DM-STAT (United States)

Risk differences allow decision makers to easily estimate the excess safety risk associated with a medical product relative to the potential benefits. However, in post-market observational surveillance studies that actively monitor (e.g., sequentially over time) for safety risk of new medical products, available methods target a relative measure (e.g., odds ratio and relative risk), which can be especially unstable in the rare event setting. These studies are typically conducted within distributed healthcare networks (e.g., Food and Drug Administration [FDA] Sentinel and Centers for Disease Control [CDC] Vaccine Safety Datalink) with patient-level data protected behind firewalls, but sharing of aggregate, deidentified data for centralized analyses. We propose an inverse probability of treatment weighting (IPTW) method that uses site-specific propensity scores to estimate site-specific risk differences that are combined to create an overall stratified risk difference estimate. This method is tailored to the rare event setting and requires minimal data sharing. The stratified IPTW approach is then extended to the active post-market surveillance setting by incorporating group sequential monitoring boundaries using a novel permutation approach. A simulation study is conducted to evaluate the performance of the new methods relative to two centralized analysis approaches, and the methods are applied to a safety surveillance study comparing the risk of febrile seizure between two vaccines using FDA Sentinel Data from three healthcare organizations.

Mizoram is one of the hilly forested states in India and has the highest malaria cases based on population wise. Indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) are malaria vector control measures but the emergence of insecticide resistance presents a significant challenge to the effectiveness of vector control strategies. The survey was conducted in 3 highly malaria endemic districts to generate data on insecticide resistance in malaria vectors. Susceptibility tests were conducted on adult vector species as per the WHO standard technique with wild-caught mosquitoes. Female mosquitoes were exposed in 3 to 4 replicates on each occasion to the impregnated papers with specified discriminating dosages of the insecticides (DDT: 4%, deltamethrin: 0.05%, and alphacypermethrin: 0.05%), for one hour, and mortality was recorded after a 24-hour holding. DDT (4%) resistance was detected among the vector species in all 3 districts with mortality ranging from 64% to 84.3%. Deltamethrin was found susceptible while the possibility of resistance was also observed. Alpha-cypermethrin was found susceptible to all the selected study sites (98.75-100% mortality). Regular monitoring of insecticide susceptibility in malaria vectors is needed for implementing effective vector management strategies.

Abstract Moore swabs have been used extensively for passive sampling in wastewater surveillance, typically yielding presence/absence information for targets of interest. Quantitative analysis of Moore swab data is only possible if target uptake is well characterized, specifically the relationship between quantity of the target in the liquid sample matrix and the quantity of target sorbing to the Moore swab as a function of time. The mechanism of Moore swab absorption remains unclear and is important to understand toward using them more quantitatively. We conducted viral adsorption and desorption experiments using nonpathogenic SARS-CoV-2 surrogates: Φ6, MHV, and BCoV as well as heat-inactivated Zika virus (ZIKV). We fit empirical adsorption data from batch experiments to Langmuir, Freundlich and Redlich-Peterson isotherm models. We observed the adsorption behavior of viral targets onto Moore swabs is best characterized by the Redlich-Peterson isotherm model. Moore swabs retained the highest viral RNA concentrations after exposure durations between 9-12 hours in the presence of target microbes during kinetic viral adsorption experiments. The results inform current and future use of Moore swabs to produce quantitative data during wastewater surveillance, especially in settings where composite sampling remains infeasible.ImportanceThis paper describes the adsorption behavior of viruses and bacteriophages to Moore swabs. Passive sampling via Moore swabs is among the most scalable form of passive wastewater sampling, considered critical to advance wastewater surveillance globally. But key unknowns constrain the utility of Moore swabs and all passive sampling approaches, including the quantitative relationship between targets in wastewater and recovery via Moore swabs. Practical questions such as how long they should be deployed and whether they can be interpreted quantitatively really depend on a characterization of viral target loading behaviors on Moore swab material as a function of time and concentration in the wastewater. Here, we use an approach that is seldom applied to microbial targets to examine adsorption behavior of viruses to Moore swabs, deriving isotherms that describe the relationships between concentration of the viral targets in wastewater and time on attachment to swab material. This is a critical step in advancing the application of Moore swab passive sampling for wastewater surveillance, with potential relevance to other microbial targets of interest.

