Propensity score methods for confounding control in observational studies of therapeutics for COVID-19 infection.

The authors provide a brief overview of different propensity score methods that can be used in observational research studies that lack randomization. Under specific assumptions, these methods result in unbiased estimates of causal effects, but the different ways propensity score are used may require different assumptions and result in estimated treatment effects that can have meaningfully different interpretations. The authors review these issues and consider their implications for studies of therapeutics for COVID-19.

Prolonged second stage of labor and risk of postpartum hemorrhage in nullipara with epidural anesthesia and vaginal delivery: A cohort study with propensity score analysis.

OBJECTIVE: To conduct an analysis using propensity score methods, exploring the association between a prolonged second stage (>3 h) and the risk of postpartum hemorrhage (PPH) in a diverse population. METHODS: We conducted a prospective cohort study involving nullipara with epidural anesthesia and vaginal delivery, aged ≥18 years, presenting cephalically, and with a gestational age (GA) of ≥24 weeks at a tertiary maternity hospital in China (chictr.org.cn identifier: ChiCTR2200063094). Women undergoing emergency cesarean section in labor were excluded. The primary outcome was PPH, with secondary outcomes including severe postpartum hemorrhage and blood transfusion. We employed propensity score overlap weighting to analyze the association between prolonged second stage labor and PPH. RESULTS: The study included 3643 nullipara with epidural anesthesia, comprising 77 with a second stage of labor >3 h and 3566 with a second stage ≤3 h. Utilizing propensity score overlap weighting, there were no significant differences observed between the two groups regarding the risk of PPH (29.87% in >3 h group vs 17.64% in ≤3 h group; weighted odds ratio 1.01; 95% CI: 0.51-2.02). Subgroup interaction tests for PPH were not significant for assisted vaginal delivery, induction of labor, macrosomia, third-/fourth-degree perineal laceration, GA >41 weeks, twin pregnancies, episiotomy and GA >37 weeks. Sensitivity analysis did not reveal significant differences. CONCLUSION: This study did not find evidence supporting an increased risk of PPH associated with a second stage of labor lasting >3 h in our population, providing additional evidence for clinical practice.

Comparisons of Percutaneous Ablation, Open or Laparoscopic Liver Resection for Barcelona Clinic Liver Cancer Stage 0-A Hepatocellular Carcinoma: A Concurrent Generalized Propensity Score Analysis.

Purpose: Liver resection and ablation remain the most common therapeutic options for Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC), but there is a lack of evidence to show which is the most suitable therapy. This study aimed to make concurrent multi-arm comparisons of the short-term and long-term outcomes of percutaneous ablation (PA), open (OLR) or laparoscopic liver resection (LLR) for these patients. Patients and Methods: This was a retrospective observational cohort study. A series of generalized propensity score methods for multiple treatment groups were performed to concurrently compare the clinical outcomes of these three treatment options to balance potential confounders. Regression standardization was used to account for hazard of all-cause mortality and recurrence of intergroup differences. Results: Of the 1778 patients included, 1237, 307 and 234 underwent OLR, LLR and PA, respectively. After overlap weighting, which was the optimal adjustment strategy, patients in the minimally invasive group (LLR and PA groups) had few postoperative complications and short postoperative hospital stays (both P < 0.001). The 5-year recurrence-free survival (RFS) rate and 5-year overall survival (OS) rate were significantly higher in the LLR group when compared with the OLR and PA groups (RFS: 55.6% vs 48.0% vs 30.2%, P < 0.001; OS: 89.1% vs 79.7% vs 84.0%, P = 0.020). Multivariable Cox analysis and regression standardization showed that LLR was an independent factor for better RFS when compared with OLR and PA. In subgroup analysis, the long-term outcomes of patients with BCLC stage A HCC were consistent with the whole population. Conclusion: In the observational study using various covariate adjustment analysis with excellent balance, LLR is not only minimally invasive, but also provides better RFS and equivalent OS for patients with BCLC stage 0-A HCC when compared with OLR and PA.

Can metformin prevent cancer relative to sulfonylureas? A target trial emulation accounting for competing risks and poor overlap via double/debiased machine learning estimators.

