Differential recall bias in estimating treatment effects in observational studies.

Observational studies are frequently used to estimate the effect of an exposure or treatment on an outcome. To obtain an unbiased estimate of the treatment effect, it is crucial to measure the exposure accurately. A common type of exposure misclassification is recall bias, which occurs in retrospective cohort studies when study subjects may inaccurately recall their past exposure. Particularly challenging is differential recall bias in the context of self-reported binary exposures, where the bias may be directional rather than random and its extent varies according to the outcomes experienced. This paper makes several contributions: (1) it establishes bounds for the average treatment effect even when a validation study is not available; (2) it proposes multiple estimation methods across various strategies predicated on different assumptions; and (3) it suggests a sensitivity analysis technique to assess the robustness of the causal conclusion, incorporating insights from prior research. The effectiveness of these methods is demonstrated through simulation studies that explore various model misspecification scenarios. These approaches are then applied to investigate the effect of childhood physical abuse on mental health in adulthood.

Sensitivity analyses for average treatment effects when outcome is censored by death in instrumental variable models.

Two problems that arise in making causal inferences for nonmortality outcomes such as bronchopulmonary dysplasia (BPD) are unmeasured confounding and censoring by death, ie, the outcome is observed only when subjects survive. In randomized experiments with noncompliance and no censoring by death, instrumental variable (IV) methods can be used to control for the unmeasured confounding. But, when there is censoring by death, the average causal treatment effect cannot be identified under usual assumptions but can be studied for a specific subpopulation by using sensitivity analysis with additional assumptions. However, evaluating the local average treatment effect (LATE) in observational studies with censoring by death problems while controlling for unmeasured confounding is not well studied. We develop a novel sensitivity analysis method based on IV models for studying the LATE. Specifically, we present the identification results under an additional assumption and propose a three-step procedure for the LATE estimation. Also, we propose an improved two-step procedure by simultaneously estimating the instrument propensity score (ie, the probability of instrument given covariates) and the parameters induced by the assumption. We show with simulation studies that the two-step procedure can be more robust and efficient than the three-step procedure. Finally, we apply our sensitivity analysis methods to a study on the effect of delivery at high-level neonatal intensive care units on the risk of BPD.

A powerful approach to the study of moderate effect modification in observational studies.

Effect modification means the magnitude or stability of a treatment effect varies as a function of an observed covariate. Generally, larger and more stable treatment effects are insensitive to larger biases from unmeasured covariates, so a causal conclusion may be considerably firmer if this pattern is noted if it occurs. We propose a new strategy, called the submax-method, that combines exploratory, and confirmatory efforts to determine whether there is stronger evidence of causality-that is, greater insensitivity to unmeasured confounding-in some subgroups of individuals. It uses the joint distribution of test statistics that split the data in various ways based on certain observed covariates. For L binary covariates, the method splits the population L times into two subpopulations, perhaps first men and women, perhaps then smokers and nonsmokers, computing a test statistic from each subpopulation, and appends the test statistic for the whole population, making 2 L + 1 test statistics in total. Although L binary covariates define 2 L interaction groups, only 2 L + 1 tests are performed, and at least L + 1 of these tests use at least half of the data. The submax-method achieves the highest design sensitivity and the highest Bahadur efficiency of its component tests. Moreover, the form of the test is sufficiently tractable that its large sample power may be studied analytically. The simulation suggests that the submax method exhibits superior performance, in comparison with an approach using CART, when there is effect modification of moderate size. Using data from the NHANES I epidemiologic follow-up survey, an observational study of the effects of physical activity on survival is used to illustrate the method. The method is implemented in the R package submax which contains the NHANES example. An online Appendix provides simulation results and further analysis of the example.

Causal inference analysis of the radiologic progression in the chronic obstructive pulmonary disease.

