Effect of cytomegalovirus infection on post-transplant hospitalization days among children undergoing allogeneic hematopoietic cell transplantation: A marginal structural model approach.

BACKGROUND: Cytomegalovirus (CMV) commonly reactivates after allogeneic hematopoietic cell transplant (HCT), potentially leading to CMV disease and significant morbidity and mortality. To reduce morbidity and mortality, many centers conduct weekly CMV blood polymerase chain reaction (PCR) surveillance testing with subsequent initiation of antiviral therapy upon CMV DNAemia detection. However, the impact of CMV DNAemia on subsequent hospitalization risk has not been assessed using models accounting for the time-varying nature of the exposure, outcome, and confounders. METHODS: All allogeneic HCTs at the Children's Hospital of Philadelphia from January 2004-April 2017 were considered for inclusion. Patients were monitored with CMV surveillance via PCR testing for up to 105 days after HCT receipt. We estimated the association between CMV DNAemia and rate of hospitalization using marginal structural models (MSM). RESULTS: There were 343 allogeneic HCT episodes in 330 with CMV surveillance; median age was 9.0 (range: 0.1-26.2) and 46.5% were female. And 24.1% of HCT patients had at least one positive CMV blood PCR during the follow-up period. Median time to CMV DNAemia detection was 19 days (range: 4-97). The MSM estimated the incidence rate ratios for an association of CMV DNAemia with hospitalization to be 1.24, (95% confidence interval: 1.04-1.47). CONCLUSIONS: CMV DNAemia was associated with an increased hospitalization in the post-HCT period. The MSM accounted for time-varying nature of the outcome, exposure and confounders. The findings support prevention of CMV DNAemia in this population. We recommend further investigation into the effectiveness and safety of prophylaxis versus pre-emptive CMV prevention approaches.

Inverse Probability of Treatment Weighting and Confounder Missingness in Electronic Health Record-based Analyses: A Comparison of Approaches Using Plasmode Simulation.

BACKGROUND: Electronic health record (EHR) data represent a critical resource for comparative effectiveness research, allowing investigators to study intervention effects in real-world settings with large patient samples. However, high levels of missingness in confounder variables is common, challenging the perceived validity of EHR-based investigations. METHODS: We investigated performance of multiple imputation and propensity score (PS) calibration when conducting inverse probability of treatment weights (IPTW)-based comparative effectiveness research using EHR data with missingness in confounder variables and outcome misclassification. Our motivating example compared effectiveness of immunotherapy versus chemotherapy treatment of advanced bladder cancer with missingness in a key prognostic variable. We captured complexity in EHR data structures using a plasmode simulation approach to spike investigator-defined effects into resamples of a cohort of 4361 patients from a nationwide deidentified EHR-derived database. We characterized statistical properties of IPTW hazard ratio estimates when using multiple imputation or PS calibration missingness approaches. RESULTS: Multiple imputation and PS calibration performed similarly, maintaining ≤0.05 absolute bias in the marginal hazard ratio even when ≥50% of subjects had missing at random or missing not at random confounder data. Multiple imputation required greater computational resources, taking nearly 40 times as long as PS calibration to complete. Outcome misclassification minimally increased bias of both methods. CONCLUSION: Our results support multiple imputation and PS calibration approaches to missingness in missing completely at random or missing at random confounder variables in EHR-based IPTW comparative effectiveness analyses, even with missingness ≥50%. PS calibration represents a computationally efficient alternative to multiple imputation.

Impact of Label Restriction on Checkpoint-Inhibitor Use in Bladder Cancer and Changes in Mortality.