There is mounting interest in the possibility that metformin, indicated for glycemic control in type 2 diabetes, has a range of additional beneficial effects. Randomized trials have shown that metformin prevents adverse cardiovascular events, and metformin use has also been associated with reduced cognitive decline and cancer incidence. In this paper, we dig more deeply into whether metformin prevents cancer by emulating target randomized trials comparing metformin to sulfonylureas as first line diabetes therapy using data from Clinical Practice Research Datalink, a U.K. primary care database (1987-2018). We included individuals with diabetes, no prior cancer diagnosis, no chronic kidney disease, and no prior diabetes therapy who initiated metformin (N=93353) or a sulfonylurea (N=13864). In our cohort, the estimated overlap weighted additive separable direct effect of metformin compared to sulfonylureas on cancer risk at 6 years was -1% (.95 CI=-2.2%, 0.1%), which is consistent with metformin providing no direct protection against cancer incidence or substantial protection. The analysis faced two methodological challenges-poor overlap, and pre-cancer death as a competing risk. To address these issues while minimizing nuisance model misspecification, we develop and apply double/debiased machine learning estimators of overlap weighted separable effects in addition to more traditional effect estimates.

High-dimensional mediation analysis for continuous outcome with confounders using overlap weighting method in observational epigenetic study.

BACKGROUND: Mediation analysis is a powerful tool to identify factors mediating the causal pathway of exposure to health outcomes. Mediation analysis has been extended to study a large number of potential mediators in high-dimensional data settings. The presence of confounding in observational studies is inevitable. Hence, it's an essential part of high-dimensional mediation analysis (HDMA) to adjust for the potential confounders. Although the propensity score (PS) related method such as propensity score regression adjustment (PSR) and inverse probability weighting (IPW) has been proposed to tackle this problem, the characteristics with extreme propensity score distribution of the PS-based method would result in the biased estimation. METHODS: In this article, we integrated the overlapping weighting (OW) technique into HDMA workflow and proposed a concise and powerful high-dimensional mediation analysis procedure consisting of OW confounding adjustment, sure independence screening (SIS), de-biased Lasso penalization, and joint-significance testing underlying the mixture null distribution. We compared the proposed method with the existing method consisting of PS-based confounding adjustment, SIS, minimax concave penalty (MCP) variable selection, and classical joint-significance testing. RESULTS: Simulation studies demonstrate the proposed procedure has the best performance in mediator selection and estimation. The proposed procedure yielded the highest true positive rate, acceptable false discovery proportion level, and lower mean square error. In the empirical study based on the GSE117859 dataset in the Gene Expression Omnibus database using the proposed method, we found that smoking history may lead to the estimated natural killer (NK) cell level reduction through the mediation effect of some methylation markers, mainly including methylation sites cg13917614 in CNP gene and cg16893868 in LILRA2 gene. CONCLUSIONS: The proposed method has higher power, sufficient false discovery rate control, and precise mediation effect estimation. Meanwhile, it is feasible to be implemented with the presence of confounders. Hence, our method is worth considering in HDMA studies.

Comparison of two propensity score-based methods for balancing covariates: the overlap weighting and fine stratification methods in real-world claims data.

BACKGROUND: Two propensity score (PS) based balancing covariate methods, the overlap weighting method (OW) and the fine stratification method (FS), produce superb covariate balance. OW has been compared with various weighting methods while FS has been compared with the traditional stratification method and various matching methods. However, no study has yet compared OW and FS. In addition, OW has not yet been evaluated in large claims data with low prevalence exposure and with low frequency outcomes, a context in which optimal use of balancing methods is critical. In the study, we aimed to compare OW and FS using real-world data and simulations with low prevalence exposure and with low frequency outcomes. METHODS: We used the Texas State Medicaid claims data on adult beneficiaries with diabetes in 2012 as an empirical example (N = 42,628). Based on its real-world research question, we estimated an average treatment effect of health center vs. non-health center attendance in the total population. We also performed simulations to evaluate their relative performance. To preserve associations between covariates, we used the plasmode approach to simulate outcomes and/or exposures with N = 4,000. We simulated both homogeneous and heterogeneous treatment effects with various outcome risks (1-30% or observed: 27.75%) and/or exposure prevalence (2.5-30% or observed:10.55%). We used a weighted generalized linear model to estimate the exposure effect and the cluster-robust standard error (SE) method to estimate its SE. RESULTS: In the empirical example, we found that OW had smaller standardized mean differences in all covariates (range: OW: 0.0-0.02 vs. FS: 0.22-3.26) and Mahalanobis balance distance (MB) (< 0.001 vs. > 0.049) than FS. In simulations, OW also achieved smaller MB (homogeneity: <0.04 vs. > 0.04; heterogeneity: 0.0-0.11 vs. 0.07-0.29), relative bias (homogeneity: 4.04-56.20 vs. 20-61.63; heterogeneity: 7.85-57.6 vs. 15.0-60.4), square root of mean squared error (homogeneity: 0.332-1.308 vs. 0.385-1.365; heterogeneity: 0.263-0.526 vs 0.313-0.620), and coverage probability (homogeneity: 0.0-80.4% vs. 0.0-69.8%; heterogeneity: 0.0-97.6% vs. 0.0-92.8%), than FS, in most cases. CONCLUSIONS: These findings suggest that OW can yield nearly perfect covariate balance and therefore enhance the accuracy of average treatment effect estimation in the total population.

