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1.
Pharm Stat ; 23(1): 31-45, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37743566

RESUMO

Phase Ib/II oncology trials, despite their small sample sizes, aim to provide information for optimal internal company decision-making concerning novel drug development. Hybrid controls (a combination of the current control arm and controls from one or more sources of historical trial data [HTD]) can be used to increase statistical precision. Here we assess combining two sources of Roche HTD to construct a hybrid control in targeted therapy for decision-making via an extensive simulation study. Our simulations are based on the real data of one of the experimental arms and the control arm of the MORPHEUS-UC Phase Ib/II study and two Roche HTD for atezolizumab monotherapy. We consider potential complications such as model misspecification, unmeasured confounding, different sample sizes of current treatment groups, and heterogeneity among the three trials. We evaluate two frequentist methods (with both Cox and Weibull accelerated failure time [AFT] models) and three different commensurate priors in Bayesian dynamic borrowing (with a Weibull AFT model), and modifications within each of those, when estimating the effect of treatment on survival outcomes and measures of effect such as marginal hazard ratios. We assess the performance of these methods in different settings and the potential of generalizations to supplement decisions in early-phase oncology trials. The results show that the proposed joint frequentist methods and noninformative priors within Bayesian dynamic borrowing with no adjustment on covariates are preferred, especially when treatment effects across the three trials are heterogeneous. For generalization of hybrid control methods in such settings, we recommend more simulation studies.


Assuntos
Neoplasias , Projetos de Pesquisa , Humanos , Teorema de Bayes , Simulação por Computador , Neoplasias/tratamento farmacológico , Tamanho da Amostra , Ensaios Clínicos como Assunto
2.
Alzheimers Dement ; 20(2): 1102-1111, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37882364

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual-level benefit from amyloid beta removal therapy. METHODS: Random forest models were applied to the EMERGE trial to create an individual-level treatment response (ITR) score which represents individual-level benefit of high-dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE). RESULTS: We found statistical evidence of HTE in the Clinical Dementia Rating-Sum of Boxes (CDR-SB;P =  0.034). The observed CDR-SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P = 0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline. DISCUSSION: This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development. HIGHLIGHTS: Emerging trials have shown a population-level benefit from amyloid beta (Aß) removal in slowing cognitive decline in early Alzheimer's disease (AD). This work demonstrates significant heterogeneity of individual-level treatment effect of aducanumab in early AD. The greatest clinical responders to Aß removal therapy have a pattern of more severe neurodegenerative process.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Medicina de Precisão , Disfunção Cognitiva/patologia , Hipocampo/patologia
3.
BMC Geriatr ; 23(1): 124, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36879199

RESUMO

BACKGROUND: The Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale for use in Mild Cognitive Impairment (MCI), the ADCS-ADL-MCI, is an evaluation scale with information provided by an informant/caregiver to describe the functional impairment of patients with MCI. As the ADCS-ADL-MCI has yet to undergo a full psychometric evaluation, this study aimed to evaluate the measurement properties of the ADCS-ADL-MCI in subjects with amnestic MCI. METHODS: Measurement properties, including item-level analysis, internal consistency reliability, test-retest reliability, construct validity (convergent/discriminant, known-groups validity), and responsiveness were evaluated using data from the ADCS ADC-008 trial, a 36-month, multicenter, placebo-controlled study in 769 subjects with amnestic MCI (defined by clinical criteria and a global clinical dementia rating, CDR, score of 0.5). Due to most subjects' mild condition at baseline and resulting low variance in scores, psychometric properties were assessed using both baseline and 36-month data. RESULTS: Ceiling effects were not apparent at the total score level, with 3% of the cohort reaching the maximum score of 53, despite most subjects having a relatively high score at baseline (mean score = 46.0 [standard deviation = 4.8]). Item-total correlations were overall weak at baseline, most likely due to low variability in responses; however, at month 36, good item homogeneity was found. Cronbach's alpha values ranged from acceptable (0.64 at baseline) to good (0.87 at month 36), indicating overall very good internal consistency reliability. Further, moderate to good test-retest reliability was found (intraclass correlation coefficients ranging from 0.62-0.73). The analyses also largely supported convergent/discriminant validity, especially at month 36. Finally, the ADCS-ADL-MCI discriminated well between groups showing good known-groups validity, and was responsive in patients who indicated a longitudinal change in other instruments. CONCLUSIONS: This study provides a comprehensive psychometric evaluation of the ADCS-ADL-MCI. Findings suggest that the ADCS-ADL-MCI is a reliable, valid and responsive measure capable of capturing functional abilities in patients with amnestic MCI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00000173.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Atividades Cotidianas , Psicometria , Reprodutibilidade dos Testes , Disfunção Cognitiva/diagnóstico
4.
Alzheimers Dement ; 19(4): 1292-1299, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36043526

