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Understanding the potential for, direction, and magnitude of uncontrolled confounding is critical for generating informative real-world evidence. Many sensitivity analyses are available to assess robustness of study results to residual confounding, but it is unclear how researchers are using these methods. We conducted a systematic review of published active comparator cohort studies of drugs or biologics to summarize use of sensitivity analyses aimed at assessing uncontrolled confounding from an unmeasured variable. We reviewed articles in five medical and seven epidemiologic journals published between January 1, 2017, and June 30, 2022. We identified 158 active comparator cohort studies, 76 from medical and 82 from epidemiologic journals. Residual, unmeasured, or uncontrolled confounding was noted as a potential concern in 93% of studies, but only 84 (53%) implemented one or more sensitivity analysis to assess uncontrolled confounding from an unmeasured variable. The most common analyses were E-values among medical journal articles (21%) and restriction on measured variables among epidemiologic journal articles (22%). Researchers must rigorously consider the role of residual confounding in their analyses and the best sensitivity analyses for assessing this potential bias.
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PURPOSE: Although the limitations of hazard ratios (HRs) for quantifying treatment effects in right-censored data have been widely discussed, HRs are still preferentially reported over other, more interpretable effect measures. This may stem from the fact that there are few applied examples that directly contrast the HR and its interpretation with alternative effect measures. METHODS: We analyzed data from two randomized clinical trials comparing panitumumab plus standard-of-care chemotherapy (SOCC) with SOCC alone as first- and second-line treatment for metastatic colorectal cancer. We report the effect of treatment with panitumumab on progression-free survival (PFS) using a Cox proportional hazards model to estimate the HR and the Kaplan-Meier estimator of cumulative incidence (risk). Further analyses included examining the cumulative incidence curves; kernel-smoothed, non-parametric hazards curves; fitting the Cox model with a continuous time variable; and estimating restricted mean survival as well as median survival. RESULTS: The HR was 0.82 (95% confidence interval [CI]: 0.71, 0.93), while the risk ratio (or relative risk [i.e., ratio of the cumulative incidence among the treated versus comparator]) was 0.99 (95% CI: 0.96, 1.02). These two measures suggest apparently different conclusions: either a treatment benefit or no effect. Through subsequent analyses, we demonstrated that, while the cumulative incidence of the outcome was similar by the end of follow-up regardless of treatment, the panitumumab treated group experienced longer PFS than those randomized to SOCC. Substantial nonproportional hazards were evident with panitumumab treatment reducing the hazard of progression/mortality during the first ~1.75 years but associated with an increased hazard of progress/mortality thereafter. DISCUSSION: This example underscores the difficulties in interpreting HRs, particularly in the setting of qualitative violations of proportional hazards, and the value of quantifying treatment effects via multiple effect measures.
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Neoplasias Colorretais , Panitumumabe , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Panitumumabe/uso terapêutico , Panitumumabe/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/epidemiologia , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Estimativa de Kaplan-Meier , Feminino , Masculino , Pessoa de Meia-Idade , Antineoplásicos Imunológicos/uso terapêutico , IdosoRESUMO
Active comparator studies are increasingly common, particularly in pharmacoepidemiology. In such studies, the parameter of interest is a contrast (difference or ratio) in the outcome risks between the treatment of interest and the selected active comparator. While it may appear treatment is dichotomous, treatment is actually polytomous as there are at least 3 levels: no treatment, the treatment of interest, and the active comparator. Because misclassification may occur between any of these groups, independent nondifferential treatment misclassification may not be toward the null (as expected with a dichotomous treatment). In this work, we describe bias from independent nondifferential treatment misclassification in active comparator studies with a focus on misclassification that occurs between each active treatment and no treatment. We derive equations for bias in the estimated outcome risks, risk difference, and risk ratio, and we provide bias correction equations that produce unbiased estimates, in expectation. Using data obtained from US insurance claims data, we present a hypothetical comparative safety study of antibiotic treatment to illustrate factors that influence bias and provide an example probabilistic bias analysis using our derived bias correction equations.