Pulmonary Hypertension and the Risk of 30-Day Postoperative Pulmonary Complications after Gastrointestinal Surgical or Endoscopic Procedures: A Retrospective Propensity Score-Weighted Cohort Analysis.

Background: Pulmonary hypertension (PH) patients are at higher risk of postoperative complications. We analyzed the association of PH with 30-day postoperative pulmonary complications (PPCs). Methods: A single-center propensity score overlap weighting (OW) retrospective cohort study was conducted on 164 patients with a mean pulmonary artery pressure (mPAP) of >20 mmHg within 24 months of undergoing elective inpatient abdominal surgery or endoscopic procedures under general anesthesia and a control cohort (N = 1981). The primary outcome was PPCs, and the secondary outcomes were PPC sub-composites, namely respiratory failure (RF), pneumonia (PNA), aspiration pneumonia/pneumonitis (ASP), pulmonary embolism (PE), length of stay (LOS), and 30-day mortality. Results: PPCs were higher in the PH cohort (29.9% vs. 11.2%, p < 0.001). When sub-composites were analyzed, higher rates of RF (19.3% vs. 6.6%, p < 0.001) and PNA (11.2% vs. 5.7%, p = 0.01) were observed. After OW, PH was still associated with greater PPCs (RR 1.66, 95% CI (1.05-2.71), p = 0.036) and increased LOS (median 8.0 days vs. 4.9 days) but not 30-day mortality. Sub-cohort analysis showed no difference in PPCs between pre- and post-capillary PH patients. Conclusions: After covariate balancing, PH was associated with a higher risk for PPCs and prolonged LOS. This elevated PPC risk should be considered during preoperative risk assessment.

Is there a prognostic difference among stage I lung adenocarcinoma patients with different BRAF-mutation status?

BACKGROUND: The data of the prognostic role of V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in early-stage lung adenocarcinoma (LUAD) patients is scarce. This study aimed to investigate the proportion, clinicopathological features, and prognostic significance of patients with stage I LUAD carrying BRAF mutations. METHODS: We collected 431 patients with pathological stage I LUAD from cBioPortal for Cancer Genomics and 1604 LUAD patients tested for BRAF V600E and epidermal growth factor receptor (EGFR) mutations from Shanghai Pulmonary Hospital. Survival curves were drawn by the Kaplan-Meier method and compared by log-rank test. Cox proportional hazard models, propensity-score matching (PSM), and overlap weighting (OW) were performed in this study. The primary endpoint was recurrence-free survival (RFS). RESULTS: The proportion of BRAF mutations was estimated at 5.6% in a Caucasian cohort. BRAF V600E mutations were detected in six (1.4%) patients in Caucasian populations and 16 (1.0%) patients in Chinese populations. Two BRAF V600E-mutant patients were detected to have concurrent EGFR mutations, one for 19-del and one for L858R. For pathological stage I LUAD patients, BRAF mutations were not significantly associated with worse RFS than wild-type BRAF patients (HR = 1.111; p = 0.885). After PSM and OW, similar results were presented (HR = 1.352; p = 0.742 and HR = 1.246; p = 0.764, respectively). BRAF V600E mutation status also lacked predictive significance for RFS (HR, 1.844; p = 0.226; HR = 1.144; p = 0.831 and HR = 1.466; p = 0.450, respectively). CONCLUSIONS: In this study, we demonstrated that BRAF status may not be capable of predicting prognosis in stage I LUAD patients. There is a need for more data to validate our findings.

Patients with high nuclear grade pT1-ccRCC are more suitable for radical nephrectomy than partial nephrectomy: a multicenter retrospective study using propensity score.

