Abstract

In the evaluation of the effect of different treatments well-conducted randomized controlled trials have been widely accepted as the scientific standard. When on the other hand observational studies are used to assess treatment effects, the absence of a randomized assignment of treatments will in general result in treatment groups that
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are systematically different on factors that can be alternative explanations for the observed treatment effect. Therefore, in these types of studies is adjustment for confounding necessary. An overview of such methods is given and two methods are further described, evaluated and applied in real data sets. Furthermore, improvements are suggested. One of these adjustment methods, propensity scores, is increasingly used in the medical literature as an alternative for traditional regression-based methods like logistic regression and Cox proportional hazards regression. Nonetheless, an important advantage of propensity scores is frequently overlooked by researchers, that is, its treatment effect estimate is in general closer to the true average treatment effect than regression methods using the odds ratio or the hazard ratio. The difference can be substantial, especially when the number of confounding factors is more than 5, the treatment effect is larger than an odds ratio of 1.25 (or smaller than 0.8) or the incidence proportion is between 0.05 and 0.95. An important step in the application of propensity score methods is the creation of the propensity score model, including the check for balance. In many applications this model is routinely chosen and information on the balance of covariates between treatment groups is missing. We proposed to use a measure for balance, the overlapping coefficient, to select the best propensity score model and to report the amount of balance uniformly. Its inverse association with bias and the low mean squared error support the use of this measure. For smaller sample sizes the method does not seem to work well for model selection purposes. We also explored alternative measures, the Kolmogorov-Smirnov distance and the Lévy metric, but these were slightly less promising. The other adjustment method that has been evaluated, is the method of instrumental variables. Its potential ability to adjust for all confounders, whether observed or not is an attractive property. We applied this method on censored survival data and used the difference in survival probabilities as the treatment effect. Formulas for standard errors are provided, which can be large in absolute value in case of a low number of events or at the end of the survival curve. Nonetheless, this method is worthwile when a suitable instrumental variable can be found or can be created. In the literature a warning can be found against a weak correlation between the instrumental variable and treatment. We demonstrated the existence of an upper bound on this correlation, which can be a practical limitation when considerable confounding exists. This can result in a fairly weak instrument in order to fulfill the main assumption of the method, or worse, can indicate a violation of the main assumption when the instrumental variable turns out to be strong.
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