RESUMO

INTRODUCTION: Whether the reduction in brain amyloid beta (Aß) plaque alone may substantially slow cognitive and functional decline in patients with dementia or mild cognitive impairment due to Alzheimer's disease (AD) remains debated. METHODS: An instrumental variable meta-analysis was performed to infer the effect of change in positron emission tomography (PET)-measured Aß standardized uptake value ratio (SUVR) on cognitive and functional decline. RESULTS: Pooling data from 16 randomized trials demonstrates that each 0.1-unit decrease in PET Aß SUVR is associated with a reduction (95% confidence interval) by 0.09 (0.034-0.15), 0.33 (0.12-0.55), and 0.13 (0.017-0.24) point in the average change of the Clinical Dementia Rating-Sum of Boxes, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, and the Mini-Mental State Examination, respectively. DISCUSSION: This meta-analysis provides statistically significant evidence of a likely causal relationship between a reduction in Aß plaque and a reduction in cognitive and functional decline in patients with AD. HIGHLIGHTS: A widely cited meta-analysis article concluded amyloid beta reduction does not substantially improve cognition. We identified data inconsistencies in the initial publication and found new trial data. We repeated the meta-analysis after correcting data inconsistencies and adding new trial data. Updated results suggested statistically significant clinical benefit of amyloid beta reduction. Amyloid beta is a viable biological target for the treatment and prevention of AD.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Amiloide , Cognição
5.
Am J Epidemiol ; 190(12): 2664-2670, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34151374

RESUMO

Epidemiologists commonly use an adjusted hazard ratio or incidence density ratio, or a standardized mortality ratio, to measure a difference in all-cause mortality rates. They seldom translate it into an age-, time-, or probability-based measure that would be easier to communicate and to relate to. Several articles have shown how to translate from a standardized mortality ratio or hazard ratio to a longevity difference, a difference in actuarial ages, or a probability of being outlived. In this paper, we describe the settings where these translations are and are not appropriate and provide some of the heuristics behind the formulae. The tools that yield differences in "effective age" and in longevity are applicable when both 1) the mortality rate ratio (hazard ratio) is constant over age and 2) the rates themselves are log-linear in age. The "probability/odds of being outlived" metric is applicable whenever the first condition holds, and thus it provides no direct information on the magnitude of the effective age/longevity difference.


Assuntos
Expectativa de Vida/tendências , Longevidade , Modelos Estatísticos , Mortalidade/tendências , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Probabilidade , Modelos de Riscos Proporcionais , Fatores Sexuais , Fatores de Tempo
6.
Stat Med ; 40(2): 481-497, 2021 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-33105513

RESUMO

The accelerated failure time (AFT) model has been suggested as an alternative to the Cox proportional hazards model. However, a parametric AFT model requires the specification of an appropriate distribution for the event time, which is often difficult to identify in real-life studies and may limit applications. A semiparametric AFT model was developed by Komárek et al based on smoothed error distribution that does not require such specification. In this article, we develop a spline-based AFT model that also does not require specification of the parametric family of event time distribution. The baseline hazard function is modeled by regression B-splines, allowing for the estimation of a variety of smooth and flexible shapes. In comprehensive simulations, we validate the performance of our approach and compare with the results from parametric AFT models and the approach of Komárek. Both the proposed spline-based AFT model and the approach of Komárek provided unbiased estimates of covariate effects and survival curves for a variety of scenarios in which the event time followed different distributions, including both simple and complex cases. Spline-based estimates of the baseline hazard showed also a satisfactory numerical stability. As expected, the baseline hazard and survival probabilities estimated by the misspecified parametric AFT models deviated from the truth. We illustrated the application of the proposed model in a study of colon cancer.