BACKGROUND: Partial nephrectomy (PN) is usually recommended for T1 stage clear cell renal cell carcinoma (ccRCC) regardless of the nuclear grades. However, the question remains unresolved as to whether PN is non-inferior to RN in patients with T1-ccRCC at higher risk of recurrence. In fact, we found that patients with high nuclear grades treated with PN had poorer prognosis compared with those treated with radical nephrectomy (RN). Therefore, this study was designed to evaluate the associations of PN and RN in the four nuclear grade subsets with oncologic outcomes. METHODS: A retrospective study was conducted in three Chinese urological centers that included 1,714 patients who underwent PN or RN for sporadic, unilateral, pT1, N0, and M0 ccRCC without positive surgical margins and neoadjuvant therapy between 2010 and 2019. Associations of nephrectomy type with local ipsilateral recurrence, distant metastases, and all-cause mortality (ACM) were evaluated using the Kaplan-Meier method and multivariable Cox proportional hazards regression models after overlap weighting (OW). RESULTS: A total of 1675 patients entered the OW cohort. After OW, in comparison to PN, RN associated with a reduced risk of local ipsilateral recurrence in the G2 subset (HR = 0.148, 95% CI 0.046-0.474; p < 0.05), G3 subset (HR = 0.097, 95% CI 0.021-0.455; p < 0.05), and G4 subset (HR = 0.091, 95% CI 0.011-0.736; p < 0.05), and resulting in increased five-year local recurrence-free survival rates of 7.0%, 17.9%, and 36.2%, respectively. An association between RN and a reduced risk of distant metastases in the G4 subset (HR = 0.071, 95% CI 0.016-0.325; p < 0.05), with the five-year distant metastases-free survival rate increasing by 33.1% was also observed. No significant difference in ACM between PN and RN was identified. CONCLUSIONS: Our findings substantiate that opting for RN, as opposed to PN, is more advantageous for local recurrence-free survival and distant metastases-free survival in patients with high nuclear grade (especially G4) pT1-ccRCC. We recommend placing a heightened emphasis on enhancing preoperative nuclear grade assessment, as it can significantly influence the choice of surgical plan. TRIAL REGISTRATION: This study was registered at Chinese Clinical Trial Registry (ID: ChiCTR2200063333).

Observational methods for COVID-19 vaccine effectiveness research: an empirical evaluation and target trial emulation.

BACKGROUND: There are scarce data on best practices to control for confounding in observational studies assessing vaccine effectiveness to prevent COVID-19. We compared the performance of three well-established methods [overlap weighting, inverse probability treatment weighting and propensity score (PS) matching] to minimize confounding when comparing vaccinated and unvaccinated people. Subsequently, we conducted a target trial emulation to study the ability of these methods to replicate COVID-19 vaccine trials. METHODS: We included all individuals aged ≥75 from primary care records from the UK [Clinical Practice Research Datalink (CPRD) AURUM], who were not infected with or vaccinated against SARS-CoV-2 as of 4 January 2021. Vaccination status was then defined based on first COVID-19 vaccine dose exposure between 4 January 2021 and 28 January 2021. Lasso regression was used to calculate PS. Location, age, prior observation time, regional vaccination rates, testing effort and COVID-19 incidence rates at index date were forced into the PS. Following PS weighting and matching, the three methods were compared for remaining covariate imbalance and residual confounding. Last, a target trial emulation comparing COVID-19 at 3 and 12 weeks after first vaccine dose vs unvaccinated was conducted. RESULTS: Vaccinated and unvaccinated cohorts comprised 583 813 and 332 315 individuals for weighting, respectively, and 459 000 individuals in the matched cohorts. Overlap weighting performed best in terms of minimizing confounding and systematic error. Overlap weighting successfully replicated estimates from clinical trials for vaccine effectiveness for ChAdOx1 (57%) and BNT162b2 (75%) at 12 weeks. CONCLUSION: Overlap weighting performed best in our setting. Our results based on overlap weighting replicate previous pivotal trials for the two first COVID-19 vaccines approved in Europe.

Addressing substantial covariate imbalance with propensity score stratification and balancing weights: connections and recommendations.

Objectives: Propensity score (PS) weighting methods are commonly used to adjust for confounding in observational treatment comparisons. However, in the setting of substantial covariate imbalance, PS values may approach 0 and 1, yielding extreme weights and inflated variance of the estimated treatment effect. Adaptations of the standard inverse probability of treatment weights (IPTW) can reduce the influence of extremes, including trimming methods that exclude people with PS values near 0 or 1. Alternatively, overlap weighting (OW) optimizes criteria related to bias and variance, and performs well compared to other PS weighting and matching methods. However, it has not been compared to propensity score stratification (PSS). PSS has some of the same potential advantages; being insensitive extreme values. We sought to compare these methods in the setting of substantial covariate imbalance to generate practical recommendations. Methods: Analytical derivations were used to establish connections between methods, and simulation studies were conducted to assess bias and variance of alternative methods. Results: We find that OW is generally superior, particularly as covariate imbalance increases. In addition, a common method for implementing PSS based on Mantel-Haenszel weights (PSS-MH) is equivalent to a coarsened version of OW and can perform nearly as well. Finally, trimming methods increase bias across methods (IPTW, PSS and PSS-MH) unless the PS model is re-fit to the trimmed sample and weights or strata are re-derived. After trimming with re-fitting, all methods perform similarly to OW. Conclusions: These results may guide the selection, implementation and reporting of PS methods for observational studies with substantial covariate imbalance.

