scholarly journals Is there sufficient scientific evidence to rule out the use of hydroxychloroquine for postexposure prophylaxis of COVID-19?

2020 ◽  
Author(s):  
Llorenç Quintó ◽  
Jose Miguel Morales-Asencio ◽  
Raquel González ◽  
Clara Menéndez
Keyword(s):  
Public Health ◽  
Effect Size ◽  
Statistical Power ◽  
Scientific Evidence ◽  
Post Exposure Prophylaxis ◽  
Postexposure Prophylaxis ◽  
Post Hoc Analysis ◽  
Exposure Prophylaxis ◽  
Post Hoc ◽  
Rule Out

Since the beginning of the COVID-19 pandemic, the use of hydroxychloroquine (HCQ) has been surrounded by a lot of controversy, both scientific and non-scientific. This has continued with the publication of two trials of HCQ for post-exposure prophylaxis of the infection, which concluded that HCQ is not efficacious to prevent SARS-CoV-2 infection, and their results are influencing public health decisions.We have carried out a comprehensive post-hoc analysis of the statistical power of the two trials, which shows that their power to detect an effect of HCQ in preventing COVID-19 is low, not only for their observed effect size, but also for other clinically important levels of efficacy, and therefore both studies are inconclusive.

Exploring the Morning Morality Effect in the context of moral utilitarianism: a post-hoc analysis

2021 ◽  
Author(s):  
Bastien Trémolière ◽  
Corentin J Gosling
Keyword(s):  
Effect Size ◽  
Autonomous Vehicles ◽  
Meta Analysis ◽  
Individual Study ◽  
Post Hoc Analysis ◽  
Cognitive Reflection ◽  
Confounding Variables ◽  
Small Effect Size ◽  
Large Heterogeneity ◽  
Post Hoc

Recent research has shown mixed evidence for the morning morality effect (i.e., the observation that individuals are less immoral in the morning than in the afternoon). In the present research, we target the morning morality effect in the context of moral utilitarianism, by reanalyzing observational data previously collected by our lab. These data include different tasks capturing moral utilitarianism (i.e., standard sacrificial dilemmas, an ecological utilitarian scale, and/or dilemmas involving the morality of autonomous vehicles). We report a meta-analysis of 6 studies which showed that participants became less utilitarian as the day goes on, but with a small effect size (r = -0.14) and a large heterogeneity. Exploration of this heterogeneity showed that such a conclusion was statistically significant for classic sacrificial dilemmas only. Notably, even when restricting the analysis to the classic sacrificial dilemmas, a moderate inconsistency remained. Post-hoc analysis of an individual study showed that this small effect did not survive the inclusion of potentially confounding variables, such as psychopathy trait and cognitive reflection. Implications and limitations are discussed.

scholarly journals Partial derivatives meta-analysis: pooled analyses when individual participant data cannot be shared

2016 ◽  
Author(s):  
Hieab HH Adams ◽  
Hadie Adams ◽  
Lenore J Launer ◽  
Sudha Seshadri ◽  
Reinhold Schmidt ◽  
...  
Keyword(s):  
Gold Standard ◽  
Statistical Power ◽  
Large Scale ◽  
Meta Analysis ◽  
Scientific Evidence ◽  
Joint Analysis ◽  
Individual Participant Data ◽  
Partial Derivatives ◽  
Individual Participant ◽  
Post Hoc

Joint analysis of data from multiple studies in collaborative efforts strengthens scientific evidence, with the gold standard approach being the pooling of individual participant data (IPD). However, sharing IPD often has legal, ethical, and logistic constraints for sensitive or high-dimensional data, such as in clinical trials, observational studies, and large-scale omics studies. Therefore, meta-analysis of study-level effect estimates is routinely done, but this compromises on statistical power, accuracy, and flexibility. Here we propose a novel meta-analytical approach, named partial derivatives meta-analysis, that is mathematically equivalent to using IPD, yet only requires the sharing of aggregate data. It not only yields identical results as pooled IPD analyses, but also allows post-hoc adjustments for covariates and stratification without the need for site-specific re-analysis. Thus, in case that IPD cannot be shared, partial derivatives meta-analysis still produces gold standard results, which can be used to better inform guidelines and policies on clinical practice.

scholarly journals Chemoprophylaxis trial designs in epidemics: insights from a systematic review of COVID-19 study registrations

