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1.
JAMA Intern Med ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32065600

RESUMO

Importance: Chlorthalidone is currently recommended as the preferred thiazide diuretic to treat hypertension, but no trials have directly compared risks and benefits. Objective: To compare the effectiveness and safety of chlorthalidone and hydrochlorothiazide as first-line therapies for hypertension in real-world practice. Design, Setting, and Participants: This is a Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) observational comparative cohort study with large-scale propensity score stratification and negative-control and synthetic positive-control calibration on databases spanning January 2001 through December 2018. Outpatient and inpatient care episodes of first-time users of antihypertensive monotherapy in the United States based on 2 administrative claims databases and 1 collection of electronic health records were analyzed. Analysis began June 2018. Exposures: Chlorthalidone and hydrochlorothiazide. Main Outcomes and Measures: The primary outcomes were acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease outcome including the first 3 outcomes and sudden cardiac death. Fifty-one safety outcomes were measured. Results: Of 730 225 individuals (mean [SD] age, 51.5 [13.3] years; 450 100 women [61.6%]), 36 918 were dispensed or prescribed chlorthalidone and had 149 composite outcome events, and 693 337 were dispensed or prescribed hydrochlorothiazide and had 3089 composite outcome events. No significant difference was found in the associated risk of myocardial infarction, hospitalized heart failure, or stroke, with a calibrated hazard ratio for the composite cardiovascular outcome of 1.00 for chlorthalidone compared with hydrochlorothiazide (95% CI, 0.85-1.17). Chlorthalidone was associated with a significantly higher risk of hypokalemia (hazard ratio [HR], 2.72; 95% CI, 2.38-3.12), hyponatremia (HR, 1.31; 95% CI, 1.16-1.47), acute renal failure (HR, 1.37; 95% CI, 1.15-1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30). Chlorthalidone was associated with a significantly lower risk of diagnosed abnormal weight gain (HR, 0.73; 95% CI, 0.61-0.86). Conclusions and Relevance: This study found that chlorthalidone use was not associated with significant cardiovascular benefits when compared with hydrochlorothiazide, while its use was associated with greater risk of renal and electrolyte abnormalities. These findings do not support current recommendations to prefer chlorthalidone vs hydrochlorothiazide for hypertension treatment in first-time users was found. We used advanced methods, sensitivity analyses, and diagnostics, but given the possibility of residual confounding and the limited length of observation periods, further study is warranted.

2.
Korean Circ J ; 50(1): 52-68, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31642211

RESUMO

BACKGROUND AND OBJECTIVES: 2018 ESC/ESH Hypertension guideline recommends 2-drug combination as initial anti-hypertensive therapy. However, real-world evidence for effectiveness of recommended regimens remains limited. We aimed to compare the effectiveness of first-line anti-hypertensive treatment combining 2 out of the following classes: angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor blocker (A), calcium channel blocker (C), and thiazide-type diuretics (D). METHODS: Treatment-naïve hypertensive adults without cardiovascular disease (CVD) who initiated dual anti-hypertensive medications were identified in 5 databases from US and Korea. The patients were matched for each comparison set by large-scale propensity score matching. Primary endpoint was all-cause mortality. Myocardial infarction, heart failure, stroke, and major adverse cardiac and cerebrovascular events as a composite outcome comprised the secondary measure. RESULTS: A total of 987,983 patients met the eligibility criteria. After matching, 222,686, 32,344, and 38,513 patients were allocated to A+C vs. A+D, C+D vs. A+C, and C+D vs. A+D comparison, respectively. There was no significant difference in the mortality during total of 1,806,077 person-years: A+C vs. A+D (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.97-1.20; p=0.127), C+D vs. A+C (HR, 0.93; 95% CI, 0.87-1.01; p=0.067), and C+D vs. A+D (HR, 1.18; 95% CI, 0.95-1.47; p=0.104). A+C was associated with a slightly higher risk of heart failure (HR, 1.09; 95% CI, 1.01-1.18; p=0.040) and stroke (HR, 1.08; 95% CI, 1.01-1.17; p=0.040) than A+D. CONCLUSIONS: There was no significant difference in mortality among A+C, A+D, and C+D combination treatment in patients without previous CVD. This finding was consistent across multi-national heterogeneous cohorts in real-world practice.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31816040