Assuntos
Modelos de Riscos Proporcionais , Humanos , Análise de Sobrevida , Tempo
7.
Br J Clin Pharmacol ; 87(6): 2589-2601, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33242339

RESUMO

AIMS: There are conflicting signals in the literature about comparative safety and effectiveness of direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF). METHODS: We conducted multicentre matched cohort studies with secondary meta-analysis to assess safety and effectiveness of dabigatran, rivaroxaban and apixaban across 9 administrative healthcare databases. We included adults with NVAF initiating anticoagulation therapy (dabigatran, rivaroxaban or apixaban), and constructed 3 cohorts to compare DOACs pairwise. The primary outcome was pooled hazard ratio (pHR) of ischaemic stroke or systemic thromboembolism. Secondary outcomes included pHR of major bleeding, and a composite of stroke, major bleeding, or all-cause mortality. We used proportional hazard Cox regressions models, and pooled estimates were obtained with random effect meta-analyses. RESULTS: The cohorts included 73 414 new users of dabigatran, 92 881 of rivaroxaban, and 61 284 of apixaban. After matching, the pHRs (95% confidence intervals) comparing rivaroxaban initiation to dabigatran were: 1.11 (0.93, 1.32) for ischaemic stroke or systemic thromboembolism, 1.26 (1.09, 1.46) for major bleeding, and 1.17 (1.05, 1.30) for the composite endpoint. For apixaban vs dabigatran, they were: 0.91 (0.74, 1.12) for ischaemic stroke or systemic thromboembolism, 0.89 (0.75, 1.05) for major bleeding, and 0.94 (0.78 to 1.14) for the composite endpoint. For apixaban vs rivaroxaban, they were: 0.85 (0.74, 0.99) for ischaemic stroke or systemic thromboembolism, 0.61 (0.53, 0.70) for major bleeding, and 0.82 (0.76, 0.88) for the composite endpoint. CONCLUSION: We found that apixaban use is associated with lower risks of stroke and bleeding compared with rivaroxaban, and similar risks compared with dabigatran.


Assuntos
Fibrilação Atrial , Isquemia Encefálica , Acidente Vascular Cerebral , Administração Oral , Adulto , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Estudos de Coortes , Dabigatrana/efeitos adversos , Humanos , Piridonas/efeitos adversos , Estudos Retrospectivos , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento , Varfarina
8.
Epidemiology ; 29(2): 191-198, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29166301

RESUMO

The use of retrospective health care claims datasets is frequently criticized for the lack of complete information on potential confounders. Utilizing patient's health status-related information from claims datasets as surrogates or proxies for mismeasured and unobserved confounders, the high-dimensional propensity score algorithm enables us to reduce bias. Using a previously published cohort study of postmyocardial infarction statin use (1998-2012), we compare the performance of the algorithm with a number of popular machine learning approaches for confounder selection in high-dimensional covariate spaces: random forest, least absolute shrinkage and selection operator, and elastic net. Our results suggest that, when the data analysis is done with epidemiologic principles in mind, machine learning methods perform as well as the high-dimensional propensity score algorithm. Using a plasmode framework that mimicked the empirical data, we also showed that a hybrid of machine learning and high-dimensional propensity score algorithms generally perform slightly better than both in terms of mean squared error, when a bias-based analysis is used.


Assuntos
Algoritmos , Aprendizado de Máquina , Pontuação de Propensão , Confiabilidade dos Dados , Conjuntos de Dados como Assunto/normas , Pesquisa Empírica , Estudos Retrospectivos , Reino Unido
10.
Epidemiology ; 27(4): 570-7, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27031037

RESUMO

BACKGROUND: Targeted maximum likelihood estimation has been proposed for estimating marginal causal effects, and is robust to misspecification of either the treatment or outcome model. However, due perhaps to its novelty, targeted maximum likelihood estimation has not been widely used in pharmacoepidemiology. The objective of this study was to demonstrate targeted maximum likelihood estimation in a pharmacoepidemiological study with a high-dimensional covariate space, to incorporate the use of high-dimensional propensity scores into this method, and to compare the results to those of inverse probability weighting. METHODS: We implemented the targeted maximum likelihood estimation procedure in a single-point exposure study of the use of statins and the 1-year risk of all-cause mortality postmyocardial infarction using data from the UK Clinical Practice Research Datalink. A range of known potential confounders were considered, and empirical covariates were selected using the high-dimensional propensity scores algorithm. We estimated odds ratios using targeted maximum likelihood estimation and inverse probability weighting with a variety of covariate selection strategies. RESULTS: Through a real example, we demonstrated the double robustness of targeted maximum likelihood estimation. We showed that results with this method and inverse probability weighting differed when a large number of covariates were included in the treatment model. CONCLUSIONS: Targeted maximum likelihood can be used in high-dimensional covariate settings. In high-dimensional covariate settings, differences in results between targeted maximum likelihood and inverse probability weighted estimation are likely due to sensitivity to (near) positivity violations. Further investigations are needed to gain better understanding of the advantages and limitations of this method in pharmacoepidemiological studies.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Mortalidade , Infarto do Miocárdio/tratamento farmacológico , Adolescente , Adulto , Idoso , Causas de Morte , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Farmacoepidemiologia , Estudos Retrospectivos , Reino Unido , Adulto Jovem
11.
Pharmacoepidemiol Drug Saf ; 24(9): 1004-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25866189

