Association Between Stimulant Treatment and Substance Use Through Adolescence Into Early Adulthood.

Importance: Possible associations between stimulant treatment of attention-deficit/hyperactivity disorder (ADHD) and subsequent substance use remain debated and clinically relevant. Objective: To assess the association of stimulant treatment of ADHD with subsequent substance use using the Multimodal Treatment Study of ADHD (MTA), which provides a unique opportunity to test this association while addressing methodologic complexities (principally, multiple dynamic confounding variables). Design, Setting, and Participants: MTA was a multisite study initiated at 6 sites in the US and 1 in Canada as a 14-month randomized clinical trial of medication and behavior therapy for ADHD but transitioned to a longitudinal observational study. Participants were recruited between 1994 and 1996. Multi-informant assessments included comprehensively assessed demographic, clinical (including substance use), and treatment (including stimulant treatment) variables. Children aged 7 to 9 years with rigorously diagnosed DSM-IV combined-type ADHD were repeatedly assessed until a mean age of 25 years. Analysis took place between April 2018 and February 2023. Exposure: Stimulant treatment of ADHD was measured prospectively from baseline for 16 years (10 assessments) initially using parent report followed by young adult report. Main Outcomes and Measures: Frequency of heavy drinking, marijuana use, daily cigarette smoking, and other substance use were confidentially self-reported with a standardized substance use questionnaire. Results: A total of 579 children (mean [SD] age at baseline, 8.5 [0.8] years; 465 [80%] male) were analyzed. Generalized multilevel linear models showed no evidence that current (B [SE] range, -0.62 [0.55] to 0.34 [0.47]) or prior stimulant treatment (B [SE] range, -0.06 [0.26] to 0.70 [0.37]) or their interaction (B [SE] range, -0.49 [0.70] to 0.86 [0.68]) were associated with substance use after adjusting for developmental trends in substance use and age. Marginal structural models adjusting for dynamic confounding by demographic, clinical, and familial factors revealed no evidence that more years of stimulant treatment (B [SE] range, -0.003 [0.01] to 0.04 [0.02]) or continuous, uninterrupted stimulant treatment (B [SE] range, -0.25 [0.33] to -0.03 [0.10]) were associated with adulthood substance use. Findings were the same for substance use disorder as outcome. Conclusions and Relevance: This study found no evidence that stimulant treatment was associated with increased or decreased risk for later frequent use of alcohol, marijuana, cigarette smoking, or other substances used for adolescents and young adults with childhood ADHD. These findings do not appear to result from other factors that might drive treatment over time and findings held even after considering opposing age-related trends in stimulant treatment and substance use.

Doubly robust nonparametric instrumental variable estimators for survival outcomes.

Instrumental variable (IV) methods allow us the opportunity to address unmeasured confounding in causal inference. However, most IV methods are only applicable to discrete or continuous outcomes with very few IV methods for censored survival outcomes. In this article, we propose nonparametric estimators for the local average treatment effect on survival probabilities under both covariate-dependent and outcome-dependent censoring. We provide an efficient influence function-based estimator and a simple estimation procedure when the IV is either binary or continuous. The proposed estimators possess double-robustness properties and can easily incorporate nonparametric estimation using machine learning tools. In simulation studies, we demonstrate the flexibility and double robustness of our proposed estimators under various plausible scenarios. We apply our method to the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial for estimating the causal effect of screening on survival probabilities and investigate the causal contrasts between the two interventions under different censoring assumptions.

Model Performance Metrics in Assessing the Value of Adding Intraoperative Data for Death Prediction: Applications to Noncardiac Surgery.

We tested the value of adding data from the operating room to models predicting in-hospital death. We assessed model performance using two metrics, the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC), to illustrate the differences in information they convey in the setting of class imbalance. Data was collected on 74,147 patients who underwent major noncardiac surgery and 112 unique features were extracted from electronic health records. Sets of features were incrementally added to models using logistic regression, naïve Bayes, random forest, and gradient boosted machine methods. AUROC increased as more features were added, but changes were small for some modeling approaches. In contrast, AUPRC, which reflects positive predicted value, exhibited improvements across all models. Using AUPRC highlighted the added value of intraoperative data, not seen consistently with AUROC, and that with class imbalance AUPRC may serve as the more clinically relevant criterion.