This work deals with the generation of theoretical correlation matrices with specific sparsity patterns, associated to graph structures. We present a novel approach based on convex optimization, offering greater flexibility compared to existing techniques, notably by controlling the mean of the entry distribution in the generated correlation matrices. This allows for the generation of correlation matrices that better represent realistic data and can be used to benchmark statistical methods for graph inference.

Abstract Analytical validation (AV) is a crucial step in the evaluation of algorithms that process data from sensor-based digital health technologies (sDHTs). AV of novel digital measures can be complicated when reference measures with direct correspondence are not available. To address this, we conducted a simulation study. Data was simulated assuming a latent physical ability trait, indirectly accessed through an sDHT-derived target measure collecting step count data, and the items of a clinical outcome assessment measuring self-reported physical activity. We quantified the ability of two methods to assess the latent relationship between reference and target measures: the Pearson Correlation Coefficient (PCC) (a classical, simple method frequently used for AV), and factor correlations from a two-factor confirmatory factor analysis (CFA) model (a more novel approach to AV, able to capture more complex relationships). Additionally, three multiple linear regression models were used to evaluate if multiple clinical outcome assessment reference measures can more completely represent a target measure of interest.Our findings show that PCC was more stable, easier to compute, and relatively robust with respect to violations of parametric assumptions than CFA, particularly with small sample sizes. However, CFA was less biased than PCC in all scenarios investigated. We demonstrate that using both PCC and CFA allows a researcher to be more confident that their AV results reflect the true relationship between the sDHT-derived target measure and a reference measure. Finally, regression results suggest that incorporating multiple reference measures with more frequent collection time points can provide a more complete presentation of the sDHT’s analytical validity.Novel digital measures are being developed at an accelerating pace and promise to revolutionize public health, patient care, and medical product development. Our findings provide investigators with crucial information for choosing appropriate methods to perform rigorous AV of these novel measures.

In patients with oligometastatic disease (OMD) treated with stereotactic body radiation therapy (SBRT), those who develop brain metastases (BrM) may have poor outcomes. We aimed to investigate variables associated with BrM development in this population. Patients with ≤ 5 extracranial metastases from solid tumors treated with SBRT from 2008 to 2016 at Sunnybrook Odette Cancer Centre were included. We investigated the association between covariates and CIBrM (cumulative incidence of BrM) using Fine-Gray analysis, and progression-free survival (PFS) and overall survival (OS) using Cox regression. We investigated the association between extracranial progression and CIBrM using time-based conditional analysis. Among 404 patients, the most common primary sites were lung, colorectal, prostate, breast and kidney. Median follow-up was 49 months. Median PFS was 25 months. Median OS was 70 months. 58 patients developed BrM, and 5-year CIBrM was 16%. On multivariable analysis, number of extracranial metastases, location of metastases, total planning target volume (PTV), and time from primary diagnosis to OMD were not associated with CIBrM, although several of these variables were associated with extracranial PFS and OS. Primary site was associated with CIBrM, with colorectal and prostate cancer associated with lower CIBrM compared to lung cancer. Widespread extracranial progression (≥ 5 sites) within 24, 36, 48 and 60 months of OMD diagnosis was independently associated with higher CIBrM. In patients with OMD treated with SBRT, baseline variables related to extracranial disease burden and distribution were not associated with BrM development, while primary site and widespread extracranial progression were associated with BrM development.

