Analysis of multicenter clinical trials with very low event rates

INTRODUCTION: In a five-arm randomized clinical trial (RCT) with stratified randomization across 54 sites, we encountered low primary outcome event proportions, resulting in multiple sites with zero events either overall or in one or more study arms. In this paper, we systematically evaluated different statistical methods of accounting for center in settings with low outcome event proportions. METHODS: We conducted a simulation study and a reanalysis of a completed RCT to compare five popular methods of estimating an odds ratio for multicenter trials with stratified randomization by center: (i) no center adjustment, (ii) random intercept model, (iii) Mantel-Haenszel model, (iv) generalized estimating equation (GEE) with an exchangeable correlation structure, and (v) GEE with small sample correction (GEE-small sample correction). We varied the number of total participants (200, 500, 1000, 5000), number of centers (5, 50, 100), control group outcome percentage (2%, 5%, 10%), true odds ratio (1, > 1), intra-class correlation coefficient (ICC) (0.025, 0.075), and distribution of participants across the centers (balanced, skewed). RESULTS: Mantel-Haenszel methods generally performed poorly in terms of power and bias and led to the exclusion of participants from the analysis because some centers had no events. Failure to account for center in the analysis generally led to lower power and type I error rates than other methods, particularly with ICC = 0.075. GEE had an inflated type I error rate except in some settings with a large number of centers. GEE-small sample correction maintained the type I error rate at the nominal level but suffered from reduced power and convergence issues in some settings when the number of centers was small. Random intercept models generally performed well in most scenarios, except with a low event rate (i.e., 2% scenario) and small total sample size (n ≤ 500), when all methods had issues. DISCUSSION: Random intercept models generally performed best across most scenarios. GEE-small sample correction performed well when the number of centers was large. We do not recommend the use of Mantel-Haenszel, GEE, or models that do not account for center. When the expected event rate is low, we suggest that the statistical analysis plan specify an alternative method in the case of non-convergence of the primary method

Fracture toughness of AlSi10Mg alloy produced by direct energy deposition with different crack plane orientations

The fracture and tensile behaviors of the AlSi10Mg alloy processed by Direct Energy Deposition were investigated. Three-point bending fracture toughness and tensile specimens were tested at room temperature along different crack plane orientations and loading directions. Before being machined and tested, the printed samples were subjected to heat treatment at 300 °C for 2 h to relieve the residual stresses. Microstructural and fractographic analyses were performed to investigate the fracture mechanisms and the crack propagation paths for each crack orientation. Significant differences in the fracture toughness were observed among the crack plane orientations. Specimens with cracks oriented in the X-Y direction featured the highest fracture toughness values (JIc = 11.96 kJ/m2), whereas the Z-Y crack orientation (perpendicular to the printing direction) performed the lowest fracture toughness values (JIc = 8.91 kJ/m2). The anisotropy in fracture toughness is mainly related to a preferential crack propagation path along the melt pool boundaries. At melt pool boundaries, pores are preferentially placed, coarsening of the microstructure occurs and there is higher Si content, leading to that area being less ductile and less resistant to crack propagation

Association Between State Policies Using Medicaid Exclusions to Sanction Noncompliance With Welfare Work Requirements and Medicaid Participation Among Low-Income Adults

Twenty states have pursued community engagement requirements (ie, work requirements) as a condition for Medicaid eligibility among adults considered able-bodied. Work requirements seek to improve health by incentivizing work, but may result in coverage losses. The impact of work requirements on Medicaid coverage may extend beyond qualifying beneficiaries, by increasing confusion around benefit rules or deterring individuals from applying for coverage. However, the spillover effects of work requirements on individuals not directly subject to them are difficult to study because these programs have only recently been implemented. To examine this possibility, we studied Temporary Assistance for Needy Families (TANF), the cash welfare program enacted under welfare reform in 1996. The TANF program requires able-bodied beneficiaries to fulfill work requirements, and states can elect to terminate Medicaid benefits as a sanction for nonpregnant adult TANF participants who do not comply with them. In states adopting these sanctions, Medicaid eligibility for dual TANF-Medicaid enrollees was effectively conditional on meeting work requirements. This quasi-experimental cohort study examines whether TANF-Medicaid sanctions had spillover effects on Medicaid coverage among low-income adults who were not likely to participate in TANF and, therefore, were not directly subject to these sanctions

Consumers\u27 Misunderstanding of Health Insurance.

