A multiple imputation strategy for sequential multiple assignment randomized trials

Sequential multiple assignment randomized trials (SMARTs) are increasingly being used to inform clinical and intervention science. In a SMART, each patient is repeatedly randomized over time. Each randomization occurs at a critical decision point in the treatment course. These critical decision points often correspond to milestones in the disease process or other changes in a patient's health status. Thus, the timing and number of randomizations may vary across patients and depend on evolving patient‐specific information. This presents unique challenges when analyzing data from a SMART in the presence of missing data. This paper presents the first comprehensive discussion of missing data issues typical of SMART studies: we describe five specific challenges and propose a flexible imputation strategy to facilitate valid statistical estimation and inference using incomplete data from a SMART. To illustrate these contributions, we consider data from the Clinical Antipsychotic Trial of Intervention and Effectiveness, one of the most well‐known SMARTs to date. Copyright © 2014 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108622/1/sim6223-sup-0001-SupInfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/108622/2/sim6223.pd

Results of phase 3 of the CATIE schizophrenia trial

Objective—The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study examined the comparative effectiveness of antipsychotic treatments for individuals with chronic schizophrenia. Patients who had discontinued antipsychotic treatment in phases 1 and 2 were eligible for phase 3, in which they selected one of nine antipsychotic regimens with the help of their study doctor. We describe the characteristics of the patients who selected each treatment option and their outcomes. Method—Two hundred and seventy patients entered phase 3. The open-label treatment options were monotherapy with oral aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone, long-acting injectable fluphenazine decanoate, or a combination of any two of these treatments. Results—Few patients selected fluphenazine decanoate (n=9) or perphenazine (n=4). Similar numbers selected each of the other options (range 33–41). Of the seven common choices, those who selected clozapine and combination antipsychotic treatment were the most symptomatic, and those who selected aripiprazole and ziprasidone had the highest body mass index. Symptoms improved for all groups, although the improvements were modest for the groups starting with relatively mild levels of symptoms. Side effect profiles of the medications varied considerably but medication discontinuations due to intolerability were rare (7% overall). Conclusions—Patients and their doctors made treatment selections based on clinical factors, including severity of symptoms, response to prior treatments, and physical health status. Fluphenazine decanoate was rarely used among those with evidence of treatment non-adherence and clozapine was underutilized for those with poor previous response. Combination antipsychotic treatment warrants further study

Cost-Effectiveness of Long-Acting Injectable Paliperidone Palmitate Versus Haloperidol Decanoate in Maintenance Treatment of Schizophrenia

This study assessed the relative cost-effectiveness of a first generation and a second generation long-acting injectable antipsychotic: haloperidol decanoate (HD) and paliperidone palmitate (PP), respectively

Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer's Disease

BACKGROUND Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease. METHODS In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks. RESULTS There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22). CONCLUSIONS Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease

Levofloxacin pharmacokinetics in saliva as measured by a mobile microvolume UV spectrophotometer among people treated for rifampicin-resistant TB in Tanzania

Background: Early detection and correction of low fluoroquinolone exposure may improve treatment of MDR-TB. Objectives: To explore a recently developed portable, battery-powered, UV spectrophotometer for measuring levofloxacin in saliva of people treated for MDR-TB. Methods: Patients treated with levofloxacin as part of a regimen for MDR-TB in Northern Tanzania had serum and saliva collected concurrently at 1 and 4 h after 2 weeks of observed levofloxacin administration. Saliva levofloxacin concentrations were quantified in the field via spectrophotometry, while serum was analysed at a regional laboratory using HPLC. A Bayesian population pharmacokinetics model was used to estimate the area under the concentration-time curve (AUC(0-24)). Subtarget exposures of levofloxacin were defined by serum AUC(0-24) Results: Among 45 patients, 11 (25.6%) were women and 16 (37.2%) were living with HIV. Median AUC(0- 24) in serum was 140 (IQR = 102.4-179.09) mg.h/L and median AUC(0- 24) in saliva was 97.10 (IQR = 74.80-121.10) mg.h/L. A positive linear correlation was observed with serum and saliva AUC(0-24), and a receiver operating characteristic curve constructed to detect serum AUC(0- 24) below 80mg.h/L demonstrated excellent prediction [AUC 0.80 (95% CI = 0.62-0.94)]. Utilizing a saliva AUC(0- 24) cut-off of 91.6mg.h/L, the assay was 88.9% sensitive and 69.4% specific in detecting subtarget serum AUC(0- 24) values, including identifying eight of nine patients below target. Conclusions: Portable UV spectrophotometry as a point-of-care screen for subtarget levofloxacin exposure was feasible. Use for triage to other investigation or personalized dosing strategy should be tested in a randomized study