RESUMO

PURPOSE: The high-dimensional propensity score algorithm attempts to improve control of confounding in typical treatment effect studies in pharmacoepidemiology and is increasingly being used for the analysis of large administrative databases. Within this multi-step variable selection algorithm, the marginal prevalence of non-zero covariate values is considered to be an indicator for a count variable's potential confounding impact. We investigate the role of the marginal prevalence of confounder variables on potentially caused bias magnitudes when estimating risk ratios in point exposure studies with binary outcomes. METHODS: We apply the law of total probability in conjunction with an established bias formula to derive and illustrate relative bias boundaries with respect to marginal confounder prevalence. RESULTS: We show that maximum possible bias magnitudes can occur at any marginal prevalence level of a binary confounder variable. In particular, we demonstrate that, in case of rare or very common exposures, low and high prevalent confounder variables can still have large confounding impact on estimated risk ratios. CONCLUSIONS: Covariate pre-selection by prevalence may lead to sub-optimal confounder sampling within the high-dimensional propensity score algorithm. While we believe that the high-dimensional propensity score has important benefits in large-scale pharmacoepidemiologic studies, we recommend omitting the prevalence-based empirical identification of candidate covariates.


Assuntos
Algoritmos , Fatores de Confusão Epidemiológicos , Farmacoepidemiologia/estatística & dados numéricos , Pontuação de Propensão , Bases de Dados Factuais/estatística & dados numéricos , Humanos , Razão de Chances , Prevalência
12.
Neurodegener Dis Manag ; 14(2): 21-33, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38623894

RESUMO

Aim: To assess time to improvement in Quality of Life in Neurological Disorders (Neuro-QoL) domains for patients treated with natalizumab versus ocrelizumab. Methods: Patients enrolled in the MS PATHS network who initiated treatment with either natalizumab or ocrelizumab rated the Neuro-QoL domains of physical function, symptoms, emotional health, cognitive function and social ability. Results: Time to clinically meaningful improvement was significantly shorter with natalizumab versus ocrelizumab for cognitive function (event time ratio [95% CI]: 0.37 [0.24-0.57]; p < 0.001), sleep disturbance (0.45 [0.28-0.72]; p = 0.001), social role participation (0.37 [0.21-0.66]; p = 0.001) and social role satisfaction (0.5 [0.31-0.8]; p = 0.004). Conclusion: Natalizumab had shorter time to clinically meaningful improvement in cognitive, sleep, and social role Neuro-QoL domains versus ocrelizumab.


Knowledge of treatment-related benefits associated with medication choices, including improvement of quality of life (QoL), are strong influential factors for patients to start and continue their therapies. Little is known about patient-reported time to onset of functional improvement upon the initiation of medications for multiple sclerosis (MS). The Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network, a repository of collaborative international data on routine MS management, includes patient-reported information on the health-related QoL using the Quality of Life in Neurological Disorders (Neuro-QoL) measure. This study included data from 883 eligible patients enrolled in MS PATHS, with the aim of assessing and comparing the time to improvement in physical, mental and social health for patients treated with natalizumab versus ocrelizumab using Neuro-QoL. Natalizumab and ocrelizumab are both high-efficacy treatment options for relapsing forms of MS. The results demonstrated that, compared with ocrelizumab, natalizumab treatment led to faster effect on mental and social health, as well as quicker improvements in physical functioning in the arms and hands. Overall, it took shorter time for natalizumab-treated patients to achieve better QoL compared with ocrelizumab. These findings highlight the importance of QoL in disease management and provide a patient perspective for healthcare providers when making decisions about high-efficacy treatments for their patients with MS.