Preoperative Metyrosine Improves Cardiovascular Outcomes for Patients Undergoing Surgery for Pheochromocytoma and Paraganglioma.

BACKGROUND: The goal of preoperative pharmacotherapy for pheochromocytoma (PCC) and paraganglioma (PGL) resection is to minimize intraoperative hemodynamic instability and perioperative cardiovascular complications, but no standard preoperative regimen exists. Historically, treatment used metyrosine and phenoxybenzamine (MP). The recent metyrosine shortage required that phenoxybenzamine alone (PA) be used for treatment. The authors examined their experience to determine the impact of preoperative metyrosine treatment on patient outcomes. METHODS: A retrospective cohort study investigated patients who underwent initial PCC/PGL resection (2000-2014). The primary outcome was intraoperative hemodynamics, measured by heart rate (HR) and systolic blood pressure (SBP). The secondary outcomes included perioperative complications and cardiovascular-specific complications (CVC). Univariate analysis was performed, and adjusted risk differences were estimated after confounding was taken into account. RESULTS: Of 174 patients, 142 (81.6 %) were in the MP group. The MP and PA patients had comparable intraoperative use of antihypertensives (83.9 vs 78.1 %; p = 0.443), vasopressors (74.6 vs 87.5 %; p = 0.120), and fluid resuscitation (mean, 24.4 vs 24.8 ml/min; p = 0.761). Although the perioperative complication rate did not differ significantly between the MP and PA groups (respectively 23.4 vs 34.4 %; p = 0.198), the PA patients had a 15.8 % higher rate of CVC even after controlling for confounders (p = 0.034). Compared with the MP patients, the PA patients had significantly more hemodynamic instability intraoperatively, with a greater range in HR (7.4 bpm; p = 0.034) and SBP (14.8 mmHg; p = 0.020). CONCLUSIONS: In this study, preoperative metyrosine improved intraoperative hemodynamic stability and decreased CVC rates in patients undergoing PCC/PGLresection. These data suggest that the addition of preoperative metyrosine may improve operative outcomes.

Comparison of methods for estimating the effect of salvage therapy in prostate cancer when treatment is given by indication.

For patients who were previously treated for prostate cancer, salvage hormone therapy is frequently given when the longitudinal marker prostate-specific antigen begins to rise during follow-up. Because the treatment is given by indication, estimating the effect of the hormone therapy is challenging. In a previous paper we described two methods for estimating the treatment effect, called two-stage and sequential stratification. The two-stage method involved modeling the longitudinal and survival data. The sequential stratification method involves contrasts within matched sets of people, where each matched set includes people who did and did not receive hormone therapy. In this paper, we evaluate the properties of these two methods and compare and contrast them with the marginal structural model methodology. The marginal structural model methodology involves a weighted survival analysis, where the weights are derived from models for the time of hormone therapy. We highlight the different conditional and marginal interpretations of the quantities being estimated by the three methods. Using simulations that mimic the prostate cancer setting, we evaluate bias, efficiency, and accuracy of estimated standard errors and robustness to modeling assumptions. The results show differences between the methods in terms of the quantities being estimated and in efficiency. We also demonstrate how the results of a randomized trial of salvage hormone therapy are strongly influenced by the design of the study and discuss how the findings from using the three methodologies can be used to infer the results of a trial.

Despite variation in volume, Veterans Affairs hospitals show consistent outcomes among patients with non-postoperative mechanical ventilation.