RESUMO

OBJECTIVES: We propose a one-shot, privacy-preserving distributed algorithm to perform logistic regression (ODAL) across multiple clinical sites. MATERIALS AND METHODS: ODAL effectively utilizes the information from the local site (where the patient-level data are accessible) and incorporates the first-order (ODAL1) and second-order (ODAL2) gradients of the likelihood function from other sites to construct an estimator without requiring iterative communication across sites or transferring patient-level data. We evaluated ODAL via extensive simulation studies and an application to a dataset from the University of Pennsylvania Health System. The estimation accuracy was evaluated by comparing it with the estimator based on the combined individual participant data or pooled data (ie, gold standard). RESULTS: Our simulation studies revealed that the relative estimation bias of ODAL1 compared with the pooled estimates was <3%, and the ratio of standard errors was <1.25 for all scenarios. ODAL2 achieved higher accuracy (with relative bias <0.1% and ratio of standard errors <1.05). In real data analysis, we investigated the associations of 100 medications with fetal loss during pregnancy. We found that ODAL1 provided estimates with relative bias <10% for 85% of medications, and ODAL2 has relative bias <10% for 99% of medications. For communication cost, ODAL1 requires transferring p numbers from each site to the local site and ODAL2 requires transferring (p×p+p) numbers from each site to the local site, where p is the number of parameters in the regression model. CONCLUSIONS: This study demonstrates that ODAL is privacy-preserving and communication-efficient with small bias and high statistical efficiency.

4.
Lancet ; 394(10211): 1816-1826, 2019 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-31668726

RESUMO

BACKGROUND: Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice. METHODS: We developed a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. The framework addressed residual confounding, publication bias, and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested. FINDINGS: Using 4·9 million patients, we generated 22 000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR 0·84, 95% CI 0·75-0·95), hospitalisation for heart failure (0·83, 0·74-0·95), and stroke (0·83, 0·74-0·95) risk while on initial treatment. Safety profiles also favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes. INTERPRETATION: This comprehensive framework introduces a new way of doing observational health-care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension-in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers. FUNDING: US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Adolescente , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Criança , Estudos de Coortes , Pesquisa Comparativa da Efetividade/métodos , Bases de Dados Factuais , Diuréticos/efeitos adversos , Diuréticos/uso terapêutico , Medicina Baseada em Evidências/métodos , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Adulto Jovem
5.
Pharmacoepidemiol Drug Saf ; 28(12): 1620-1628, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31456304

RESUMO

PURPOSE: To compare the incidence of diabetic ketoacidosis (DKA) among patients with type 2 diabetes mellitus (T2DM) who were new users of sodium glucose co-transporter 2 inhibitors (SGLT2i) versus other classes of antihyperglycemic agents (AHAs). METHODS: Patients were identified from four large US claims databases using broad (all T2DM patients) and narrow (intended to exclude patients with type 1 diabetes or secondary diabetes misclassified as T2DM) definitions of T2DM. New users of SGLT2i and seven groups of comparator AHAs were matched (1:1) on exposure propensity scores to adjust for imbalances in baseline covariates. Cox proportional hazards regression models, conditioned on propensity score-matched pairs, were used to estimate hazard ratios (HRs) of DKA for new users of SGLT2i versus other AHAs. When I2 <40%, a combined HR across the four databases was estimated. RESULTS: Using the broad definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (HR [95% CI]: 1.53 [1.31-1.79]), DPP-4i (1.28 [1.11-1.47]), GLP-1 receptor agonists (1.34 [1.12-1.60]), metformin (1.31 [1.11-1.54]), and insulinotropic AHAs (1.38 [1.15-1.66]). Using the narrow definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (1.43 [1.01-2.01]). New users of SGLT2i had a lower risk of DKA versus insulin and a similar risk as thiazolidinediones, regardless of T2DM definition. CONCLUSIONS: Increased risk of DKA was observed for new users of SGLT2i versus several non-SGLT2i AHAs when T2DM was defined broadly. When T2DM was defined narrowly to exclude possible misclassified patients, an increased risk of DKA with SGLT2i was observed compared with sulfonylureas.