The neuregulin 1 promoter polymorphism rs6994992 is not associated with chronic schizophrenia or neurocognition

The neuregulin 1 (NRG1) promoter single nucleotide polymorphism (SNP) rs6994992 has shown association with decreased activation of frontal and temporal lobe regions, increased risk of psychosis, and decreased premorbid IQ. This SNP is part of a putative schizophrenia risk-associated haplotype and was associated with increased expression of the type IV transcript in postmortem tissue. We tested for association between rs6994992 and chronic schizophrenia by genotyping 738 cases from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and 733 matched controls. We further tested for associations with age at onset and baseline neurocognition in cases with schizophrenia reasoning that these phenotypes might yield results similar to those seen for premorbid IQ. Affection status was weakly associated with rs6994992 genotypes and trended towards association under a recessive model. This association did not survive correction for multiple comparisons and was in the opposite direction than has been reported. There was no association between rs6994992 and age at onset, an estimate of premorbid IQ, or neurocognition at study baseline. We were unable to replicate previous associations of rs6994992 with schizophrenia and, moreover, did not find significant associations with age of onset, an estimate of pre-morbid IQ, or neurocognition

Ethnic Stratification of the Association of RGS4 Variants with Antipsychotic Treatment Response in Schizophrenia

Genetic association studies, including a large meta-analysis, report association of Regulator of G Protein Signaling 4 (RGS4) with schizophrenia in the context of heterogeneity. The central role of RGS4 in regulating signaling via Gi/o coupled neurotransmitter receptors led us to hypothesize that there may be RGS4 genotypes predictive of specific disease phenotypes and antipsychotic treatment responses

The impact of obesity on health care costs among persons with schizophrenia

Obesity is the second leading cause of preventable death in the US, and is twice as common among individuals with schizophrenia as the general population

Derivation, validation, and clinical relevance of a pediatric sepsis phenotype with persistent hypoxemia, encephalopathy, and shock

OBJECTIVES: Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to analyze the organ dysfunction trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify reproducible and clinically relevant sepsis phenotypes and determine if they are associated with heterogeneity of treatment effect (HTE) to common therapies. DESIGN: Multicenter observational cohort study. SETTING: Thirteen PICUs in the United States. PATIENTS: Patients admitted with suspected infections to the PICU between 2012 and 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-based phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. Overall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS with an in-hospital mortality of 10.1%. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia, encephalopathy, and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score-matched analysis, patients with persistent hypoxemia, encephalopathy, and shock phenotype appeared to have HTE and benefit from adjuvant therapy with hydrocortisone and albumin. When compared with other high-risk clinical syndromes, the persistent hypoxemia, encephalopathy, and shock phenotype only overlapped with 50%-60% of patients with septic shock, moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tier of organ dysfunction burden, suggesting that it represents a nonsynonymous clinical phenotype of sepsis-associated MODS. CONCLUSIONS: We derived and validated the persistent hypoxemia, encephalopathy, and shock phenotype, which is highly reproducible, clinically relevant, and associated with HTE to common adjuvant therapies in children with sepsis