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Viés , Humanos , Razão de Chances , RiscoRESUMO
BACKGROUND: Despite known differences in breast cancer by both race and sexual orientation, data on the intersectional experiences of Black sexual minority women (BSMW) along the care continuum are scant. This study sought to understand delays in breast cancer care by examining the intersection of race and sexual orientation. METHODS: This online, cross-sectional survey enrolled racially and sexually diverse women aged ≥ 35 years who had been diagnosed with breast cancer within the prior 10 years or had an abnormal screening in the prior 24 months. The authors calculated summary statistics by race/sexual orientation categories, and they conducted univariate and multivariable modeling by using multiple imputation for missing data. RESULTS: BSMW (n = 101) had the highest prevalence of care delays with 5.17-fold increased odds of a care delay in comparison with White heterosexual women (n = 298) in multivariable models. BSMW reported higher intersectional stigma and lower social support than all other groups. In models adjusted for race, sexual orientation, and income, intersectional stigma was associated with a 2.43-fold increase in care delays, and social support was associated with a 32% decrease in the odds of a care delay. CONCLUSIONS: Intersectional stigma may be an important driver of breast cancer inequities for BSMW. Reducing stigma and ensuring access to appropriate social support that addresses known barriers can be an important approach to reducing inequities in the breast cancer care continuum.
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Neoplasias da Mama , Minorias Sexuais e de Gênero , Adulto , Negro ou Afro-Americano , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/terapia , Estudos Transversais , Feminino , Humanos , Masculino , Comportamento Sexual , Estados Unidos/epidemiologiaRESUMO
OBJECTIVES: To study using cobalt-tetraphenylporphyrin/reduced graphene oxide (CoTPP/RGO), a nanocomposite highly catalytic both for oxidizing and for reducing hydrogen peroxide (H2 O2 ), to whiten teeth. METHODS: Dyes (D&C Red 34, Orange No. 4), tea, and betel nuts (Areca catechu) were used to stain the tooth specimens for three days and subsequently bleached using H2 O2 alone, H2 O2 plus CoTPP, or H2 O2 plus CoTPP/RGO for 0.5-70 hours. The process was photographed using an electronic chromometer and a camera. Color change was assessed after each session. The results of bleaching teeth with and without photoirradiation were compared. RESULTS: CoTPP/RGO increased the tooth-whitening efficacy of H2 O2 for specimens stained with dyes, tea, and betel nuts. Using lamps (photoactivation) (wavelengths: 254 nm and 310 nm) to catalyze the H2 O2 bleaching agent reduced the bleaching treatment time. CLINICAL SIGNIFICANCE: First, the Co/TPP/RGO complex allows improved tooth bleaching and shorter treatment times. Second, because the Co/TPP/RGO complex bleached D&C Red 34 at a similar rate and to a similar degree as tea and other natural agents stain teeth, it is a convenient staining agent for studying many vital aspects of tooth bleaching. (J Esthet Restor Dent 28:321-329, 2016).
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Nanocompostos , Porfirinas , Clareamento Dental , Descoloração de Dente , Cobalto , Cor , Grafite , Peróxido de Hidrogênio , Chá , Dente , Clareadores DentáriosRESUMO
PURPOSE: Mortality data can complement primary end points from cancer clinical trials. Yet, identifying deaths after trial completion is challenging, as timely and comprehensive vital status data are unavailable in the United States. We developed and evaluated a multisource approach to capture death data after clinical trial completion. METHODS: Individuals age 70 years and older with incurable solid tumors or lymphoma and ≥1 aging-related condition were enrolled from October 2014 to March 2019 (ClinicalTrials.gov identifier: NCT02107443 and NCT02054741). Participants provided consent to link trial information to external sources. We developed a stepped approach for extended death capture using (1) active trial follow-up up to 1 year, (2) linkage to the National Death Index (NDI), and (3) obituary searches, thus generating a 5-year survival curve. In a random sample of 50 participants who died during trial follow-up, we estimated sensitivity of death data using NDI and obituary sources and computed survival times by data source. RESULTS: The two trials enrolled 1,169 participants; mean age was 76 years; 46% were female; and gastrointestinal cancer (30%) and lung cancer (26%) were the most common cancer types. Across data sources, maximum follow-up was >7 years; 5-year survival was 18%. In total, there were 841 deaths: 603 identified during trial follow-up; 199 from the NDI; and 39 from obituary searches. The sensitivity for death capture was 92% for the NDI and 94% for the obituary searches compared with the trial data, and computed survival times were similar across data sources. CONCLUSION: Extending clinical trial mortality follow-up through linkage with external data sources was feasible and accurate. Future cancer clinical trials should collect necessary consent and patient identifiers for vital status linkages that can enhance understanding of longer-term outcomes.