Perioperative Use of Intravenous Levodopa as an Anti-Parkinsonian Drug: A Propensity Score Analysis.

Background: Perioperative discontinuation of oral anti-parkinsonian medication can negatively impact the prognosis of abdominal surgery in patients with Parkinson's disease. Although intravenous levodopa may be an alternative, its efficacy has not yet been investigated. Objectives: To determine the efficacy of intravenous levodopa as an alternative to oral anti-Parkinsonian drugs during gastric or colorectal cancer surgery. Methods: We identified patients with Parkinson's disease who underwent surgery for gastric or colorectal cancer between April 2010 and March 2020, using the Diagnosis Procedure Combination database, a nationwide inpatient database in Japan. Patients were divided into two groups: those who received intravenous levodopa during the perioperative period and those who did not. We compared in-hospital mortalities, major complications, and postoperative length of stay between the groups after adjusting for background characteristics with overlap weights based on propensity scores. Results: We identified 648 patients who received intravenous levodopa and 1207 who did not receive levodopa during the perioperative period. In the adjusted cohort, the mean postoperative length of stay was 24.7 and 29.0 days (percent difference, -7.7%; 95% confidence interval, -13.1 to -1.5); in-hospital death was 3.2% and 3.3% (adjusted odds ratio, 0.95; 95% CI: 0.54-1.67); and incidence of major complications were 21.4% and 19.3% (adjusted odds ratio, 0.89; 95% confidence interval, 0.70-1.13) in those with and without intravenous levodopa, respectively. Conclusions: Intravenous levodopa was associated with a shorter postoperative length of stay, but not with mortality or morbidity. Intravenous levodopa may improve perioperative care in patients with Parkinson's disease.

Effectiveness and safety of the co-administration of Yokukan-San (Japanese herbal medicine) with antipsychotics in hospitalized older patients with pneumonia.

AIM: Behavioral and psychological symptoms and delirium frequently occur in hospitalized older patients with pneumonia and are associated with longer hospital stays. Yokukan-San (YKS, traditional Japanese [Kampo] medicine) and antipsychotics are often used to treat delirium and behavioral and psychological symptoms in Japan. Hence, this study aimed to assess the effectiveness and safety of the co-administration of YKS with atypical antipsychotics in older patients with pneumonia. METHODS: We used the Japanese Diagnosis Procedure Combination inpatient database to retrospectively identify older patients (≥65 years) hospitalized for pneumonia who received antipsychotics within 3 days of hospitalization. The patients were divided into two groups: those who received atypical antipsychotics alone (control group) and those who received both atypical antipsychotics and YKS (YKS group). We compared length of hospital stay, in-hospital mortality, bone fractures, and administration of potassium products between the two groups using propensity score overlap weighting. RESULT: We identified 4789 patients in the YKS group and 61 641 in the control group. After propensity score overlap weighting, length of hospital stay was statistically significantly shorter in the YKS group (percentage difference -3.0%; 95% confidence interval -5.8% to -0.3%). The proportion of patients who received potassium products was higher in the YKS group (odds ratio 1.34; 95% confidence interval 1.15-1.55). In-hospital death and bone fractures were not significantly different. CONCLUSION: Co-administration of YKS with atypical antipsychotics could be a reasonable treatment option for hospitalized older patients with pneumonia and aggressive psychiatric symptoms. Geriatr Gerontol Int 2023; 23: 849-854.

Propensity score weighting methods for causal subgroup analysis with time-to-event outcomes.

