1,059 research outputs found

    Beyond ‘significance’:Principles and practice of the analysis of credibility

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    The inferential inadequacies of statistical significance testing are now widely recognized. There is, however, no consensus on how to move research into a ‘post p < 0.05’ era. We present a potential route forward via the Analysis of Credibility, a novel methodology that allows researchers to go beyond the simplistic dichotomy of significance testing and extract more insight from new findings. Using standard summary statistics, AnCred assesses the credibility of significant and non-significant findings on the basis of their evidential weight, and in the context of existing knowledge. The outcome is expressed in quantitative terms of direct relevance to the substantive research question, providing greater protection against misinterpretation. Worked examples are given to illustrate how AnCred extracts additional insight from the outcome of typical research study designs. Its ability to cast light on the use of p-values, the interpretation of non-significant findings and the so-called ‘replication crisis’ is also discussed

    Molecular pathological epidemiology: the role of epidemiology in the omics-era

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    Altered Gene Expression in Pulmonary Tissue of Tryptophan Hydroxylase-1 Knockout Mice: Implications for Pulmonary Arterial Hypertension

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    The use of fenfluramines can increase the risk of developing pulmonary arterial hypertension (PAH) in humans, but the mechanisms responsible are unresolved. A recent study reported that female mice lacking the gene for tryptophan hydroxylase-1 (Tph1(−/−) mice) were protected from PAH caused by chronic dexfenfluramine, suggesting a pivotal role for peripheral serotonin (5-HT) in the disease process. Here we tested two alternative hypotheses which might explain the lack of dexfenfluramine-induced PAH in Tph1(−/−) mice. We postulated that: 1) Tph1(−/−) mice express lower levels of pulmonary 5-HT transporter (SERT) when compared to wild-type controls, and 2) Tph1(−/−) mice display adaptive changes in the expression of non-serotonergic pulmonary genes which are implicated in PAH. SERT was measured using radioligand binding methods, whereas gene expression was measured using microarrays followed by quantitative real time PCR (qRT-PCR). Contrary to our first hypothesis, the number of pulmonary SERT sites was modestly up-regulated in female Tph1(−/−) mice. The expression of 51 distinct genes was significantly altered in the lungs of female Tph1(−/−) mice. Consistent with our second hypothesis, qRT-PCR confirmed that at least three genes implicated in the pathogenesis of PAH were markedly up-regulated: Has2, Hapln3 and Retlna. The finding that female Tph1(−/−) mice are protected from dexfenfluramine-induced PAH could be related to compensatory changes in pulmonary gene expression, in addition to reductions in peripheral 5-HT. These observations emphasize the intrinsic limitation of interpreting data from studies conducted in transgenic mice that are not fully characterized

    A cost effectiveness and capacity analysis for the introduction of universal rotavirus vaccination in Kenya : comparison between Rotarix and RotaTeq vaccines

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    Background Diarrhoea is an important cause of death in the developing world, and rotavirus is the single most important cause of diarrhoea associated mortality. Two vaccines (Rotarix and RotaTeq) are available to prevent rotavirus disease. This analysis was undertaken to aid the decision in Kenya as to which vaccine to choose when introducing rotavirus vaccination. Methods Cost-effectiveness modelling, using national and sentinel surveillance data, and an impact assessment on the cold chain. Results The median estimated incidence of rotavirus disease in Kenya was 3015 outpatient visits, 279 hospitalisations and 65 deaths per 100,000 children under five years of age per year. Cumulated over the first five years of life vaccination was predicted to prevent 34% of the outpatient visits, 31% of the hospitalizations and 42% of the deaths. The estimated prevented costs accumulated over five years totalled US1,782,761(directandindirectcosts)withanassociated48,585DALYs.FromasocietalperspectiveRotarixhadacost−effectivenessratioofUS1,782,761 (direct and indirect costs) with an associated 48,585 DALYs. From a societal perspective Rotarix had a cost-effectiveness ratio of US142 per DALY (US5forthefullcourseoftwodoses)andRotaTeqUS5 for the full course of two doses) and RotaTeq US288 per DALY ($10.5 for the full course of three doses). RotaTeq will have a bigger impact on the cold chain compared to Rotarix. Conclusion Vaccination against rotavirus disease is cost-effective for Kenya irrespective of the vaccine. Of the two vaccines Rotarix was the preferred choice due to a better cost-effectiveness ratio, the presence of a vaccine vial monitor, the requirement of fewer doses and less storage space, and proven thermo-stability

    Promotion of Prescription Drugs to Consumers and Providers, 2001–2010

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    Background: Pharmaceutical firms heavily promote their products and may have changed marketing strategies in response to reductions in new product approvals, restrictions on some forms of promotion, and the expanding role of biologic therapies. Methods: We used descriptive analyses of annual cross-sectional data from 2001 through 2010 to examine direct-to-consumer advertising (DTCA) (Kantar Media) and provider-targeted promotion (IMS Health and SDI), including: (1) inflation-adjusted total promotion spending (andpercentofsales);(2)distributionbychannel(consumerv.provider);and(3)providerspecialtybothfortheindustryasawholeandfortop−sellingbiologicandsmallmoleculetherapies.Results:Totalpromotionpeakedin2004atUS and percent of sales); (2) distribution by channel (consumer v. provider); and (3) provider specialty both for the industry as a whole and for top-selling biologic and small molecule therapies. Results: Total promotion peaked in 2004 at US36.1 billion (13.4% of sales). By 2010 it had declined to 27.7B(9.027.7B (9.0% of sales). Between 2006 and 2010, similar declines were seen for promotion to providers and DTCA (both by 25%). DTCA’s share of total promotion increased from 12% in 2002 to 18% in 2006, but then declined to 16% and remains highly concentrated. Number of products promoted to providers peaked in 2004 at over 3000, and then declined 20% by 2010. In contrast to top-selling small molecule therapies having an average of 370 million (8.8% of sales) spent on promotion, top biologics were promoted less, with only $33 million (1.4% of sales) spent per product. Little change occurred in the composition of promotion between primary care physicians and specialists from 2001–2010. Conclusions: These findings suggest that pharmaceutical companies have reduced promotion following changes in the pharmaceutical pipeline and patent expiry for several blockbuster drugs. Promotional strategies for biologic drugs differ substantially from small molecule therapies