Daß die Music eine der allerangenehmsten Vergnügungen in der ganzen Welt sey / ist so gewiß und unstreitig wahr!daß niemand mit Recht etwas darwieder einzuwenden haben wird. Denn alle andere Lustbarkeiten / die sich ein Mensch in diesem Leben zu machen weiß/ erfordern zu ihrer Vollkommenheit allzeit mehrere Personen; diese aber ergötzet sich ganz allein / mit sich Selbsten / eben so wohl / als bei einer angenehmen Compagnie. Es ist solche eine edle Wissenschaft: Dann es haben sowohl Hohe als Niedere/sowohl Reiche als Arme ihre Freude an Derselben; und ist bekandt/daß Kayser / Könige /Fürsten und andere vornehme Stands-Personen! sich nicht gescheuetl sich darinnen zu üben/und bei langwiehrig verdrießlichen Geschäften damit zu ergötzen / wie deren Exempel fwo es nöthig) genug könten allegirt werden. Sie ist auch eine nöthige Wissenschafft; indem Sie unter die Requisita eines galant-Home gezehlet wird / und können die in Italien /Frankreich und andern Königlichen und Fürstlichen Höfen Europae befindlichen Virtuosi zur Genüge bezeugen/daß sie auch eine nützliche und einträgliche Wissenschafft sey. Sie gehöret dieserwegen auch unter die freye Künsten/und kan niemand verwehret werden/ seine erlernte Kunst zu exerciren / und sich übique locorum damit hören zu lassen. Wann alle Wissenschafften /Handthierungen und Gewerbe durch den verderblichen Krieg zu Boden liegen/so stehet diese noch im Flor. Die sumsende Paucken! die hellklingende Trompeten und andere musicalische Instrumenten müssen denen Soldaten den besten Muth zum Streit machen/daß sie in diesem angenehmen Getümmel ihr Leben getrost und mit Freuden für das Vatterland wagen und aufopfern. Die Music ergötzet die Frölichen/tröstet die Traurigen/ heilet die von Tarantulen beschädigte Personen; Davids Harfe vertreibt den bösen Geist. In Summa, die Music ist die allgemeine Vergnügung!Sie dienet in diesem und jenem Leben x . In der reichen und blühenden Reichsstadt Schwäbisch Hall, die einen wesentlichen Teil ihres Reichtums einer schon von den Kelten genutzten, dann aber verschütteten und im Mittelalter wiederentdeckten Salzquelle verdankte, reichen die frühesten bekannten musikalischen Quellen bis etwa ins Jahr 1400 zurück: aus den städtischen Steuerrechnungen, die ab 1411 erhalten sind, kennen wir die Namen 1 Zitiert nach dem Faksimile-Nachdruck, hrsg. von Heinz Becker, Kassel/Basel 1954.

The coronavirus pandemic (COVID) has been an extraordinary test of modern government scientific procedures that inform and shape policy. Many governments implemented COVID quarantine (stay-at-home) orders on the notion that this nonpharmaceutical intervention would delay and flatten the epidemic peak and largely benefit public health outcomes. The overall research capacity response to COVID since late 2019 has been massive. Given a lack of research transparency, only a small fraction of published research has been judged by others to be reproducible before COVID. Independent evaluation of published meta-analysis on a common research question can be used to assess the reproducibility of a claim coming from that field of research. We used a p-value plotting statistical method to independently evaluate reproducibility of specific research claims made in four meta-analysis studies related to benefits/harms of COVID quarantine orders. Research claims that these meta-analyses covered included: mortality, mental health symptoms, incidence of domestic violence, and suicidal ideation (thoughts of killing yourself). Three of the four meta-analysis studies that we evaluated (mortality, mental health symptoms, incidence of domestic violence) raise further questions about benefits/harms of this form of intervention. The fourth meta-analysis study (suicidal ideation) is judged to be unreliable. Given lack of research transparency and irreproducibility of published research, independent evaluation of meta-analysis studies using p-value plotting is offered as a way to strengthen or refute (falsify) claims made in COVID research.

PurposeStudies have shown that multiple genes influence antibiotic susceptibility, but the relationship between genotypic and phenotypic antibiotic susceptibility is unclear. We sought to analyze the concordance between the presence of antibiotic resistance (ABR) genes and antibiotic susceptibility results in urine samples collected from patients with symptomatic urinary tract infection (UTI).Patients and MethodsUrine samples were collected from patients presenting to 37 geographically disparate urology clinics across the United States from July 2018 to February 2019. Multiplex polymerase chain reaction was used to detect 27 ABR genes. In samples containing at least one culturable organism at a concentration of ≥ 104 cells per mL, pooled antibiotic susceptibility testing (P-AST), which involves simultaneous growing all detected bacteria together in the presence of antibiotic and then measure susceptibility, was performed against 14 antibiotics. The concordance rate between the ABR genes and the P-AST results was generated for the overall group. The concordance rates for each antibiotic between monomicrobial and polymicrobial infection were compared using chi-square test.ResultsResults from ABR gene detection and P-AST of urine samples from 1155 patients were included in the concordance analysis. Overall, there was a 60% concordance between the presence or absence of ABR genes and corresponding antimicrobial susceptibility with a range of 49–78% across antibiotic classes. Vancomycin, meropenem, and piperacillin/tazobactam showed significantly lower concordance rates in polymicrobial infections than in monomicrobial infections.ConclusionGiven the 40% discordance rate, the detection of ABR genes alone may not provide reliable data to make informed clinical decisions in UTI management. However, when used in conjunction with susceptibility testing, ABR gene data can offer valuable clinical information for antibiotic stewardship.

Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.).