Estimating causal effects from large data sets using propensity scores.

Many observational studies based on large databases attempt to estimate the causal effects of some new treatment or exposure relative to a control condition, such as the effect of smoking on mortality. In most such studies, it is necessary to control for naturally occurring systematic differences in background characteristics between the treatment group and the control group, such as age or sex distributions, that would not occur in the context of a randomized experiment. Typically, many background characteristics need to be controlled. Propensity score technology, introduced by Rosenbaum and Rubin , addresses this situation by reducing the entire collection of background characteristics to a single composite characteristic that appropriately summarizes the collection. This reduction from many characteristics to one composite characteristic allows the straightforward assessment of whether the treatment and control groups overlap enough with respect to background characteristics to allow a sensible estimation of treatment versus control effects from the data set. Moreover, when such overlap is present, the propensity score approach allows a straightforward estimation of treatment versus control effects that reflects adjustment for differences in all observed background characteristics. Subclassification on One Confounding Variable Before describing the use of propensity scores in the statistical analysis of observational studies with many confounding background characteristics, I begin with an example showing how subclassification adjusts for a single confounding covariate, such as age, in a study of smoking and mortality. I then show how propensity score methods generalize subclassification in the presence of many confounding covariates, such as age, region of the country, and sex. The potential for a large database to suggest causal effects of treatments is indicated in Table 1, adapted from Cochran's work , which concerns mortality rates per 1000 person-years for nonsmokers, cigarette smokers, and cigar and pipe smokers drawn from three large databases in the United States, the United Kingdom, and Canada. The treatment factor here involves three levels of smoking. The unadjusted mortality rates in Table 1 make it seem that cigarette smoking is good for health, especially relative to cigar and pipe smoking; clearly, this result is contrary to current wisdom. A problem with this naive conclusion is exposed in Table 1, where the average ages of the subpopulations are given. Age correlates with both mortality rates and smoking behavior. In this example, age is a confounding covariate, and conclusions about the effects of smoking should be adjusted for its effects. Table 1. Comparison of Mortality Rates for Three Smoking Groups in Three Databases* A straightforward way of adjusting for age is to 1) divide the population into age categories of approximately equal size [such as younger and older if two categories are appropriate; younger, middle-aged, and older if three are appropriate; and so on], 2) compare mortality rates within an age category [for example, compare mortality rates for the three treatment groups within the younger population and similarly for the older population], and 3) average the age-group-specific comparisons to obtain overall estimates of the age-adjusted mortality rates per 1000 person-years for each of the three groups. Table 1 shows the results for different numbers of age categories where the subclass-age boundaries were defined to have equal numbers of nonsmokers in each subclass. These results align better than the unadjusted mortality rates with our current understanding of the effects of smoking, especially when 9 to 11 subclasses are used. Incidentally, having approximately equal numbers of nonsmokers within each subclass is not necessary, but if the nonsmokers are considered the baseline group, it is a convenient and efficient choice because then the overall estimated effect is the simple unweighted average of the subclass-specific results. That is, the mortality rates in all three groups are being standardized  to the age distribution of nonsmokers as defined by their subclass counts.  calls this method subclassification and offers theoretical results showing that as long as the treatment and exposure groups overlap in their age distributions (that is, as long as a reasonable number of persons from each treatment group are in each subclass), comparisons using five or six subclasses will typically remove 90% or more of the bias present in the raw comparisons shown in Table 1. More than five subclasses were used for the adjusted mortality rates because the large size of the data sets made it possible to do so. A particular statistical model, such as a linear regression (or a logistic regression model; or in other settings, a hazard model) could have been used to adjust for age, but subclassification has two distinct advantages over such models, at least for offering initial trustworthy comparisons that are easy to communicate. First, if the treatment or exposure groups do not adequately overlap on the confounding covariate age, the investigator will see it immediately and be warned. Thus, if members of one group have ages outside the range of another group's ages, it will be obvious because one or more age-specific subclasses will consist almost solely of members exposed to one treatment. In contrast, nothing in the standard output of any regression modeling software will display this critical fact; the reason is that models predict an outcome (such as death) from regressors (such as age and treatment indicators), and standard regression diagnostics do not include careful analysis of the joint distribution of the regressors (such as a comparison of the distributions of age across treatment groups). When the overlap on age is too limited, the database, no matter how large, cannot support any causal conclusions about the differential effects of the treatments. For example, comparing 5-year survival rates among 70-year-old smokers and 40-year-old nonsmokers gives essentially no information about the effect of smoking or nonsmoking for either 70-year-old or 40-year-old persons. The second reason for preferring subclassification to models concerns situations such as that found in Table 1, in which the groups overlap enough on the confounding covariate to make a comparison possible. Subclassification does not rely on any particular functional form, such as linearity, for the relation between the outcome (death) and the covariate (age) within each treatment group, whereas models do. If the groups have similar distributions of the covariate, such specific assumptions like linearity are usually harmless, but when the groups have different covariate distributions, model-based methods of adjustment are dependent on the specific form of the model (for example, linearity or log linearity) and their results are determined by untrustworthy extrapolations. If standard models can be so dangerous, why are they commonly used for such adjustments when large databases are examined for estimates of causal effects? One reason is the ease with which automatic data analysis can be done using existing, pervasive software on plentiful, speedy hardware. A second reason is the seeming difficulty of using subclassification when many confounding covariates need adjustment, which is the common case. Standard modeling software can automatically handle many regressor variables and produce results, although they can be remarkably misleading. With many confounding covariates, however, the issues of lack of adequate overlap and reliance on untrustworthy model-based extrapolations are even more serious than with only one confounding covariate. The reason is that small differences in many covariates can accumulate into a substantial overall difference. For example, if members of one treatment or exposure group are slightly older, have slightly higher cholesterol levels, and have slightly more familial history of cancer, that group may be substantially less healthy. Moreover, although standard comparisons of means between the groups like those in Table 1, or comparisons of histograms for each confounding covariate among groups are adequate with one covariate, they are inadequate with more than one. The groups may differ in a multivariate direction to an extent that cannot be discerned from separate analyses of each covariate. This multivariate direction is closely related to the statistical concept of the best linear discriminant and intuitively is the single combination of the covariates on which the treatment groups are farthest apart. Subclassification techniques can be applied with many covariates with almost the same reliability as with only one covariate. The key idea is to use propensity score techniques, as developed by Rosenbaum and Rubin . These methods can be viewed as important extensions of discriminant matching techniques, which calculate the best linear discriminant between the treatment groups and match on it . Since their introduction approximately 15 years ago, propensity score methods have been used in various applied problems in medical and other research disciplines [5-23] but not nearly as frequently as they should have been relative to model-based methods.  Propensity score methods must be applied to groups two at a time. Therefore, an example with three treatment or exposure conditions will generally yield three distinct propensity scores, one for each comparison (for the example in Table 1, non-smokers compared with cigarette smokers, non-smokers compared with cigar and pipe smokers, and cigarette smokers compared with cigar and pipe smokers). To describe the way propensity scores work, I first assume two treatment conditions. Cases with more than two treatment groups are considered later. The basic idea of propensity score methods is to replace