6.
Stat Med ; 38(22): 4199-4208, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31436848

RESUMO

The case-control design is widely used in retrospective database studies, often leading to spectacular findings. However, results of these studies often cannot be replicated, and the advantage of this design over others is questionable. To demonstrate the shortcomings of applications of this design, we replicate two published case-control studies. The first investigates isotretinoin and ulcerative colitis using a simple case-control design. The second focuses on dipeptidyl peptidase-4 inhibitors and acute pancreatitis, using a nested case-control design. We include large sets of negative control exposures (where the true odds ratio is believed to be 1) in both studies. Both replication studies produce effect size estimates consistent with the original studies, but also generate estimates for the negative control exposures showing substantial residual bias. In contrast, applying a self-controlled design to answer the same questions using the same data reveals far less bias. Although the case-control design in general is not at fault, its application in retrospective database studies, where all exposure and covariate data for the entire cohort are available, is unnecessary, as other alternatives such as cohort and self-controlled designs are available. Moreover, by focusing on cases and controls it opens the door to inappropriate comparisons between exposure groups, leading to confounding for which the design has few options to adjust for. We argue that this design should no longer be used in these types of data. At the very least, negative control exposures should be used to prove that the concerns raised here do not apply.

8.
PLoS One ; 14(3): e0212999, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30830923

RESUMO

BACKGROUND: Propensity score (PS) methods are commonly used to control for confounding in comparative effectiveness studies. Electronic health records (EHRs) contain much unstructured data that could be used as proxies for potential confounding factors. The goal of this study was to assess whether the unstructured information can also be used to construct PS models that would allow to properly deal with confounding. We used an example of coxibs (Cox-2 inhibitors) vs. traditional NSAIDs and the risk of upper gastro-intestinal bleeding as example, since this association is often confounded due to channeling of coxibs to patients at higher risk of upper gastro-intestinal bleeding. METHODS: In a cohort study of new users of nonsteroidal anti-inflammatory drugs (NSAIDs) from the Dutch Integrated Primary Care Information (IPCI) database, we identified all patients who experienced an upper gastrointestinal bleeding (UGIB). We used a large-scale regularized regression to fit two PS models using all structured and unstructured information in the EHR. We calculated hazard ratios (HRs) to estimate the risk of UGIB among selective cyclo-oxygenase-2 (COX-2) inhibitor users compared to nonselective NSAID (nsNSAID) users. RESULTS: The crude hazard ratio of UGIB for COX-2 inhibitors compared to nsNSAIDs was 0.50 (95% confidence interval 0.18-1.36). Matching only on age resulted in an HR of 0.36 (0.11-1.16), and of 0.35 (0.11-1.11) when further adjusted for sex. Matching on PS only, the first model yielded an HR of 0.42 (0.13-1.38), which reduced to 0.35 (0.96-1.25) when adjusted for age and sex. The second model resulted in an HR of 0.42 (0.13-1.39), which dropped to 0.31 (0.09-1.08) after adjustment for age and sex. CONCLUSIONS: PS models can be created using unstructured information in EHRs. An incremental benefit was observed by matching on PS over traditional matching and adjustment for covariates.