Assuntos
Anticorpos Monoclonais Humanizados , Fatores Imunológicos , Natalizumab , Qualidade de Vida , Humanos , Masculino , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Natalizumab/uso terapêutico , Adulto , Pessoa de Meia-Idade , Fatores Imunológicos/uso terapêutico , Resultado do Tratamento , Fatores de Tempo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/psicologia , Doenças do Sistema Nervoso/tratamento farmacológico
13.
J Extracell Vesicles ; 12(5): e12328, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37165987

RESUMO

Preeclampsia (PE) is a multisystem disorder with high maternal morbidity and mortality rates. Currently, no practical therapeutic approach is available to prevent PE progression, except for early delivery. Gut dysbiosis is associated with PE development. Previous data showed that the abundance of Akkermansia muciniphila (Am) was lower in patients with PE than in normotensive pregnant women. Here, in this study, decreased abundance of Am was observed in a PE mouse model. Also, we found that administration with Am could significantly attenuate systolic blood pressure, promote foetal growth and improve the placental pathology in mice with PE. Moreover, Am-derived extracellular vesicles (AmEVs) were transferred from the gastrointestinal (GI) tract to the placenta and mitigated pre-eclamptic symptoms in PE mice. These beneficial effects of AmEVs were mediated by enhanced trophoblast invasion of the spiral artery (SpA) and SpA remodelling through activation of the epidermal growth factor receptor (EGFR)-phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT) signalling pathway. Collectively, our findings revealed the potential benefit of using AmEVs for PE treatment and highlighted important host-microbiota interactions.


Assuntos
Vesículas Extracelulares , Pré-Eclâmpsia , Gravidez , Feminino , Camundongos , Humanos , Animais , Placentação , Placenta/metabolismo , Placenta/patologia , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/prevenção & controle , Vesículas Extracelulares/metabolismo
14.
J Ovarian Res ; 15(1): 69, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35668504

RESUMO

BACKGROUND: Dysregulation of Ectonucleoside Triphospahate Diphosphohydrolase 5 (ENTPD5) in tumors might be associated with tumor progression, while the role of ENTPD5 in the growth and metastasis of serous ovarian cancer (SOC) is still unclear. METHODS: ENTPD5 expression patterns in ovarian cancer tissues were analyzed by qRT-PCR and immunohistochemistry assay (IHC). Two SOC cell lines, SKOV3 and OVCAR8, were stably transfected with lentivirus to build knockdown and overexpression cell lines. Clone formation assay, collagen gel droplet culture technology, wound healing assay and flow cytometry were used to assess the migration and growth traits of SOC cells. Expression levels of ENTPD5, glucose regulated protein 78 (GRP78), eukaryotic translation initiation factor 2 alpha (eIF-2α), phosphorylated -eIF-2α and, C/EBP homologous protein (CHOP) in SOC cells were detected by Western blot. RESULTS: Compared to fallopian tube tissues, the expression of ENTPD5 was significantly higher in tumor tissues obtained from SOC patients, and positively correlated with clinical stage and metastasis. ENTPD5 knockdown robustly inhibited cell proliferation, migration, whereas ENTPD5 overexpression elicited the opposite effect on SOC cells. ENTPD5 knockdown arrested cell cycle in G0/G1 phase and increased apoptosis. Importantly, ENTPD5 knockdown was associated with significantly decreased protein levels for GRP78, CHOP, and p-eIF-2α, suggesting possible involvement of ENTPD5 in endoplasmic reticulum stress (ERS). CONCLUSIONS: Our study demonstrates that ENTPD5 knockdown inhibited SOC cell proliferation, migration and restrained the activation of the GRP78/p-eIF-2α/CHOP pathway, which provides a potentially effective therapeutic target for the treatment of SOC.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Apoptose , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/patologia , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fator de Iniciação 2 em Eucariotos/farmacologia , Feminino , Glucose , Humanos , Proteínas Oncogênicas , Neoplasias Ovarianas/patologia , Proteína C/farmacologia , Pirofosfatases/farmacologia
15.
Stat Methods Med Res ; 30(11): 2526-2542, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34547928

