Using Instrumental Variables to Measure Causation over Time in Cross-Lagged Panel Models.

Cross-lagged panel models (CLPMs) are commonly used to estimate causal influences between two variables with repeated assessments. The lagged effects in a CLPM depend on the time interval between assessments, eventually becoming undetectable at longer intervals. To address this limitation, we incorporate instrumental variables (IVs) into the CLPM with two study waves and two variables. Doing so enables estimation of both the lagged (i.e., "distal") effects and the bidirectional cross-sectional (i.e., "proximal") effects at each wave. The distal effects reflect Granger-causal influences across time, which decay with increasing time intervals. The proximal effects capture causal influences that accrue over time and can help infer causality when the distal effects become undetectable at longer intervals. Significant proximal effects, with a negligible distal effect, would imply that the time interval is too long to estimate a lagged effect at that time interval using the standard CLPM. Through simulations and an empirical application, we demonstrate the impact of time intervals on causal inference in the CLPM and present modeling strategies to detect causal influences regardless of the time interval in a study. Furthermore, to motivate empirical applications of the proposed model, we highlight the utility and limitations of using genetic variables as IVs in large-scale panel studies.

MR-DoC2: Bidirectional Causal Modeling with Instrumental Variables and Data from Relatives.

Establishing causality is an essential step towards developing interventions for psychiatric disorders, substance use and many other conditions. While randomized controlled trials (RCTs) are considered the gold standard for causal inference, they are unethical in many scenarios. Mendelian randomization (MR) can be used in such cases, but importantly both RCTs and MR assume unidirectional causality. In this paper, we developed a new model, MRDoC2, that can be used to identify bidirectional causation in the presence of confounding due to both familial and non-familial sources. Our model extends the MRDoC model (Minica et al. in Behav Genet 48:337-349,  https://doi.org/10.1007/s10519-018-9904-4 , 2018), by simultaneously including risk scores for each trait. Furthermore, the power to detect causal effects in MRDoC2 does not require the phenotypes to have different additive genetic or shared environmental sources of variance, as is the case in the direction of causation twin model (Heath et al. in Behav Genet 23:29-50,  https://doi.org/10.1007/BF01067552 , 1993).

Power, measurement error, and pleiotropy robustness in twin-design extensions to Mendelian Randomization.

Mendelian Randomization (MR) has become an important tool for causal inference in the health sciences. It takes advantage of the random segregation of alleles to control for background confounding factors. In brief, the method works by using genetic variants as instrumental variables, but it depends on the assumption of exclusion restriction, i.e., that the variants affect the outcome exclusively via the exposure variable. Equivalently, the assumption states that there is no horizontal pleiotropy from the variant to the outcome. This assumption is unlikely to hold in nature, so several extensions to MR have been developed to increase its robustness against horizontal pleiotropy, though not eliminating the problem entirely (Sanderson et al. 2022). The Direction of Causation (DoC) model, which affords information from the cross-twin cross-trait correlations to estimate causal paths, was extended with polygenic scores to explicitly model horizontal pleiotropy and a causal path (MR-DoC, Minica et al 2018). MR-DoC was further extended to accommodate bidirectional causation (MR-DoC2 ; Castro-de-Araujo et al. 2023). In the present paper, we compared the power of the DoC model, MR-DoC, and MR-DoC2. We investigated the effect of phenotypic measurement error and the effect of misspecification of unshared (individual-specific) environmental factors on the parameter estimates.

Implementing an Inpatient Pediatric Prospective Audit and Feedback Antimicrobial Stewardship Program Within a Larger Medical Center.

BACKGROUND: Pediatric antimicrobial stewardship programs (ASPs) within larger institutions have unique opportunities to develop programs specialized to the needs of the pediatric program. In January 2013, our institution established a formalized pediatric ASP utilizing the prospective audit and feedback process. In an effort to standardize therapy and improve quality of care, members of the ASP developed evidence-based guidelines for management of common inpatient pediatric infections. ASP members met periodically with faculty and house staff to discuss guidelines and ways to improve prescribing. METHODS: Provider adherence with clinical inpatient practice guidelines, frequency of interventions suggested by ASP, and acceptance of interventions by providers were elements used to measure process change. We measured outcome data by analyzing antimicrobial utilization (defined as days of therapy) and length of therapy. RESULTS: Over a period of 2 years, institutional ASP guidelines were applicable to nearly half (44%) of all antimicrobial orders. Interventions were performed on 30% of all antimicrobial orders, of which 89% were accepted. Total antimicrobial days of therapy and length of therapy decreased significantly when comparing pre- and post-ASP. Overall, the susceptibility profiles of common bacterial pathogens to antibiotics remained stable. CONCLUSIONS: Pediatric ASPs within larger institutions have opportunities to create programs specific to the needs of the population they serve. We observed high rates of adherence by providers and a subsequent reduction in antibiotic utilization when implementing an audit feedback-based process.

Virologic Outcome of Using Tenofovir/Emtricitabine to Treat Hepatitis B in HIV-Coinfected Patients.

Goal. To study the effect of combination antiviral therapy with tenofovir and emtricitabine or lamivudine with and without prior monotherapy with lamivudine. Study. We reviewed charts of 31 HIV-/HBV-coinfected patients. Twelve 3TC-naïve patients initially received tenofovir plus emtricitabine. Nineteen epivir experienced patients who had previously failed epivir were given tenofovir plus emtricitabine. Results. Baseline median HBV DNA was similar in the epivir-naïve (5.8×10(7) copies/mL) and experienced group (7.3×10(7) copies/mL, P = .65). The median time to complete suppression of HBV was 466 days in the naïve group and 877 days in the experienced (P = .001). After 12 months, 6/10 (60%) naïve patients and 3/14 (21%) experienced patients had HBV DNA below the detectionlimit (P = .067). After 24 months, 5/5 (100%) naïve patients and 4/13 (31%) experienced patients had an undetectable HBV DNA level (P = .015). Conclusions. The median time to suppression of HBV DNA was significantly shorter among treatment naïve patients. There was a significantly greater proportion of naïve patients with suppressed HBV DNA at 24 months. Our results support using initial dual therapy in those with HIV/HBV coinfection.

Efficacy of deep venous thrombosis prophylaxis in the medical intensive care unit.

The purpose of this study was to determine the incidence of deep venous thrombosis in medical intensive care unit patients receiving deep venous thrombosis prophylaxis. This was a prospective cohort study of 141 consecutive adult patients anticipated to remain in the medical intensive care unit for >48 hours. Deep venous thrombosis prophylaxis was provided using subcutaneous unfractionated heparin or a sequential compression device according to risk-stratified protocol. Compression ultrasound was performed. Fourteen patients (9.9%) developed deep venous thrombosis on follow-up studies. Incidence of deep venous thrombosis was 7.9% per person year (95% confidence interval, 4.8-12.8). Two of 14 developed pulmonary embolism. Eight patients required full anticoagulation with intravenous heparin or coumadin. In-hospital mortality was similar in both groups. Patients with deep venous thrombosis had a statistically higher risk of pulmonary embolism: 14.2% (95% confidence interval, 2.0-43.0) versus 0.0% (95% confidence interval, 0-3; P = .009). Incidence of deep venous thrombosis is high in medical intensive care unit patients receiving standard prophylaxis. Adherence to strict deep venous thrombosis prophylaxis protocol and exploration of other prophylaxis regimens should be pursued.