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Neoplasias , Idoso , Feminino , Humanos , Masculino , Seguimentos , Neoplasias/diagnóstico , Neoplasias/terapia , Estados Unidos , Ensaios Clínicos como AssuntoRESUMO
Randomized controlled trials (RCT) are the gold standard in determining efficacy of cancer screening tests. Yet, systematic differences between RCT and the general populations eligible for screening raise concerns about the generalizability and relevance of RCT findings to guide the development and dissemination of cancer screening programs. Observational studies from clinical practice settings have documented selective uptake in screening-i.e., variation across subgroups regarding who is screened and not screened-as well as suboptimal adherence to screening recommendations, including follow-up of positive findings with subsequent imaging studies and diagnostic invasive procedures. When the effectiveness of a screening intervention varies across subgroups, and there is selective uptake and suboptimal adherence to screening in clinical practice relative to that in the RCT, the effects of screening reported in RCTs are not expected to generalize to clinical practice settings. Understanding the impacts of selective uptake and suboptimal adherence on estimates of the effectiveness of cancer screening in clinical practice will generate evidence that can be used to inform future screening recommendations and enhance shared decision-making tools.
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Detecção Precoce de Câncer , Neoplasias , Humanos , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/estatística & dados numéricos , Neoplasias/diagnóstico , Cooperação do Paciente/estatística & dados numéricos , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Programas de Rastreamento/normas , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Photo-assisted catalytic reduction of nitric oxide (NO) was studied over different metal-loaded TiO2 catalysts at room temperature. The activities of metal-loaded (Pt, Ag, Cu) TiO2 photocatalysts, prepared by the sol-gel method, were compared in a batch system using CH4 as the reducing agent. The Pt/TiO2 catalyst showed the highest activity for NO reduction. Thus, Pt/TiO2 was coated on optical fibres and used in a continuous-flow optical-fibre photoreactor. The optical-fibre photoreactor provides light irradiation on the photocatalyst through the optical fibre, thus improving the efficiency ofphotoreactions. Ten per cent conversion of NO was found using CH4 as the reducing agent. The NO conversions increased to 90% in the presence of water vapour and oxygen. However, most NO was oxidized to NO2. Hydrogen had superior reducing capabilities over CH4 on Pt/TiO2 photocatalyst, and the conversion of NO reached 85%. But the conversion of NO was substantially decreased to less than 10% in the presence of water vapour and oxygen. Our research proposed an alternative way to reduce NO pollutant to N2 at room temperature using an optical-fibre photoreactor, which could possibly utilize sunlight in the future.
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Poluentes Atmosféricos/química , Óxido Nítrico/química , Fibras Ópticas , Fotoquímica , Catálise , Cromatografia Gasosa , Microscopia Eletrônica de Varredura , Oxirredução , Temperatura , Difração de Raios XRESUMO
This cross-sectional study compares lung cancer screening prevalence in 2022 among individuals eligible by 2021 vs 2013 criteria by sociodemographics and state.