Assuntos
Interpretação Estatística de Dados , Pontuação de Propensão , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Modelos de Riscos Proporcionais , Medição de Risco/métodos
9.
PLoS One ; 13(11): e0204746, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30383755

RESUMO

BACKGROUND: Use of selective COX-2 non-steroidal anti-inflammatory drugs (NSAIDs) (coxibs) has been associated with an increased risk of acute myocardial infarction (AMI). However, the risk of AMI has only been studied for very few NSAIDs that are frequently used. OBJECTIVES: To estimate the risk of AMI for individual NSAIDs. METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) matching cases to a maximum of 100 controls on database, sex, age, and calendar time. Data were retrieved from six healthcare databases. Adjusted odds ratios (ORs) of current use of individual NSAIDs compared to past use were estimated per database. Pooling was done by two-stage pooling using a random effects model (ORmeta) and by one-stage pooling (ORpool). RESULTS: Among 8.5 million new NSAID users, 79,553 AMI cases were identified. The risk was elevated for current use of ketorolac (ORmeta 2.06;95%CI 1.83-2.32, ORpool 1.80; 1.49-2.18) followed, in descending order of point estimate, by indometacin, etoricoxib, rofecoxib, diclofenac, fixed combination of diclofenac with misoprostol, piroxicam, ibuprofen, naproxen, celecoxib, meloxicam, nimesulide and ketoprofen (ORmeta 1.12; 1.03-1.22, ORpool 1.00;0.86-1.16). Higher doses showed higher risk estimates than lower doses. CONCLUSIONS: The relative risk estimates of AMI differed slightly between 28 individual NSAIDs. The relative risk was highest for ketorolac and was correlated with COX-2 potency, but not restricted to coxibs.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Infarto do Miocárdio/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diclofenaco/efeitos adversos , Etoricoxib/efeitos adversos , Feminino , Humanos , Indometacina/efeitos adversos , Cetorolaco/efeitos adversos , Lactonas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Sulfonas/efeitos adversos
10.
PLoS One ; 13(9): e0203362, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30231067

RESUMO

BACKGROUND AND PURPOSE: A multi-country European study using data from six healthcare databases from four countries was performed to evaluate in a large study population (>32 million) the risk of ischemic stroke (IS) associated with individual NSAIDs and to assess the impact of risk factors of IS and co-medication. METHODS: Case-control study nested in a cohort of new NSAID users. For each case, up to 100 sex- and age-matched controls were selected and confounder-adjusted odds ratios for current use of individual NSAIDs compared to past use calculated. RESULTS: 49,170 cases of IS were observed among 4,593,778 new NSAID users. Use of coxibs (odds ratio 1.08, 95%-confidence interval 1.02-1.15) and use of traditional NSAIDs (1.16, 1.12-1.19) were associated with an increased risk of IS. Among 32 individual NSAIDs evaluated, the highest significant risk of IS was observed for ketorolac (1.46, 1.19-1.78), but significantly increased risks (in decreasing order) were also found for diclofenac, indomethacin, rofecoxib, ibuprofen, nimesulide, diclofenac with misoprostol, and piroxicam. IS risk associated with NSAID use was generally higher in persons of younger age, males, and those with a prior history of IS. CONCLUSIONS: Risk of IS differs between individual NSAIDs and appears to be higher in patients with a prior history of IS or transient ischemic attack (TIA), in younger or male patients. Co-medication with aspirin, other antiplatelets or anticoagulants might mitigate this risk. The small to moderate observed risk increase (by 13-46%) associated with NSAIDs use represents a public health concern due to widespread NSAID usage.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Isquemia Encefálica/etiologia , Acidente Vascular Cerebral/etiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Infarto Cerebral/etiologia , Estudos de Coortes , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Bases de Dados Factuais , Europa (Continente) , Feminino , Humanos , Cetorolaco/efeitos adversos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
11.
Philos Trans A Math Phys Eng Sci ; 376(2128)2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30082302

