 0, del)) %>%
ungroup()
dat2 < bind_rows(dat2_treat, dat2_notreat)
mod_ccw < specify_models(identify_treatment(treat),
identify_outcome(T),
identify_censoring(C2, ~W + W:t_ind),
identify_interval(start, end),
identify_subject(id))
fit_ccw < estimate_ipwrisk(dat2, mod_ccw, times = seq(0, 0.5, by = 0.01), labels = "Adjusted, CloneCensorWeight")
plot(fit_ccw, fit_adj)
make_table2(fit_ccw, fit_adj, risk_time = 0.5)
Conclusion
As you can see, besides a bit of numerical noise, the results from the two approaches are essentially the same! From this simple example, we can see how the clonecensorweight design may be able to provide a general framework for the types of studies typically encountered in epidemiology.
References
About Target RWE
As the industry's bestinclass, complete real world evidence (RWE) solution, Target RWE is a distinctly collaborative enterprise that unifies real world data (RWD) sets and advanced RWE analytics in an integrated community, shifting the paradigm in healthcare for how decisions are made to improve lives.
Target RWE sources unique, connected data sets across multiple therapeutic areas representing granular data from diverse patients in academic and community settings. Our rigorous, interactive, and advanced RWE analytics extract deep insights from RWD to answer important questions in healthcare. Target RWE brings together the brightest minds in healthcare through an unmatched community of key opinion leaders, patients, and healthcare stakeholders in a collaborative and dynamic model. www.targetrwe.com
Contact:
Kayla Slake
Marketing Manager
984.234.0268 ext 205
More News

09/21/2023
New Eosinophilic Gastrointestinal Disorders (EGIDs) Real World Registry Surpasses 1,000 Patient Milestone 
08/23/2023
Target RWE's CuttingEdge Analytical Solutions Launched to Propel RealWorld Evidence Generation 
08/22/2023
Target RWE Strengthens Industry Leadership Position with Novel Real World Evidence Approaches Presented at ICPE 2023 
06/21/2023
WorldLeading Real World Data Registry, TARGETNASH, Surpasses 7,000+ Enrolled Patients and 500,000+ Months of Patient FollowUp 
06/02/2023
Event Recap Blog: TARGETNASH Analysis Presented at ISPOR 2023 and Target RWE Leaders Present at PMSA 2023