RESUMO

The accelerated failure time model is an alternative to the Cox proportional hazards model in survival analysis. However, conclusions regarding the associations of prognostic factors with event times are valid only if the underlying modeling assumptions are met. In contrast to several flexible methods for relaxing the proportional hazards and linearity assumptions in the Cox model, formal investigation of the constant-over-time time ratio and linearity assumptions in the accelerated failure time model has been limited. Yet, in practice, prognostic factors may have time-dependent and/or nonlinear effects. Furthermore, parametric accelerated failure time models require correct specification of the baseline hazard function, which is treated as a nuisance parameter in the Cox proportional hazards model, and is rarely known in practice. To address these challenges, we propose a flexible extension of the accelerated failure time model where unpenalized regression B-splines are used to model (i) the baseline hazard function of arbitrary shape, (ii) the time-dependent covariate effects on the hazard, and (iii) nonlinear effects for continuous covariates. Simulations evaluate the accuracy of the time-dependent and/or nonlinear estimates, and of the resulting survival functions, in multivariable settings. The proposed flexible extension of the accelerated failure time model is applied to re-assess the effects of prognostic factors on mortality after septic shock.


Assuntos
Análise de Sobrevida , Modelos de Riscos Proporcionais
16.
CMAJ Open ; 8(4): E877-E886, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33355273

RESUMO

BACKGROUND: Direct oral anticoagulants (DOACs) have widely replaced warfarin for stroke prevention in nonvalvular atrial fibrillation. Our objective was to compare the safety and effectiveness of DOACs (dabigatran, rivaroxaban, apixaban) versus warfarin for stroke prevention in nonvalvular atrial fibrillation in the Canadian setting. METHODS: We conducted a population-based observational multicentre cohort study with propensity score matching and subsequent meta-analysis. We used health care databases from 7 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec and Nova Scotia). Patients with nonvalvular atrial fibrillation who initiated anticoagulation therapy in 2009-2017 were matched to an equal number who initiated warfarin. The primary outcome was the pooled hazard ratio (HR) for ischemic stroke or systemic embolization. Secondary outcomes included pooled HRs for major bleeding; a composite outcome of stroke, systemic embolization, major bleeding and all-cause mortality; and myocardial infarction. We modelled HRs using proportional hazard Cox regression with inverse probability of censoring weights, and estimated pooled HRs with random-effect meta-analyses. RESULTS: We included 128 273 patients who initiated anticoagulation with a DOAC (40 503 dabigatran, 49 498 rivaroxaban and 38 272 apixaban) and 128 273 patients who initiated anticoagulation with warfarin. The pooled HR for ischemic stroke or systemic embolization comparing DOACs to warfarin was 1.02 (95% confidence interval [CI] 0.87 to 1.19). Direct oral anticoagulants were associated with lower rates of major bleeding (pooled HR 0.81, 95% CI 0.69 to 0.97), the composite outcome (pooled HR 0.81, 95% CI 0.74 to 0.89) and all-cause mortality (pooled HR 0.81, 95% CI 0.78 to 0.85). INTERPRETATION: In this real-world study, DOACs were associated with similar risks of ischemic stroke or systemic embolization, and lower risks of bleeding and total mortality compared to warfarin. These findings support the use of DOACs for anticoagulation in nonvalvular atrial fibrillation. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT03596502.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Vitamina K/antagonistas & inibidores , Administração Oral , Idoso , Fibrilação Atrial/epidemiologia , Canadá/epidemiologia , Causas de Morte , Dabigatrana/uso terapêutico , Bases de Dados Factuais , Embolia/epidemiologia , Feminino , Hemorragia/epidemiologia , Humanos , Masculino , Metanálise como Assunto , Mortalidade , Infarto do Miocárdio/epidemiologia , Pontuação de Propensão , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Estudos Retrospectivos , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/epidemiologia , Resultado do Tratamento , Varfarina/uso terapêutico
17.
Epidemiology ; 24(4): 625-7, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23732743
18.
J Clin Epidemiol ; 88: 154-159, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28603009

RESUMO

OBJECTIVES: To increase transparency in studies reporting propensity scores by using graphical methods that clearly illustrate (1) the number of participant exclusions that occur as a consequence of the analytic strategy and (2) whether treatment effects are constant or heterogeneous across propensity scores. STUDY DESIGN AND SETTING: We applied graphical methods to a real-world pharmacoepidemiologic study that evaluated the effect of initiating statin medication on the 1-year all-cause mortality post-myocardial infarction. We propose graphical methods to show the consequences of trimming and matching on the exclusion of participants from the analysis. We also propose the use of meta-analytical forest plots to show the magnitude of effect heterogeneity. RESULTS: A density plot with vertical lines demonstrated the proportion of subjects excluded because of trimming. A frequency plot with horizontal lines demonstrated the proportion of subjects excluded because of matching. An augmented forest plot illustrates the amount of effect heterogeneity present in the data. CONCLUSION: Our proposed techniques present additional and useful information that helps readers understand the sample that is analyzed with propensity score methods and whether effect heterogeneity is present.