RESUMO

Concerns over reproducibility in science extend to research using existing healthcare data; many observational studies investigating the same topic produce conflicting results, even when using the same data. To address this problem, we propose a paradigm shift. The current paradigm centres on generating one estimate at a time using a unique study design with unknown reliability and publishing (or not) one estimate at a time. The new paradigm advocates for high-throughput observational studies using consistent and standardized methods, allowing evaluation, calibration and unbiased dissemination to generate a more reliable and complete evidence base. We demonstrate this new paradigm by comparing all depression treatments for a set of outcomes, producing 17 718 hazard ratios, each using methodology on par with current best practice. We furthermore include control hypotheses to evaluate and calibrate our evidence generation process. Results show good transitivity and consistency between databases, and agree with four out of the five findings from clinical trials. The distribution of effect size estimates reported in the literature reveals an absence of small or null effects, with a sharp cut-off at p = 0.05. No such phenomena were observed in our results, suggesting more complete and more reliable evidence.This article is part of a discussion meeting issue 'The growing ubiquity of algorithms in society: implications, impacts and innovations'.

12.
Diabetes Obes Metab ; 20(11): 2585-2597, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29938883

RESUMO

AIMS: Sodium glucose co-transporter 2 inhibitors (SGLT2i) are indicated for treatment of type 2 diabetes mellitus (T2DM); some SGLT2i have reported cardiovascular benefit, and some have reported risk of below-knee lower extremity (BKLE) amputation. This study examined the real-world comparative effectiveness within the SGLT2i class and compared with non-SGLT2i antihyperglycaemic agents. MATERIALS AND METHODS: Data from 4 large US administrative claims databases were used to characterize risk and provide population-level estimates of canagliflozin's effects on hospitalization for heart failure (HHF) and BKLE amputation vs other SGLT2i and non-SGLT2i in T2DM patients. Comparative analyses using a propensity score-adjusted new-user cohort design examined relative hazards of outcomes across all new users and a subpopulation with established cardiovascular disease. RESULTS: Across the 4 databases (142 800 new users of canagliflozin, 110 897 new users of other SGLT2i, 460 885 new users of non-SGLT2i), the meta-analytic hazard ratio estimate for HHF with canagliflozin vs non-SGLT2i was 0.39 (95% CI, 0.26-0.60) in the on-treatment analysis. The estimate for BKLE amputation with canagliflozin vs non-SGLT2i was 0.75 (95% CI, 0.40-1.41) in the on-treatment analysis and 1.01 (95% CI, 0.93-1.10) in the intent-to-treat analysis. Effects in the subpopulation with established cardiovascular disease were similar for both outcomes. No consistent differences were observed between canagliflozin and other SGLT2i. CONCLUSIONS: In this large comprehensive analysis, canagliflozin and other SGLT2i demonstrated HHF benefits consistent with clinical trial data, but showed no increased risk of BKLE amputation vs non-SGLT2i. HHF and BKLE amputation results were similar in the subpopulation with established cardiovascular disease. This study helps further characterize the potential benefits and harms of SGLT2i in routine clinical practice to complement evidence from clinical trials and prior observational studies.


Assuntos
Amputação/estatística & dados numéricos , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Hospitalização/estatística & dados numéricos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados como Assunto/estatística & dados numéricos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/prevenção & controle , Angiopatias Diabéticas/terapia , Pé Diabético/epidemiologia , Pé Diabético/etiologia , Pé Diabético/prevenção & controle , Pé Diabético/cirurgia , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
13.
Int J Epidemiol ; 47(6): 2005-2014, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29939268

RESUMO

Background: Propensity score adjustment is a popular approach for confounding control in observational studies. Reliable frameworks are needed to determine relative propensity score performance in large-scale studies, and to establish optimal propensity score model selection methods. Methods: We detail a propensity score evaluation framework that includes synthetic and real-world data experiments. Our synthetic experimental design extends the 'plasmode' framework and simulates survival data under known effect sizes, and our real-world experiments use a set of negative control outcomes with presumed null effect sizes. In reproductions of two published cohort studies, we compare two propensity score estimation methods that contrast in their model selection approach: L1-regularized regression that conducts a penalized likelihood regression, and the 'high-dimensional propensity score' (hdPS) that employs a univariate covariate screen. We evaluate methods on a range of outcome-dependent and outcome-independent metrics. Results: L1-regularization propensity score methods achieve superior model fit, covariate balance and negative control bias reduction compared with the hdPS. Simulation results are mixed and fluctuate with simulation parameters, revealing a limitation of simulation under the proportional hazards framework. Including regularization with the hdPS reduces commonly reported non-convergence issues but has little effect on propensity score performance. Conclusions: L1-regularization incorporates all covariates simultaneously into the propensity score model and offers propensity score performance superior to the hdPS marginal screen.


