Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

Cost-minimization analysis of two algorithms for diagnosing acute pulmonary embolism.

INTRODUCTION: Pulmonary embolism is a common disorder that often requires extensive diagnostic testing. We hypothesized that an algorithmic approach to diagnosis of pulmonary embolism based upon clinical risk stratification and D-dimer testing would be less costly than a standard approach. MATERIALS AND METHODS: We constructed a decision tree based upon two published algorithms for diagnosing acute pulmonary embolism. Branch point probabilities were obtained from the best available published literature. Costs were based upon Medicare charges. From this we obtained a base-case analysis and conducted sensitivity analysis. RESULTS: Our base-case analysis revealed that the cost-per-patient for diagnostic testing were US$216.52 for the algorithm based upon pre-test probability and D-dimer testing and US$538.62 for the standard algorithm. The cost difference per patient evaluated was US$322.10. One- and two-way sensitivity analyses did not reveal any instances in which the clinical risk algorithm was more costly than the standard algorithm. Two-way sensitivity analysis revealed several scenarios in which the standard algorithm would be less costly; however, the conditions required for these scenarios are rarely encountered in clinical practice. CONCLUSIONS: Costs of testing using an algorithm based on clinical pre-test probability and D-dimer testing are less than with a standard approach for evaluating suspected acute pulmonary embolism. This new algorithm has previously been shown to be safe and has the potential for large cost savings if widely applied.

New choices for central venous catheters: potential financial implications.

OBJECTIVE: To determine the cost-effectiveness of the newer antiseptic and antibiotic-impregnated central venous catheters (CVCs) relative to uncoated CVCs and to each other. DESIGN: Decision model analysis of the cost and efficacy of CVCs coated with either chlorhexidine silver sulfadiazine (CSS) or rifampin-minocycline (RM) at preventing catheter-related bloodstream infections (CRBSIs). The primary outcome is the incremental cost (or savings) to prevent one additional CRBSI. Model estimates are derived from prospective trials of the CSS and RM CVCs and from other studies describing the costs of CRBSIs. SETTING AND PATIENTS: Hypothetical cohort of 1,000 patients requiring placement of a CVC. INTERVENTIONS: In the model, patients were managed with either an uncoated CVC, CSS CVC, or RM CVC. MEASUREMENTS AND MAIN RESULTS: The incremental cost-effectiveness of the treated CVCs was calculated as the savings resulting from CRBSIs averted less the additional costs of the newer devices. Sensitivity analysis of the effect of the major clinical inputs was performed. For the base case analysis, we assumed the incidence of CRBSIs was 3.3% with traditional catheters and that the CSS and RM CVC conferred a relative risk reduction for the development of CRBSIs of 60% and 85%, respectively. Despite their significantly higher cost than older catheters, both novel CVCs yield significant savings. Employing either of the treated CVCs saves approximately $10,000 per CRBSI prevented (relative to standard catheters). Comparing the RM CVC to the CSS CVC revealed the RM product to be economically superior, saving nearly $9,600 per CRBSI averted and $81 per patient in the cohort. For sensitivity analysis, we adjusted all model variables by 50% individually and then simultaneously. This demonstrated the model to be most sensitive to the cost of a CRBSI; however, with all inputs skewed by 50% against both the CSS CVC and the RM CVC, these devices remained economically attractive. Under this scenario, use of either treated device was less costly. CONCLUSIONS: Utilization of antiseptic and antibiotic-impregnated CVCs represent an attractive alternative for the prevention of CRBSIs and may lead to significant savings. Of the two newer, coated devices, the RM CVC performs better financially. These observations hold over a range of estimates for our model inputs.