Assuntos
Gráficos por Computador , Interpretação Estatística de Dados , Pontuação de Propensão , Feminino , Humanos , Masculino , Modelos Estatísticos
19.
Stat Methods Med Res ; 25(5): 1925-1937, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-24108272

RESUMO

One approach to quantifying the magnitude of confounding in observational studies is to compare estimates with and without adjustment for a covariate, but this strategy is known to be defective for noncollapsible measures such as the odds ratio. Comparing estimates from marginal structural and standard logistic regression models, the total difference between crude and conditional effects can be decomposed into the sum of a noncollapsibility effect and confounding bias. We provide an analytic approach to assess the noncollapsibility effect in a point-exposure study and provide a general formula for expressing the noncollapsibility effect. Next, we provide a graphical approach that illustrates the relationship between the noncollapsibility effect and the baseline risk, and reveals the behavior of the noncollapsibility effect for a range of different exposure and covariate effects. Various observations about noncollapsibility can be made from the different scenarios with or without confounding; for example, the magnitude of effect of the covariate plays a more important role in the noncollapsibility effect than does that of the effect of the exposure. In order to explore the noncollapsibility effect of the odds ratio in the presence of time-varying confounding, we simulated an observational cohort study. The magnitude of noncollapsibility was generally comparable to the effect in the point-exposure study in our simulation settings. Finally, in an applied example we demonstrate that collapsibility can have an important impact on estimation in practice.


Assuntos
Modelos Logísticos , Razão de Chances , Peso Corporal , Aleitamento Materno , Estudos de Coortes , Fatores de Confusão Epidemiológicos , Feminino , Promoção da Saúde , Humanos , Lactente
20.
Int J Biostat ; 12(2)2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27889705

RESUMO

Inverse probability of treatment weighting (IPW) and targeted maximum likelihood estimation (TMLE) are relatively new methods proposed for estimating marginal causal effects. TMLE is doubly robust, yielding consistent estimators even under misspecification of either the treatment or the outcome model. While IPW methods are known to be sensitive to near violations of the practical positivity assumption (e. g., in the case of data sparsity), the consequences of this violation in the TMLE framework for binary outcomes have been less widely investigated. As near practical positivity violations are particularly likely in high-dimensional covariate settings, a better understanding of the performance of TMLE is of particular interest for pharmcoepidemiological studies using large databases. Using plasmode and Monte-Carlo simulation studies, we evaluated the performance of TMLE compared to that of IPW estimators based on a point-exposure cohort study of the marginal causal effect of post-myocardial infarction statin use on the 1-year risk of all-cause mortality from the Clinical Practice Research Datalink. A variety of treatment model specifications were considered, inducing different degrees of near practical non-positivity. Our simulation study showed that the performance of the TMLE and IPW estimators were comparable when the dimension of the fitted treatment model was small to moderate; however, they differed when a large number of covariates was considered. When a rich outcome model was included in the TMLE, estimators were unbiased. In some cases, we found irregular bias and large standard errors with both methods even with a correctly specified high-dimensional treatment model. The IPW estimator showed a slightly better root MSE with high-dimensional treatment model specifications in our simulation setting. In conclusion, for estimation of the marginal expectation of the outcome under a fixed treatment, TMLE and IPW estimators employing the same treatment model specification may perform differently due to differential sensitivity to practical positivity violations; however, TMLE, being doubly robust, shows improved performance with richer specifications of the outcome model. Although TMLE is appealing for its double robustness property, such violations in a high-dimensional covariate setting are problematic for both methods.


Assuntos
Bases de Dados Factuais , Funções Verossimilhança , Causalidade , Estudos de Coortes , Humanos , Método de Monte Carlo , Farmacoepidemiologia
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