Assuntos
Estudos Observacionais como Assunto , Pontuação de Propensão , Projetos de Pesquisa , Algoritmos , Viés , Humanos , Modelos Logísticos , Estudos Observacionais como Assunto/métodos , Estudos Observacionais como Assunto/normas , Projetos de Pesquisa/normas , Projetos de Pesquisa/estatística & dados numéricos , Tamanho da Amostra
14.
Front Pharmacol ; 9: 594, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29928230

RESUMO

Background: Several initiatives have assessed if mining electronic health records (EHRs) may accelerate the process of drug safety signal detection. In Europe, Exploring and Understanding Adverse Drug Reactions (EU-ADR) Project Focused on utilizing clinical data from EHRs of over 30 million patients from several European countries. Rofecoxib is a prescription COX-2 selective Non-Steroidal Anti-Inflammatory Drugs (NSAID) approved in 1999. In September 2004, the manufacturer withdrew rofecoxib from the market because of safety concerns. In this study, we investigated if the signal concerning rofecoxib and acute myocardial infarction (AMI) could have been identified in EHR database (EU-ADR project) earlier than spontaneous reporting system (SRS), and in advance of rofecoxib withdrawal. Methods: Data from the EU-ADR project and WHO-VigiBase (for SRS) were used for the analysis. Signals were identified when respective statistics exceeded defined thresholds. The SRS analyses was conducted two ways- based on the date the AMI events with rofecoxib as a suspect medication were entered into the database and also the date that the AMI event occurred with exposure to rofecoxib. Results: Within the databases participating in EU-ADR it was possible to identify a strong signal concerning rofecoxib and AMI since Q3 2000 [RR LGPS = 4.5 (95% CI: 2.84-6.72)] and peaked to 4.8 in Q4 2000. In WHO-VigiBase, for AMI term grouping, the EB05 threshold of 2 was crossed in the Q4 2004 (EB05 = 2.94). Since then, the EB05 value increased consistently and peaked in Q3 2006 (EB05 = 48.3) and then again in Q2 2008 (EB05 = 48.5). About 93% (2260 out of 2422) of AMIs reported in WHO-VigiBase database actually occurred prior to the product withdrawal, however, they were reported after the risk minimization/risk communication efforts. Conclusion: In this study, EU-EHR databases were able to detect the AMI signal 4 years prior to the SRS database. We believe that for events that are consistently documented in EHR databases, such as serious events or events requiring in-patient medical intervention or hospitalization, the signal detection exercise in EHR would be beneficial for newly introduced medicinal products on the market, in addition to the SRS data.

15.
J Am Med Inform Assoc ; 25(8): 969-975, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29718407

RESUMO

Objective: To develop a conceptual prediction model framework containing standardized steps and describe the corresponding open-source software developed to consistently implement the framework across computational environments and observational healthcare databases to enable model sharing and reproducibility. Methods: Based on existing best practices we propose a 5 step standardized framework for: (1) transparently defining the problem; (2) selecting suitable datasets; (3) constructing variables from the observational data; (4) learning the predictive model; and (5) validating the model performance. We implemented this framework as open-source software utilizing the Observational Medical Outcomes Partnership Common Data Model to enable convenient sharing of models and reproduction of model evaluation across multiple observational datasets. The software implementation contains default covariates and classifiers but the framework enables customization and extension. Results: As a proof-of-concept, demonstrating the transparency and ease of model dissemination using the software, we developed prediction models for 21 different outcomes within a target population of people suffering from depression across 4 observational databases. All 84 models are available in an accessible online repository to be implemented by anyone with access to an observational database in the Common Data Model format. Conclusions: The proof-of-concept study illustrates the framework's ability to develop reproducible models that can be readily shared and offers the potential to perform extensive external validation of models, and improve their likelihood of clinical uptake. In future work the framework will be applied to perform an "all-by-all" prediction analysis to assess the observational data prediction domain across numerous target populations, outcomes and time, and risk settings.