We report results from two surveys of representative samples of Americans with private health insurance. The first examines how well Americans understand, and believe they understand, traditional health insurance coverage. The second examines whether those insured under a simplified all-copay insurance plan will be more likely to engage in cost-reducing behaviors relative to those insured under a traditional plan with deductibles and coinsurance, and measures consumer preferences between the two plans. The surveys provide strong evidence that consumers do not understand traditional plans and would better understand a simplified plan, but weaker evidence that a simplified plan would have strong appeal to consumers or change their healthcare choices

Teaching Hospital Five-Year Mortality Trends in the Wake of Duty Hour Reforms

Background The Accreditation Council for Graduate Medical Education (ACGME) implemented duty hour regulations for residents in 2003 and again in 2011. While previous studies showed no systematic impacts in the first 2 years post-reform, the impact on mortality in subsequent years has not been examined. OBJECTIVE To determine whether duty hour regulations were associated with changes in mortality among Medicare patients in hospitals of different teaching intensity after the first 2 years post-reform. DESIGN Observational study using interrupted time series analysis with data from July 1, 2000 to June 30, 2008. Logistic regression was used to examine the change in mortality for patients in more versus less teaching-intensive hospitals before (2000–2003) and after (2003–2008) duty hour reform, adjusting for patient comorbidities, time trends, and hospital site. PATIENTS Medicare patients (n  = 13,678,956) admitted to short-term acute care non-federal hospitals with principal diagnoses of acute myocardial infarction (AMI), gastrointestinal bleeding, or congestive heart failure (CHF); or a diagnosis-related group (DRG) classification of general, orthopedic, or vascular surgery. MAIN MEASURE All-location mortality within 30 days of hospital admission. KEY RESULTS In medical and surgical patients, there were no consistent changes in the odds of mortality at more vs. less teaching intensive hospitals in post-reform years 1–3. However, there were significant relative improvements in mortality for medical patients in the fourth and fifth years post-reform: Post4 (OR 0.88, 95 % CI [0.93–0.94]); Post5 (OR 0.87, [0.82–0.92]) and for surgical patients in the fifth year post-reform: Post5 (OR 0.91, [0.85–0.96]). CONCLUSIONS Duty hour reform was associated with no significant change in mortality in the early years after implementation, and with a trend toward improved mortality among medical patients in the fourth and fifth years. It is unclear whether improvements in outcomes long after implementation can be attributed to the reform, but concerns about worsening outcomes seem unfounded

Binder evaporation during powder sheet Additive Manufacturing

Several Additive Manufacturing methods are well established and found access into regular production in multiple sectors. For processing metals, typically wire or powder is used as feedstock. Wire processing is typically used for comparably large structure building, while powder processes offer, in general, a more precise metal application. For Powder Bed Fusion processes, very fine powder is used (typical 20 µm to 65 µm), while for Directed Energy Deposition powders are in the range between 50 µm and 160 µm. Such fine powders can be a health risk for humans (aspiration, skin integration). Avoiding contact with the powders in a production environment can be a big effort or not avoidable. Therefore, an alternative process was developed that provides the powder not as free powder particles but in form of powder sheets. For enabling the necessary bonding between the particles, a binder is used. In order to understand the impact of the binder during laser processing of the powder sheets, single pulse and line treatments were produced and recorded with high-speed imaging. Recordings show the vaporization of the binder and the related ejections of powder particles. At lower energy input, the binder evaporation led to less spattering, which indicates that a binder heating at low heating rates induces less pressure on the powder particles.Mechanical Engineerin