Evaluating causal effects of an intervention in pre-specified subgroups is a standard goal in comparative effectiveness research. Despite recent advancements in causal subgroup analysis, research on time-to-event outcomes has been lacking. This article investigates the propensity score weighting method for causal subgroup survival analysis. We introduce two causal estimands, the subgroup marginal hazard ratio and subgroup restricted average causal effect, and provide corresponding propensity score weighting estimators. We analytically established that the bias of subgroup-restricted average causal effect is determined by subgroup covariate balance. Using extensive simulations, we compare the performance of various combinations of propensity score models (logistic regression, random forests, least absolute shrinkage and selection operator, and generalized boosted models) and weighting schemes (inverse probability weighting, and overlap weighting) for estimating the causal estimands. We find that the logistic model with subgroup-covariate interactions selected by least absolute shrinkage and selection operator consistently outperforms other propensity score models. Also, overlap weighting generally outperforms inverse probability weighting in terms of balance, bias and variance, and the advantage is particularly pronounced in small subgroups and/or in the presence of poor overlap. We applied the methods to the observational Comparing Options for Management: PAtient-centered REsults for Uterine Fibroids study to evaluate the causal effects of myomectomy versus hysterectomy on the time to disease recurrence in a number of pre-specified subgroups of patients with uterine fibroids.

Covariate adjustment in randomized clinical trials with missing covariate and outcome data.

When analyzing data from randomized clinical trials, covariate adjustment can be used to account for chance imbalance in baseline covariates and to increase precision of the treatment effect estimate. A practical barrier to covariate adjustment is the presence of missing data. In this article, in the light of recent theoretical advancement, we first review several covariate adjustment methods with incomplete covariate data. We investigate the implications of the missing data mechanism on estimating the average treatment effect in randomized clinical trials with continuous or binary outcomes. In parallel, we consider settings where the outcome data are fully observed or are missing at random; in the latter setting, we propose a full weighting approach that combines inverse probability weighting for adjusting missing outcomes and overlap weighting for covariate adjustment. We highlight the importance of including the interaction terms between the missingness indicators and covariates as predictors in the models. We conduct comprehensive simulation studies to examine the finite-sample performance of the proposed methods and compare with a range of common alternatives. We find that conducting the proposed adjustment methods generally improves the precision of treatment effect estimates regardless of the imputation methods when the adjusted covariate is associated with the outcome. We apply the methods to the Childhood Adenotonsillectomy Trial to assess the effect of adenotonsillectomy on neurocognitive functioning scores.

Association between intrauterine device type and risk of perforation and device expulsion: results from the Association of Perforation and Expulsion of Intrauterine Device study.

BACKGROUND: Intrauterine devices, including levonorgestrel-releasing and copper devices, are highly effective long-acting reversible contraceptives. The potential risks associated with intrauterine devices are low and include uterine perforation and device expulsion. OBJECTIVE: This study aimed to evaluate the risk of perforation and expulsion associated with levonorgestrel-releasing devices vs copper devices in clinical practice in the United States. STUDY DESIGN: The Association of Perforation and Expulsion of Intrauterine Device study was a retrospective cohort study of women aged ≤50 years with an intrauterine device insertion during 2001 to 2018 and information on intrauterine device type and patient and medical characteristics. Of note, 4 research sites with access to electronic health records contributed data for the study: 3 Kaiser Permanente-integrated healthcare systems (Northern California, Southern California, and Washington) and 1 healthcare system using data from a healthcare information exchange in Indiana (Regenstrief Institute). Perforation was classified as any extension of the device into or through the myometrium. Expulsion was classified as complete (not visible in the uterus or abdomen or patient reported) or partial (any portion in the cervix or malpositioned). We estimated the crude incidence rates and crude cumulative incidence by intrauterine device type. The risks of perforation and expulsion associated with levonorgestrel-releasing intrauterine devices vs copper intrauterine devices were estimated using Cox proportional-hazards regression with propensity score overlap weighting to adjust for confounders. RESULTS: Among 322,898 women included in this analysis, the incidence rates of perforation per 1000 person-years were 1.64 (95% confidence interval, 1.53-1.76) for levonorgestrel-releasing intrauterine devices and 1.27 (95% confidence interval, 1.08-1.48) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 0.22% (95% confidence interval, 0.20-0.24) and 0.63% (95% confidence interval, 0.57-0.68) for levonorgestrel-releasing intrauterine devices and 0.16% (95% confidence interval, 0.13-0.20) and 0.55% (95% confidence interval, 0.44-0.68) for copper intrauterine devices, respectively. The incidence rates of expulsion per 1000 person-years were 13.95 (95% confidence interval, 13.63-14.28) for levonorgestrel-releasing intrauterine devices and 14.08 (95% confidence interval, 13.44-14.75) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 2.30% (95% confidence interval, 2.24-2.36) and 4.52% (95% confidence interval, 4.40-4.65) for levonorgestrel-releasing intrauterine devices and 2.30% (95% confidence interval, 2.18-2.44) and 4.82 (95% confidence interval, 4.56-5.10) for copper intrauterine devices, respectively. Comparing levonorgestrel-releasing intrauterine devices with copper intrauterine devices, the adjusted hazard ratios were 1.49 (95% confidence intervals, 1.25-1.78) for perforation and 0.69 (95% confidence intervals, 0.65-0.73) for expulsion. CONCLUSION: After adjusting for potential confounders, levonorgestrel-releasing intrauterine devices were associated with an increased risk of uterine perforation and a decreased risk of expulsion relative to copper intrauterine devices. Given that the absolute numbers of these events are low in both groups, these differences may not be clinically meaningful.