In 2018, the US Food and Drug Administration (FDA) limited the indication for immune checkpoint inhibitors (ICI) in metastatic bladder cancer to patients with programmed cell death protein ligand-1 (PD-L1)-positive tumors. The impact of the label change on survival outcomes remains unknown. We conducted a controlled interrupted time series analysis using a nationwide electronic health record-derived oncology dataset. We used Cox regression to compare mortality in the post- vs prelabel change periods among affected (initiators of ICI or carboplatin-based chemotherapy) vs unaffected (initiators of cisplatin-based chemotherapy) patients. The use of ICI, carboplatin, and cisplatin was similar pre- and postlabel change, but PD-L1 testing increased postlabel change. In adjusted models, survival did not differ after the FDA label change policy compared with prior to the label change in any of the groups. The FDA label restriction on immunotherapy was associated with increased PD-L1 testing but not with changes in treatment patterns or mortality among patients with metastatic bladder cancer.

Hospital-acquired Clostridioides difficile infection among patients at an urban safety-net hospital in Philadelphia: Demographics, neighborhood deprivation, and the transferability of national statistics.

OBJECTIVE: To investigate associations between healthcare-associated Clostridioides difficile infection and patient demographics at an urban safety-net hospital and compare findings with national surveillance statistics. METHODS: Study participants were selected using a case-control design using medical records collected between August 2014 and May 2018 at Hahnemann University Hospital in Philadelphia. Controls were frequency matched to cases by age and length of stay. Final sample included 170 cases and 324 controls. Neighborhood-level factors were measured using American Community Survey data. Multilevel models were used to examine infection by census tract, deprivation index, race/ethnicity, insurance type, referral location, antibiotic use, and proton-pump inhibitor use. RESULTS: Patients on Medicare compared to private insurance had 2.04 times (95% CI, 1.31-3.20) the odds of infection after adjusting for all covariables. Prior antibiotic use (2.70; 95% CI, 1.64-4.46) was also associated with infection, but race or ethnicity and referral location were not. A smaller proportion of hospital cases occurred among white patients (25% vs 44%) and patients over the age of 65 (39% vs 56%) than expected based on national surveillance statistics. CONCLUSIONS: Medicare and antibiotics were associated with Clostridioides difficile infection, but evidence did not indicate association with race or ethnicity. This finding diverges from national data in that infection is higher among white people compared to nonwhite people. Furthermore, a greater proportion of hospital cases were aged <65 years than expected based on national data. National surveillance statistics on CDI may not be transportable to safety-net hospitals, which often disproportionately serve low-income, nonwhite patients.

Hepatitis B Birth Dose Effects on Childhood Immunization in the U.S.

INTRODUCTION: The Advisory Committee on Immunization Practices recommends administering the first dose of hepatitis B vaccine at birth, making it the first vaccine that many children receive. However, few studies examine whether children who miss the birth dose are at increased risk of vaccination delay. This study investigates birth dose as a determinant of up-to-date immunization status at age 18 months, considering 7 core childhood vaccine series: diphtheria, tetanus, and acellular pertussis; polio; measles, mumps, and rubella; Haemophilus influenzae type B; varicella; hepatitis B; and pneumococcal conjugate vaccine. METHODS: Cross-sectional data were collected in 2017 by National Immunization Survey-Child, a nationally representative survey of children aged 19-35 months living in the U.S., and were analyzed in 2019. The primary outcome was combined 7-vaccine series (4:3:1:3:3:1:4) up-to-date status at 18 months. Doubly robust estimates of association were calculated using survey logistic regression and propensity scores estimated with boosted classification and regression trees. RESULTS: Children who received the birth dose had 2.01 (95% CI=1.74, 2.33) times the odds of being up-to-date on the combined 7-vaccine series as children who did not. ORs for all the 7 individual vaccine series were positive, ranging from 1.59 (95% CI=1.28, 1.97) for measles, mumps, and rubella to 4.97 (95% CI=3.97, 6.24) for hepatitis B. CONCLUSIONS: Receiving the birth dose is positively associated with up-to-date status later in childhood, highlighting the importance of starting vaccination early. The association is insensitive to confounding by factors observed in National Immunization Survey-Child, but investigation of unobserved factors such as vaccine hesitancy could provide critical information to guide intervention strategy.