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Detecção Precoce de Câncer , Neoplasias Pulmonares , Humanos , Prevalência , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologiaRESUMO
BACKGROUND: Guillain-Barré syndrome (GBS) is a serious acute demyelinating disease, an increased risk of which was found after the 1976 swine flu vaccinations. The U.S. Food and Drug Administration, in collaboration with the Centers for Medicare & Medicaid Services, has been conducting active surveillance for GBS after influenza vaccinations of Medicare Fee-For-Service beneficiaries since 2009. METHODS: We conducted active surveillance for GBS claims in the 2015-2016 and 2016-2017 influenza seasons using the Updating Sequential Probability Ratio Test (USPRT) to monitor for signals of GBS risk. We performed self-controlled risk interval (SCRI) analyses at the end of both seasons, including chart confirmation in the 2015-2016 season, to estimate the odds ratio of GBS risk. We used 1-42 and 8-21â¯days post-vaccination as primary and secondary risk windows, respectively, and 43-84â¯days post-vaccination as the control window. RESULTS: Over 13 million beneficiaries were vaccinated in each season. USPRT found a low magnitude signal for GBS in both seasons. SCRI analyses did not find excess GBS risk following any influenza vaccine for days 1-42 post-vaccination in either season. In the 2015-2016 season, for the 8-21â¯day window, our chart-confirmation showed an attributable GBS risk of 0.87 (95% CI: 0.16, 1.49) and 1.68 (95% CI: 0.69, 2.41) cases per million vaccinees after all seasonal and high dose (HD) vaccines, respectively, an elevated GBS risk for beneficiaries aged ≥75â¯years following all seasonal vaccines (OR: 2.25; 95% CI: 1.15, 4.39) and HD vaccine (OR: 3.67, 95% CI: 1.52, 8.85), and an elevated GBS risk for males who received seasonal vaccines (OR: 2.18; 95% CI: 1.15, 4.15) and HD vaccine (OR: 3.33; 95% CI: 1.35, 8.20). The finding of elevated GBS risk with advancing age and in males is consistent with literature; however, a distinction between HD and SD was a new finding. In the 2016-17 season, for the 8-21â¯day window, attributed cases showed an attributable GBS risk of 0.87 (95% CI: 0.03, 1.61) and 1.11 (95% CI: 0.00, 2.01) cases per million vaccinees after all seasonal and HD vaccines, respectively. We found no excess GBS risk for standard dose vaccines in the 8-21â¯day window in either season. CONCLUSIONS: Our primary analysis finding of no excess GBS risk during both seasons was reassuring. The slightly elevated GBS risk, although in the expected range, in the 8-21â¯day window after all seasonal and high dose vaccines, but not after standard dose vaccines is hypothesis-generating because the difference may be due to vaccine factors such as antigen amount or strains in various seasons or due to host factors.
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Síndrome de Guillain-Barré/epidemiologia , Síndrome de Guillain-Barré/etiologia , Vacinas contra Influenza/efeitos adversos , Influenza Humana/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Vacinas contra Influenza/administração & dosagem , Masculino , Medicare/estatística & dados numéricos , Fatores de Tempo , Estados Unidos/epidemiologia , Vacinação/estatística & dados numéricosRESUMO
INTRODUCTION: Intramuscular injection of metformin has been shown to inhibit the progression of periapical lesions in rats by decreasing the number of receptor activator of nuclear factor-κß ligand- and tartrate-resistant acid phosphatase-positive cells. In this study, we investigated the effect of metformin on hypoxia-induced apoptosis of osteoblasts and the therapeutic activity of intracanal metformin in induced periapical lesions in rats. METHODS: The influence of metformin on hypoxia-induced mitochondrial superoxide production in human osteoblasts was examined by using MitoSOX (Invitrogen, Carlsbad, CA) fluorescence dye signaling. The release of cytochrome c from mitochondria and the cleavage of procaspase-9 and poly(adenosine diphosphate-ribose) polymerase were evaluated by Western blot analysis. Apoptotic cell fraction was assessed by DNA content flow cytometry. In a rat model of induced periapical lesions, the effect of intracanal metformin on disease progression was appraised by 2-dimensional radiography and micro-computed tomographic imaging. Oxidative lesions and apoptotic activity of osteoblasts in vivo were estimated, respectively, by 8-hydroxy-2'-deoxyguanosine staining and terminal deoxynucleotidyl transferase dUTP nick end labeling. RESULTS: Metformin inhibited hypoxia-enhanced mitochondrial superoxide production in osteoblasts. Metformin suppressed hypoxia-induced cytochrome c release from mitochondria and the cleavage of procaspase-9 and poly(adenosine diphosphate-ribose) polymerase. Metformin repressed hypoxia-augmented apoptotic cell fraction. In a rat model, intracanal metformin diminished the size of periapical lesions and the oxidative damage and apoptotic activity in osteoblasts. CONCLUSIONS: Hypoxia increased oxidative stress in osteoblasts and enhanced cell death through activation of the mitochondrial pathway of apoptosis. Metformin attenuated the oxidative and cytotoxic action of hypoxia. The therapeutic effect of metformin on periapical lesions is partially caused by its antioxidative activity.