Addressing Extreme Propensity Scores in Estimating Counterfactual Survival Functions via the Overlap Weights.

The inverse probability of treatment weighting (IPTW) approach is popular for evaluating causal effects in observational studies, but extreme propensity scores could bias the estimator and induce excessive variance. Recently, the overlap weighting approach has been proposed to alleviate this problem, which smoothly down-weights the subjects with extreme propensity scores. Although advantages of overlap weighting have been extensively demonstrated in literature with continuous and binary outcomes, research on its performance with time-to-event or survival outcomes is limited. In this article, we propose estimators that combine propensity score weighting and inverse probability of censoring weighting to estimate the counterfactual survival functions. These estimators are applicable to the general class of balancing weights, which includes IPTW, trimming, and overlap weighting as special cases. We conduct simulations to examine the empirical performance of these estimators with different propensity score weighting schemes in terms of bias, variance, and 95% confidence interval coverage, under various degrees of covariate overlap between treatment groups and censoring rates. We demonstrate that overlap weighting consistently outperforms IPTW and associated trimming methods in bias, variance, and coverage for time-to-event outcomes, and the advantages increase as the degree of covariate overlap between the treatment groups decreases.

Association between menorrhagia and risk of intrauterine device-related uterine perforation and device expulsion: results from the Association of Uterine Perforation and Expulsion of Intrauterine Device study.

BACKGROUND: Intrauterine devices are effective instruments for contraception, and 1 levonorgestrel-releasing device is also indicated for the treatment of heavy menstrual bleeding (menorrhagia). OBJECTIVE: To compare the incidence of intrauterine device expulsion and uterine perforation in women with and without a diagnosis of menorrhagia within the first 12 months before device insertion STUDY DESIGN: This was a retrospective cohort study conducted in 3 integrated healthcare systems (Kaiser Permanente Northern California, Southern California, and Washington) and a healthcare information exchange (Regenstrief Institute) in the United States using electronic health records. Nonpostpartum women aged ≤50 years with intrauterine device (eg, levonorgestrel or copper) insertions from 2001 to 2018 and without a delivery in the previous 12 months were studied in this analysis. Recent menorrhagia diagnosis (ie, recorded ≤12 months before insertion) was ascertained from the International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes. The study outcomes, viz, device expulsion and device-related uterine perforation (complete or partial), were ascertained from electronic medical records and validated in the data sources. The cumulative incidence and crude incidence rates with 95% confidence intervals were estimated. Cox proportional hazards models estimated the crude and adjusted hazard ratios using propensity score overlap weighting (13-16 variables) and 95% confidence intervals. RESULTS: Among 228,834 nonpostpartum women, the mean age was 33.1 years, 44.4% of them were White, and 31,600 (13.8%) had a recent menorrhagia diagnosis. Most women had a levonorgestrel-releasing device (96.4% of those with and 78.2% of those without a menorrhagia diagnosis). Women with a menorrhagia diagnosis were likely to be older, obese, and have dysmenorrhea or fibroids. Women with a menorrhagia diagnosis had a higher intrauterine device-expulsion rate (40.01 vs 10.92 per 1000 person-years) than those without, especially evident in the first few months after insertion. Women with a menorrhagia diagnosis had a higher cumulative incidence (95% confidence interval) of expulsion (7.00% [6.70-7.32] at 1 year and 12.03% [11.52-12.55] at 5 years) vs those without (1.77% [1.70-1.84] at 1 year and 3.69% [3.56-3.83] at 5 years). The risk of expulsion was increased for women with a menorrhagia diagnosis vs for those without (adjusted hazard ratio, 2.84 [95% confidence interval, 2.66-3.03]). The perforation rate was low overall (<1/1000 person-years) but higher in women with a diagnosis of menorrhagia vs in those without (0.98 vs 0.63 per 1000 person-years). The cumulative incidence (95% confidence interval) of uterine perforation was slightly higher for women with a menorrhagia diagnosis (0.09% [0.06-0.14] at 1 year and 0.39% [0.29-0.53] at 5 years) than those without it (0.07% [0.06-0.08] at 1 year and 0.28% [0.24-0.33] at 5 years). The risk of perforation was slightly increased in women with a menorrhagia diagnosis vs in those without (adjusted hazard ratio, 1.53; 95% confidence interval, 1.10-2.13). CONCLUSION: The risk of expulsion is significantly higher in women with a recent diagnosis of menorrhagia. Patient education and counseling regarding the potential expulsion risk is recommended at insertion. The absolute risk of perforation for women with a recent diagnosis of menorrhagia is very low. The increased expulsion and perforation rates observed are likely because of causal factors of menorrhagia.