Assuntos
Aprendizado de Máquina , Observação , Prognóstico , Software , Adulto , Conjuntos de Dados como Assunto , Feminino , Necessidades e Demandas de Serviços de Saúde , Humanos , Masculino , Modelos Teóricos , Estudos Observacionais como Assunto , Medição de Risco , Resultado do Tratamento
16.
Proc Natl Acad Sci U S A ; 115(11): 2571-2577, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29531023

RESUMO

Observational healthcare data, such as electronic health records and administrative claims, offer potential to estimate effects of medical products at scale. Observational studies have often been found to be nonreproducible, however, generating conflicting results even when using the same database to answer the same question. One source of discrepancies is error, both random caused by sampling variability and systematic (for example, because of confounding, selection bias, and measurement error). Only random error is typically quantified but converges to zero as databases become larger, whereas systematic error persists independent from sample size and therefore, increases in relative importance. Negative controls are exposure-outcome pairs, where one believes no causal effect exists; they can be used to detect multiple sources of systematic error, but interpreting their results is not always straightforward. Previously, we have shown that an empirical null distribution can be derived from a sample of negative controls and used to calibrate P values, accounting for both random and systematic error. Here, we extend this work to calibration of confidence intervals (CIs). CIs require positive controls, which we synthesize by modifying negative controls. We show that our CI calibration restores nominal characteristics, such as 95% coverage of the true effect size by the 95% CI. We furthermore show that CI calibration reduces disagreement in replications of two pairs of conflicting observational studies: one related to dabigatran, warfarin, and gastrointestinal bleeding and one related to selective serotonin reuptake inhibitors and upper gastrointestinal bleeding. We recommend CI calibration to improve reproducibility of observational studies.


Assuntos
Viés , Calibragem/normas , Pesquisa sobre Serviços de Saúde/estatística & dados numéricos , Pesquisa sobre Serviços de Saúde/normas , Estudos Observacionais como Assunto , Intervalos de Confiança , Humanos , Projetos de Pesquisa/normas , Projetos de Pesquisa/estatística & dados numéricos
17.
Neurosci Biobehav Rev ; 86: 1-11, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29247762

RESUMO

This systematic review assesses the association between prenatal antidepressant exposure and risk of ADHD in children. Electronic databases were searched up to 25 July 2017. Observational studies examining this association were included in the review and meta-analysis was conducted where appropriate. Eight relevant studies were identified. The seven studies included in the meta-analysis comprised a total of 2,886,502 children. The pooled estimates comparing prenatal exposure to non-exposure showed an adjusted rate ratio (aRR) of 1.39 (95%CI 1.21-1.61). Similarly, an increased risk was found comparing previous antidepressant users and non-users: aRR = 1.56 (95%CI 1.25-1.95). The relationship between maternal psychiatric conditions and ADHD in children yielded an aRR of 1.90 (95%CI 1.47-2.45). Three studies conducted sibling-matched analyses with aRR of 0.94 (95%CI 0.75-1.16). These data suggest that the observed association between prenatal use of antidepressants and risk of ADHD in offspring can be partially explained by confounding by indication because the results from sibling-matched analyses do not support an increased risk of ADHD in discordant exposed siblings.