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lakshmi Manoharan ◽  
Piero Olliaro ◽  
Peter W. Horby ◽  
Conall H. Watson
Keyword(s):  
Older Adults ◽  
Effect Size ◽  
Adaptive Design ◽  
Rapid Development ◽  
Control Group ◽  
Post Exposure Prophylaxis ◽  
Design Features ◽  
Included Trial ◽  
Term Care ◽  
Exposure Prophylaxis

Abstract Background Chemoprophylactics against emerging epidemic and pandemic infectious diseases offer potential for prevention but require efficacy and safety analysis before widespread use can be recommended. Chemoprophylaxis with repurposed drugs enables deployment ahead of development of novel vaccines. It may have particular utility as a stopgap ahead of vaccine deployment or when vaccines become less effective on virus variants, in countries where there may be structural inaccessibility to vaccines or in specific risk-groups. Rapid implementation of robust trial designs is a persistent challenge in epidemics. We systematically reviewed SARS-CoV-2 and COVID-19 chemoprophylaxis trial registrations from the first 21 weeks of the pandemic to critically appraise significant design features and alignment of study populations to clinical and public health uses, and describe candidate chemoprophylactic agents. Methods We searched online international trial databases from 31 Dec 2019 to 26 May 2020 using keywords “proph*” or “prevention”. Trial protocols assessing efficacy of chemoprophylactic agents for COVID-19 were included. Trial components were screened for eligibility and relevant studies extracted. Key trial design features were assessed. Results We found 76 chemoprophylaxis study registrations, proposing enrolment of 208,367 people with median size of 490 (IQR 262–1710). A randomised design was specified for 63 trials, 61 included a control group and total proposed enrolment size was 197,010, median 600 (IQR 236–1834). Four protocols provided information on effect size sought. We estimate that for a control group attack rate of 10%, 66% of trials would be underpowered to detect a 50% effect size, and 97% of trials would be underpowered to detect a 30% effect size (at the 80% level). We found evidence of adaptive design in one trial registration only. Laboratory-confirmed infection with or without symptoms was the most common primary outcome. Polymerase chain reaction testing alone was used in 46% of trials, serological testing in 6.6% and 14.5% used both testing methods. Healthcare workers were the target population in 52/79 (65.8%) trials: 49 pre-exposure prophylaxis (PrEP) and 3 post-exposure prophylaxis (PEP). Sixteen trials (20.3%) planned PEP in close contacts. Five studies (6.3%) considered chemoprophylaxis in clinical-risk patients. Older adults were the focus of recruitment in only 3 (3.8%) studies (all long-term care facilities). Two (2.5%) studies of PrEP in the general population included older adults. Hydroxychloroquine was the most common candidate agent in 55/79 trials (69.6%), followed by chloroquine (4/79, 5.0%) and lopinavir/ritonavir (3/79, 3.8%). Conclusion Many registered COVID-19 chemoprophylaxis efficacy trials were underpowered to detect clinically meaningful protection at epidemiologically informed attack rates. This, compounded with the time that has taken to organise these trials as compared to the rapid development of COVID-19 vaccines, has rendered these trials of marginal importance. International coordination mechanisms and collaboration is required. Supporting the design of feasible chemoprophylaxis trials, large enough to generate strong evidence, early on in an epidemic using adaptive platform trial designs will allow structured entry and exit of candidate agents and rapid stand-up of trial infrastructure. Review protocol registration Our protocol is registered at https://www.osf.io/vp56f on May 20, 2020.

Pattern and Outcome of Dog Bite Injuries among Children-a Study in 200 Cases

2021 ◽  
pp. 1-5
Author(s):  
Md Waliur Rahman ◽  
◽  
Md Habibullah Sarkar ◽  
Samir Kumar Talukder ◽  
Md Joynal Abedin ◽  
...  
Keyword(s):  
Public Health ◽  
Health Problem ◽  
Public Health Problem ◽  
Hospital Treatment ◽  
Post Exposure Prophylaxis ◽  
Dog Bite ◽  
Post Exposure ◽  
Dog Bites ◽  
Exposure Prophylaxis ◽  
Bite Injuries