Covariate adjustment in subgroup analyses of randomized clinical trials: A propensity score approach.

BACKGROUND: Subgroup analyses are frequently conducted in randomized clinical trials to assess evidence of heterogeneous treatment effect across patient subpopulations. Although randomization balances covariates within subgroups in expectation, chance imbalance may be amplified in small subgroups and adversely impact the precision of subgroup analyses. Covariate adjustment in overall analysis of randomized clinical trial is often conducted, via either analysis of covariance or propensity score weighting, but covariate adjustment for subgroup analysis has been rarely discussed. In this article, we develop propensity score weighting methodology for covariate adjustment to improve the precision and power of subgroup analyses in randomized clinical trials. METHODS: We extend the propensity score weighting methodology to subgroup analyses by fitting a logistic regression propensity model with pre-specified covariate-subgroup interactions. We show that, by construction, overlap weighting exactly balances the covariates with interaction terms in each subgroup. Extensive simulations were performed to compare the operating characteristics of unadjusted estimator, different propensity score weighting estimators and the analysis of covariance estimator. We apply these methods to the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training trial to evaluate the effect of exercise training on 6-min walk test in several pre-specified subgroups. RESULTS: Standard errors of the adjusted estimators are smaller than those of the unadjusted estimator. The propensity score weighting estimator is as efficient as analysis of covariance, and is often more efficient when subgroup sample size is small (e.g. <125), and/or when outcome model is misspecified. The weighting estimators with full-interaction propensity model consistently outperform the standard main-effect propensity model. CONCLUSION: Propensity score weighting is a transparent and objective method to adjust chance imbalance of important covariates in subgroup analyses of randomized clinical trials. It is crucial to include the full covariate-subgroup interactions in the propensity score model.

Associations between early parenteral nutrition and in-hospital outcomes in underweight patients with gastrointestinal surgery.

BACKGROUND & AIMS: Guidelines recommend early parenteral nutrition for malnourished patients. However, the effectiveness of early parenteral nutrition in underweight patients has not been established. This study aimed to determine whether in-hospital outcomes were associated with early parenteral nutrition in underweight gastrointestinal surgery patients with short-term contraindications to early enteral nutrition. METHODS: We identified underweight adult gastrointestinal surgery patients with short-term contraindications to early enteral nutrition using the Japanese Diagnosis Procedure Combination database from July 2010 to March 2018. We performed propensity-score overlap weighting to compare in-hospital outcomes between patients with and without early parenteral nutrition. The primary outcome was length of hospital stay. The secondary outcomes were total hospitalization cost, hospital-acquired pneumonia, hospital-acquired urinary tract infection, central line-associated bloodstream infection, and all-cause 28-day in-hospital mortality. RESULTS: We identified 31,898 eligible patients. Early parenteral nutrition was associated with longer hospital stay (19.2 vs. 18.4 days; difference, 0.7 days; 95% CI, 0.1 to 1.4). There were no differences between the patients with and without early parenteral nutrition in total hospitalization cost (difference, US$60; 95% CI, -277 to 397), hospital-acquired pneumonia (risk difference, -0.11%; 95% CI, -0.78 to 0.55), hospital-acquired urinary tract infection (risk difference, 0.03%; 95% CI, -0.08 to 0.14), central line-associated bloodstream infection (risk difference, 0.08%; 95% CI, -0.02 to 0.18), and all-cause 28-day in-hospital mortality (risk difference, 0.31%; 95% CI, -0.07 to 0.69). CONCLUSIONS: Early parenteral nutrition for underweight gastrointestinal surgery patients with short-term contraindications to early enteral nutrition was associated with longer hospital stay.