There is limited evidence regarding the causal inference of emphysema and functional small airway disease in the subsequent progression of chronic obstructive pulmonary disease (COPD). Patients consisting of two independent cohorts diagnosed with COPD and underwent two serial chest CT scans were included. Total percent emphysema (PRMEmph) and fSAD (PRMfSAD) was quantified via PRM. To investigate the progression of emphysema, we divided COPD patients with PRMEmph < 10% into low and high PRMfSADgroup, matched with similar baseline characteristics, and conducted nonparametric hypothesis tests based on randomization inference using Wilcoxon signed rank test and Huber's M statistics. In patients with baseline PRMEmph < 10%, there were 26 and 16 patients in the low PRMfSA group and 52 and 64 patients in the high PRMfSA in the derivation and validation cohorts, respectively. In the both low and high PRMfSAD groups, there were 0.11 and 1.43 percentage point increases (Huber's M statistic p = 0.016) and 0.58 and 2.09 percentage point increases (p = 0.038) in the proportion of emphysema in the derivation and validation cohorts, respectively. On the contrary, among patients with baseline PRMfSAD < 20%, there was no significant differences in the interval changes of PRMfSAD between the low and high PRMEmph groups in both cohorts. In COPD patients with low emphysema, group with baseline high PRMfSAD showed greater change of PRMEmph than those with low PRMfSAD in both the derivation and validation cohorts. Imaging-based longitudinal quantitative analysis may provide important evidence that small airway disease precedes emphysema in CT-based early COPD patients.

Discovering Heterogeneous Exposure Effects Using Randomization Inference in Air Pollution Studies.

Several studies have provided strong evidence that long-term exposure to air pollution, even at low levels, increases risk of mortality. As regulatory actions are becoming prohibitively expensive, robust evidence to guide the development of targeted interventions to protect the most vulnerable is needed. In this paper, we introduce a novel statistical method that (i) discovers subgroups whose effects substantially differ from the population mean, and (ii) uses randomization-based tests to assess discovered heterogeneous effects. Also, we develop a sensitivity analysis method to assess the robustness of the conclusions to unmeasured confounding bias. Via simulation studies and theoretical arguments, we demonstrate that hypothesis testing focusing on the discovered subgroups can substantially increase statistical power to detect heterogeneity of the exposure effects. We apply the proposed denovo method to the data of 1,612,414 Medicare beneficiaries in the New England region in the United States for the period 2000 to 2006. We find that seniors aged between 81-85 with low income and seniors aged 85 and above have statistically significant greater causal effects of long-term exposure to PM2.5 on 5-year mortality rate compared to the population mean.

The Use of a Quasi-Experimental Study on the Mortality Effect of a Heat Wave Warning System in Korea.

Many cities and countries have implemented heat wave warning systems to combat the health effects of extreme heat. Little is known about whether these systems actually reduce heat-related morbidity and mortality. We examined the effectiveness of heat wave alerts and health plans in reducing the mortality risk of heat waves in Korea by utilizing the discrepancy between the alerts and the monitored temperature. A difference-in-differences analysis combined with propensity score weighting was used. Mortality, weather monitoring, and heat wave alert announcement data were collected for 7 major cities during 2009-2014. Results showed evidence of risk reduction among people aged 19-64 without education (-0.144 deaths/1,000,000 people, 95% CI: -0.227, -0.061) and children aged 0-19 (-0.555 deaths/1,000,000 people, 95% CI: -0.993, -0.117). Decreased cardiovascular and respiratory mortality was found in several subgroups including single persons, widowed people, blue-collar workers, people with no education or the highest level of education (university or higher). No evidence was found for decreased all-cause mortality in the population (1.687 deaths/1,000,000 people per day; 95% CI: 1.118, 2.255). In conclusion, heat wave alerts may reduce mortality for several causes and subpopulations of age and socio-economic status. Further work needs to examine the pathways through which the alerts impact subpopulations differently.

Risk maps for cities: Incorporating streets into geostatistical models.

Vector-borne diseases commonly emerge in urban landscapes, and Gaussian field models can be used to create risk maps of vector presence across a large environment. However, these models do not account for the possibility that streets function as permeable barriers for insect vectors. We describe a methodology to transform spatial point data to incorporate permeable barriers, by distorting the map to widen streets, with one additional parameter. We use Gaussian field models to estimate this additional parameter, and develop risk maps incorporating streets as permeable barriers. We demonstrate our method on simulated datasets and apply it to data on Triatoma infestans, a vector of Chagas disease in Arequipa, Peru. We found that the transformed landscape that best fit the observed pattern of Triatoma infestans infestation, approximately doubled the true Euclidean distance between neighboring houses on different city blocks. Our findings may better guide control of re-emergent insect populations.