Introduction: Dog bites in humans are a major public health problem. Globally, millions of people are bitten by dogs but most of the fatal cases occur in children. Dog bites in human are a serious public health problem and have been well documented worldwide. As rabies is not a notifiable disease in Bangladesh and most deaths occur in rural areas where surveillance is poor. Objectives: To determine the pattern of dog bite injuries and associated health problems among children. Methods: The study was an observational retrospective study carried out at the Dept. of General Surgery, Chuadanga Sadar Hospital, Chuadanga, Bangladesh. The study reviewed the clinical data of patients managed for dog bite related injuries and rabies over a four and half year period between January 2016 and June 2020. A proforma was designed to extract relevant clinical data from the case records. Information extracted included the age, sex of the victims, site of the bite, time of presentation in the hospital, pre-hospital treatment, hospital treatment including post-exposure prophylaxis and complication. Results: In all, 200 cases of dog bite injuries were managed constituting 0.89% of the total consultations; 5 (2.5%) had rabies. Most of the victims were aged 6-12 years (55.0%) and majority (67.0%) was boys. Eighty two percent of the victims presented within 24hrs of the injury. 92 (46.0%) had WHO grade 3 dog bite injury at presentation and the lower limb was the commonest (56.0%) bite site. Use of herbal preparation was the most common pre-hospital treatment 60%. Although 95.0% received anti-rabies vaccine, only 55.5% of them completed the vaccination schedule. The case fatality rate for dog bite was 5.0%. The 5 that died all presented late, had no post exposure prophylaxis and died within 24 hours of admission. Conclusion: There is need for public enlightenment on dangers associated with dog bites and also for the government to ensure vaccination for cost of post exposure prophylaxis treatment for children free of cost

Statistical power of negative randomized clinical trials (RCTs) presented at the American Society of Clinical Oncology (ASCO) Annual Meetings

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6516-6516
Author(s):  
P. Bedard ◽  
M. K. Krzyzanowska ◽  
M. Pintilie ◽  
I. F. Tannock
Keyword(s):  
Clinical Trials ◽  
Sample Size ◽  
Annual Meeting ◽  
Primary Endpoint ◽  
Effect Size ◽  
Statistical Power ◽  
Randomized Clinical Trials ◽  
Medium Effect ◽  
Post Hoc ◽  
Adequate Sample Size

6516 Background: Underpowered randomized clinical trials (RCTs) may expose participants to risks and burdens of research without scientific merit. We investigated the prevalence of underpowered RCTs presented at ASCO annual meetings. Methods: We surveyed all two-arm parallel phase III RCTs presented at the ASCO annual meeting from 1995–2003 where differences for the primary endpoint were non-statistically significant. Post hoc calculations were performed using a power of 80% and a=0.05 (two-sided) to determine the sample size required to detect a small, medium, and large effect size between the two groups. For studies reporting a proportion or time to event as a primary endpoint, effect size was expressed as an odds ratio (OR) or hazard ratio (HR) respectively, with a small effect size defined as OR/HR=1.3, medium effect size OR/HR=1.5, and large effect OR/HR=2.0. Logistic regression was used to identify factors associated with lack of statistical power. Results: Of 423 negative RCTs for which post hoc sample size calculations could be performed, 45 (10.6%), 138 (32.6%), and 333 (78.7%) had adequate sample size to detect small, medium, and large effect sizes respectively. Only 35 negative RCTs (7.1%) reported a reason for inadequate sample size. In a multivariable model, studies presented at plenary or oral sessions (p<0.0001) and multicenter studies supported by a co-operative group were more likely to have adequate sample size (p<0.0001). Conclusion: Two-thirds of negative RCTs presented at the ASCO annual meeting do not have an adequate sample to detect a medium-sized treatment effect. Most underpowered negative RCTs do not report a sample size calculation or reasons for inadequate patient accrual. No significant financial relationships to disclose.

scholarly journals Monoclonal Antibody Treatment, Prophylaxis and Vaccines Combined to Reduce SARS CoV-2 Spread

2021 ◽  
Author(s):  
Mohamed A. Kamal ◽  
Andreas Kuznik ◽  
Luyuan Qi ◽  
Witold Więcek ◽  
Mohamed Hussein ◽  
...  
Keyword(s):  
Public Health ◽  
Diagnostic Testing ◽  
Post Exposure Prophylaxis ◽  
Antibody Treatment ◽  
Viral Shedding ◽  
The Us ◽  
Monoclonal Antibody Treatment ◽  
Exposure Prophylaxis ◽  
Respiratory Coronavirus ◽  
The Impact