OBJECTIVE: To assess the relationship between volume of nonoperative mechanically ventilated patients receiving care in a specific Veterans Health Administration hospital and their mortality. DESIGN: Retrospective cohort study. SETTING: One-hundred nineteen Veterans Health Administration medical centers. PATIENTS: We identified 5,131 hospitalizations involving mechanically ventilated patients in an intensive care unit during 2009, who did not receive surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We extracted demographic and clinical data from the VA Inpatient Evaluation Center. For each hospital, we defined volume as the total number of nonsurgical admissions receiving mechanical ventilation in an intensive care unit during 2009. We examined the hospital contribution to 30-day mortality using multilevel logistic regression models with a random intercept for each hospital. We quantified the extent of interhospital variation in 30-day mortality using the intraclass correlation coefficient and median odds ratio. We used generalized estimating equations to examine the relationship between volume and 30-day mortality and risk-adjusted all models using a patient-level prognostic score derived from clinical data representing the risk of death conditional on treatment at a high-volume hospital. Mean age for the sample was 65 (SD 11) yrs, 97% were men, and 60% were white. The median VA hospital cared for 40 (interquartile range 19-62) mechanically ventilated patients in 2009. Crude 30-day mortality for these patients was 36.9%. After reliability and risk adjustment to the median patient, adjusted hospital-level mortality varied from 33.5% to 40.6%. The intraclass correlation coefficient for the hospital-level variation was 0.6% (95% confidence interval 0.1, 3.4%), with a median odds ratio of 1.15 (95% confidence interval 1.06, 1.38). The relationship between hospital volume of mechanically ventilated and 30-day mortality was not statistically significant: each 50-patient increase in volume was associated with a nonsignificant 2% decrease in the odds of death within 30 days (odds ratio 0.98, 95% confidence interval 0.87-1.10). CONCLUSIONS: Veterans Health Administration hospitals caring for lower volumes of mechanically ventilated patients do not have worse mortality. Mechanisms underlying this finding are unclear, but, if elucidated, may offer other integrated health systems ways to overcome the disadvantages of small-volume centers in achieving good outcomes.

Reducing inappropriate urinary catheter use: a statewide effort.

BACKGROUND: Indwelling urinary catheters may lead to both infectious and noninfectious complications and are often used in the hospital setting without an appropriate indication. The objective of this study was to evaluate the results of a statewide quality improvement effort to reduce inappropriate urinary catheter use. METHODS: Retrospective analysis of data collected between 2007 and 2010 as part of a statewide collaborative initiative before, during, and after an educational intervention promoting adherence to appropriate urinary catheter indications. The data were collected from 163 inpatient units in 71 participating Michigan hospitals. The intervention consisted of educating clinicians about the appropriate indications for urinary catheter use and promoting the daily assessment of urinary catheter necessity during daily nursing rounds. The main outcome measures were change in prevalence of urinary catheter use and adherence to appropriate indications. We used flexible generalized estimating equation (GEE) and multilevel methods to estimate rates over time while accounting for the clustering of patients within hospital units. RESULTS: The urinary catheter use rate decreased from 18.1% (95% CI, 16.8%-19.6%) at baseline to 13.8% (95% CI, 12.9%-14.8%) at end of year 2 (P < .001). The proportion of catheterized patients with appropriate indications increased from 44.3% (95% CI, 40.3%-48.4%) to 57.6% (95% CI, 51.7%-63.4%) by the end of year 2 (P = .005). CONCLUSIONS: A statewide effort to reduce inappropriate urinary catheter use was associated with a significant reduction in catheter use and improved compliance with appropriate use. The effect of the intervention was sustained for at least 2 years.

The effect of salvage therapy on survival in a longitudinal study with treatment by indication.

We consider using observational data to estimate the effect of a treatment on disease recurrence, when the decision to initiate treatment is based on longitudinal factors associated with the risk of recurrence. The effect of salvage androgen deprivation therapy (SADT) on the risk of recurrence of prostate cancer is inadequately described by the existing literature. Furthermore, standard Cox regression yields biased estimates of the effect of SADT, since it is necessary to adjust for prostate-specific antigen (PSA), which is a time-dependent confounder and an intermediate variable. In this paper, we describe and compare two methods which appropriately adjust for PSA in estimating the effect of SADT. The first method is a two-stage method which jointly estimates the effect of SADT and the hazard of recurrence in the absence of treatment by SADT. In the first stage, PSA is predicted in the absence of SADT, and in the second stage, a time-dependent Cox model is used to estimate the benefit of SADT, adjusting for PSA. The second method, called sequential stratification, reorganizes the data to resemble a sequence of experiments in which treatment is conditionally randomized given the time-dependent covariates. Strata are formed, each consisting of a patient undergoing SADT and a set of appropriately matched controls, and analysis proceeds via stratified Cox regression. Both methods are applied to data from patients initially treated with radiation therapy for prostate cancer and give similar SADT effect estimates.