    Editors, Publishers, Impact Factors, and Reprint Income

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    Harvey Marcovitch discusses new research findings from Andreas Lundh and colleagues that examined the effect of publishing industry-funded clinical trials on journal citations and reprint income at six major medical journals

    Doctors and Drug Companies: Still Cozy after All These Years

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    David Henry discusses a research article by Geoffrey Spurling and colleagues that examined the relationship between exposure to promotional material from pharmaceutical companies and the quality, quantity, and cost of prescribing

    Mandatory Disclosure of Pharmaceutical Industry-Funded Events for Health Professionals

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    David Henry and colleagues examine compliance with new disclosure requirements of Medicines Australia, the pharmaceutical industry representative body, and argue that they fall short and instead more comprehensive reporting standards are needed

    Low dose radiation and cancer in A-bomb survivors: latency and non-linear dose-response in the 1950–90 mortality cohort

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    BACKGROUND: Analyses of Japanese A-bomb survivors' cancer mortality risks are used to establish recommended annual dose limits, currently set at 1 mSv (public) and 20 mSv (occupational). Do radiation doses below 20 mSv have significant impact on cancer mortality in Japanese A-bomb survivors, and is the dose-response linear? METHODS: I analyse stomach, liver, lung, colon, uterus, and all-solid cancer mortality in the 0 – 20 mSv colon dose subcohort of the 1950–90 (grouped) mortality cohort, by Poisson regression using a time-lagged colon dose to detect latency, while controlling for gender, attained age, and age-at-exposure. I compare linear and non-linear models, including one adapted from the cellular bystander effect for α particles. RESULTS: With a lagged linear model, Excess Relative Risk (ERR) for the liver and all-solid cancers is significantly positive and several orders of magnitude above extrapolations from the Life Span Study Report 12 analysis of the full cohort. Non-linear models are strongly superior to the linear model for the stomach (latency 11.89 years), liver (36.90), lung (13.60) and all-solid (43.86) in fitting the 0 – 20 mSv data and show significant positive ERR at 0.25 mSv and 10 mSv lagged dose. The slope of the dose-response near zero is several orders of magnitude above the slope at high doses. CONCLUSION: The standard linear model applied to the full 1950–90 cohort greatly underestimates the risks at low doses, which are significant when the 0 – 20 mSv subcohort is modelled with latency. Non-linear models give a much better fit and are compatible with a bystander effect

    The importance of adjusting for potential confounders in Bayesian hierarchical models synthesising evidence from randomised and non-randomised studies: an application comparing treatments for abdominal aortic aneurysms

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    <p>Abstract</p> <p>Background</p> <p>Informing health care decision making may necessitate the synthesis of evidence from different study designs (e.g., randomised controlled trials, non-randomised/observational studies). Methods for synthesising different types of studies have been proposed, but their routine use requires development of approaches to adjust for potential biases, especially among non-randomised studies. The objective of this study was to extend a published Bayesian hierarchical model to adjust for bias due to confounding in synthesising evidence from studies with different designs.</p> <p>Methods</p> <p>In this new methodological approach, study estimates were adjusted for potential confounders using differences in patient characteristics (e.g., age) between study arms. The new model was applied to synthesise evidence from randomised and non-randomised studies from a published review comparing treatments for abdominal aortic aneurysms. We compared the results of the Bayesian hierarchical model adjusted for differences in study arms with: 1) unadjusted results, 2) results adjusted using aggregate study values and 3) two methods for downweighting the potentially biased non-randomised studies. Sensitivity of the results to alternative prior distributions and the inclusion of additional covariates were also assessed.</p> <p>Results</p> <p>In the base case analysis, the estimated odds ratio was 0.32 (0.13,0.76) for the randomised studies alone and 0.57 (0.41,0.82) for the non-randomised studies alone. The unadjusted result for the two types combined was 0.49 (0.21,0.98). Adjusted for differences between study arms, the estimated odds ratio was 0.37 (0.17,0.77), representing a shift towards the estimate for the randomised studies alone. Adjustment for aggregate values resulted in an estimate of 0.60 (0.28,1.20). The two methods used for downweighting gave odd ratios of 0.43 (0.18,0.89) and 0.35 (0.16,0.76), respectively. Point estimates were robust but credible intervals were wider when using vaguer priors.</p> <p>Conclusions</p> <p>Covariate adjustment using aggregate study values does not account for covariate imbalances between treatment arms and downweighting may not eliminate bias. Adjustment using differences in patient characteristics between arms provides a systematic way of adjusting for bias due to confounding. Within the context of a Bayesian hierarchical model, such an approach could facilitate the use of all available evidence to inform health policy decisions.</p
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