Background Antiviral monoclonal antibodies (mAbs) developed for treatment of COVID-19 reduce the magnitude and duration of viral shedding and can thus potentially contribute to reducing transmission of the causative virus, severe acute respiratory coronavirus 2 (SARS-CoV-2). However, use of these mAbs in combination with a vaccine program has not been considered in public health strategic planning. Methods We developed an agent-based model to characterize SARS-CoV-2 transmission in the US population during an aggressive phase of the pandemic (October 2020 to April 2021), and simulated the effects on infections and mortality of combining mAbs as treatment and post-exposure prophylaxis (PEP) with a vaccine program plus non-pharmaceutical interventions. We also interrogated the impact of rapid diagnostic testing, increased mAb supply, and vaccine rollout. Findings Allocation of mAbs as PEP or targeting those ≥65 years provided the greatest incremental benefits relative to vaccine in averting infections and deaths, by up to 17% and 41%, respectively. Rapid testing, facilitating earlier diagnosis and mAb use, amplified these benefits. The model was sensitive to mAb supply; doubling supply further reduced infections and mortality, by up to two-fold, relative to vaccine. mAbs continued to provide incremental benefits even as proportion of the vaccinated population increased. Interpretation Use of anti-viral mAbs as treatment and PEP in combination with a vaccination program would substantially reduce SARS-CoV-2 transmission and pandemic burden. These results may help guide resource allocation and patient management decisions for COVID-19 and can also be used to inform public health policy for current and future pandemic preparedness.

scholarly journals A general and powerful stage-wise testing procedure for differential expression and differential transcript usage

2017 ◽  
Author(s):  
Koen Van den Berge ◽  
Charlotte Soneson ◽  
Mark D. Robinson ◽  
Lieven Clement
Keyword(s):  
Multiple Testing ◽  
Statistical Power ◽  
Error Control ◽  
Transcript Level ◽  
Testing Procedure ◽  
Cancer Case ◽  
Rna Seq ◽  
Post Hoc Analysis ◽  
Gene Level ◽  
Post Hoc

AbstractBackgroundReductions in sequencing cost and innovations in expression quantification have prompted an emergence of RNA-seq studies with complex designs and data analysis at transcript resolution. These applications involve multiple hypotheses per gene, leading to challenging multiple testing problems. Conventional approaches provide separate top-lists for every contrast and false discovery rate (FDR) control at individual hypothesis level. Hence, they fail to establish proper gene-level error control, which compromises downstream validation experiments. Tests that aggregate individual hypotheses are more powerful and provide gene-level FDR control, but in the RNA-seq literature no methods are available for post-hoc analysis of individual hypotheses.ResultsWe introduce a two-stage procedure that leverages the increased power of aggregated hypothesis tests while maintaining high biological resolution by post-hoc analysis of genes passing the screening hypothesis. Our method is evaluated on simulated and real RNA-seq experiments. It provides gene-level FDR control in studies with complex designs while boosting power for interaction effects without compromising the discovery of main effects. In a differential transcript usage/expression context, stage-wise testing gains power by aggregating hypotheses at the gene level, while providing transcript-level assessment of genes passing the screening stage. Finally, a prostate cancer case study highlights the relevance of combining gene with transcript level results.ConclusionStage-wise testing is a general paradigm that can be adopted whenever individual hypotheses can be aggregated. In our context, it achieves an optimal middle ground between biological resolution and statistical power while providing gene-level FDR control, which is beneficial for downstream biological interpretation and validation.

scholarly journals Passive surveillance of United Kingdom bats for lyssaviruses (2005–2015)

2017 ◽  
Vol 145 (12) ◽  
pp. 2445-2457 ◽  
Author(s):  
E. L. WISE ◽  
D. A. MARSTON ◽  
A. C. BANYARD ◽  
H. GOHARRIZ ◽  
D. SELDEN ◽  
...  
Keyword(s):  
Public Health ◽  
Phylogenetic Analysis ◽  
United Kingdom ◽  
Natural Population ◽  
Single Species ◽  
Post Exposure Prophylaxis ◽  
Passive Surveillance ◽  
Myotis Daubentonii ◽  
Geographical Clustering ◽  
Exposure Prophylaxis

SUMMARYPassive surveillance for lyssaviruses in UK bats has been ongoing since 1987 and has identified 13 cases of EBLV-2 from a single species;Myotis daubentonii. No other lyssavirus species has been detected. Between 2005 and 2015, 10 656 bats were submitted, representing 18 species, creating a spatially and temporally uneven sample of British bat fauna. Uniquely, three UK cases originate from a roost at Stokesay Castle in Shropshire, England, where daily checks for grounded and dead bats are undertaken and bat carcasses have been submitted for testing since 2007. Twenty per cent of Daubenton's bats submitted from Stokesay Castle since surveillance began, have tested positive for EBLV-2. Phylogenetic analysis reveals geographical clustering of UK viruses. Isolates from Stokesay Castle are more closely related to one another than to viruses from other regions. Daubenton's bats from Stokesay Castle represent a unique opportunity to study a natural population that appears to maintain EBLV-2 infection and may represent endemic infection at this site. Although the risk to public health from EBLV-2 is low, consequences of infection are severe and effective communication on the need for prompt post-exposure prophylaxis for anyone that has been bitten by a bat is essential.

scholarly journals Efficacy of Lurasidone in Antipsychotic-Naive vs. Antipsychotic-Exposed Adolescents with Schizophrenia: Post-Hoc Analysis of a Two-Year, Open-Label Study

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 147-147
Author(s):  
Christoph Correll ◽  
Michael Tocco ◽  
Andrei Pikalov ◽  
Jay Hsu ◽  
Robert Goldman
Keyword(s):  
Effect Size ◽  
Extension Phase ◽  
Controlled Study ◽  
Open Label ◽  
Antipsychotic Therapy ◽  
Post Hoc Analysis ◽  
Long Term Treatment ◽  
Treatment Naïve ◽  
Post Hoc

AbstractBackgroundFew studies have examined treatment response in adolescents with schizophrenia who are treatment-naive; and there is no placebo-controlled study that we are aware of in first episode treatment-naive patients with schizophrenia. The aim of this analysis was to evaluate the long-term efficacy of lurasidone in antipsychotic-naive adolescents with schizophrenia.MethodPatients aged 13–17 years with schizophrenia, and a PANSS total score ≥70 and <120, were randomized to 6 weeks of double-blind (DB) treatment with lurasidone (40 or 80 mg/day) or placebo. Six-week completers were eligible to enroll in a 2-year open-label extension phase receiving lurasidone flexibly dosed from 20–80 mg/day. In a post-hoc analysis, efficacy was evaluated for 2 patient groups based on treatment status prior to entering the initial 6-week DB study (treatment naïve [TN] vs. treated previously [TP]). Treatment-naïve was defined as never having received antipsychotic treatment. Efficacy measures included the PANSS total score and the Clinical Global Impression, Severity (CGI-S) score. Level of functioning was assessed using the Children’s Global Assessment Scale (CGAS), with a score of 70 representing normative levels of functioning.ResultsA total of 50 TN and 221 TP patients completed the 6-week DB study and entered the extension study; and 30 (60.0%) TN and 126 (57.0%) TP patients completed 104 weeks. During the initial 6 weeks of DB treatment, mean change in PANSS total score at endpoint was greater for lurasidone vs. placebo in both the TN group (−25.0 vs. −14.4; P<0.02; effect size, 0.75), and in the TP group (−17.3 vs. −10.0; P<0.001; effect size, 0.45). During OL extension phase treatment with lurasidone, mean change from DB baseline in the PANSS total score for TN and TP patients, at week 52 was −32.6 (n=38) and −28.1 (n=151), respectively; and at week 104 was −33.6 (n=30) and −29.2 (n=126), respectively. Mean change from DB baseline in CGI-S score at both weeks 52 and 104 was −1.8 for TN patients and −1.5 for TP patients. At DB baseline mean CGAS scores indicated significant functional impairment in both the TN and TP patients (CGAS=48 and 43, respectively). During OL treatment with lurasidone, mean change (from DB baseline) in the CGAS score at Weeks 52 and 104, respectively, was +22.0 and +22.9 in TN patients, and +21.1 and +22.9 in TP patients. During OL treatment with lurasidone, mean observed change from DB baseline in the weight (in kg,) at Weeks 52 and 104, respectively, was +4.2 and +4.8 in TN patients, and +4.0 and +5.0 in TP patients. These weight increases are consistent with expected weight gains in adolescents during a 2-year period (based on CDC growth charts).ConclusionsIn this post-hoc analysis of a 2-year study, adolescents with schizophrenia who had received no previous antipsychotic therapy showed greater improvement compared to previously treated patients during both short- and long-term treatment with lurasidone.FundingSunovion Pharmaceuticals Inc.

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