Assuntos
Antidepressivos/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Complicações na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/induzido quimicamente , Fatores de Risco
18.
Diabetes Obes Metab ; 20(3): 582-589, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28898514

RESUMO

AIMS: To examine the incidence of amputation in patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose co-transporter 2 (SGLT2) inhibitors overall, and canagliflozin specifically, compared with non-SGLT2 inhibitor antihyperglycaemic agents (AHAs). MATERIALS AND METHODS: Patients with T2DM newly exposed to SGLT2 inhibitors or non-SGLT2 inhibitor AHAs were identified using the Truven MarketScan database. The incidence of below-knee lower extremity (BKLE) amputation was calculated for patients treated with SGLT2 inhibitors, canagliflozin, or non-SGLT2 inhibitor AHAs. Patients newly exposed to canagliflozin and non-SGLT2 inhibitor AHAs were matched 1:1 on propensity scores, and a Cox proportional hazards model was used for comparative analysis. Negative controls (outcomes not believed to be associated with any AHA) were used to calibrate P values. RESULTS: Between April 1, 2013 and October 31, 2016, 118 018 new users of SGLT2 inhibitors, including 73 024 of canagliflozin, and 226 623 new users of non-SGLT2 inhibitor AHAs were identified. The crude incidence rates of BKLE amputation were 1.22, 1.26 and 1.87 events per 1000 person-years with SGLT2 inhibitors, canagliflozin and non-SGLT2 inhibitor AHAs, respectively. For the comparative analysis, 63 845 new users of canagliflozin were matched with 63 845 new users of non-SGLT2 inhibitor AHAs, resulting in well-balanced baseline covariates. The incidence rates of BKLE amputation were 1.18 and 1.12 events per 1000 person-years with canagliflozin and non-SGLT2 inhibitor AHAs, respectively; the hazard ratio was 0.98 (95% confidence interval 0.68-1.41; P = .92, calibrated P = .95). CONCLUSIONS: This real-world study observed no evidence of increased risk of BKLE amputation for new users of canagliflozin compared with non-SGLT2 inhibitor AHAs in a broad population of patients with T2DM.


Assuntos
Amputação/estatística & dados numéricos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/epidemiologia , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/cirurgia , Feminino , Humanos , Perna (Membro)/irrigação sanguínea , Perna (Membro)/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Estados Unidos
19.
JAMA Netw Open ; 1(4): e181755, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30646124

RESUMO

Importance: Consensus around an efficient second-line treatment option for type 2 diabetes (T2D) remains ambiguous. The availability of electronic medical records and insurance claims data, which capture routine medical practice, accessed via the Observational Health Data Sciences and Informatics network presents an opportunity to generate evidence for the effectiveness of second-line treatments. Objective: To identify which drug classes among sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, and thiazolidinediones are associated with reduced hemoglobin A1c (HbA1c) levels and lower risk of myocardial infarction, kidney disorders, and eye disorders in patients with T2D treated with metformin as a first-line therapy. Design, Setting, and Participants: Three retrospective, propensity-matched, new-user cohort studies with replication across 8 sites were performed from 1975 to 2017. Medical data of 246 558 805 patients from multiple countries from the Observational Health Data Sciences and Informatics (OHDSI) initiative were included and medical data sets were transformed into a unified common data model, with analysis done using open-source analytical tools. Participants included patients with T2D receiving metformin with at least 1 prior HbA1c laboratory test who were then prescribed either sulfonylureas, DPP-4 inhibitors, or thiazolidinediones. Data analysis was conducted from 2015 to 2018. Exposures: Treatment with sulfonylureas, DPP-4 inhibitors, or thiazolidinediones starting at least 90 days after the initial prescription of metformin. Main Outcomes and Measures: The primary outcome is the first observation of the reduction of HbA1c level to 7% of total hemoglobin or less after prescription of a second-line drug. Secondary outcomes are myocardial infarction, kidney disorder, and eye disorder after prescription of a second-line drug. Results: A total of 246 558 805 patients (126 977 785 women [51.5%]) were analyzed. Effectiveness of sulfonylureas, DPP-4 inhibitors, and thiazolidinediones prescribed after metformin to lower HbA1c level to 7% or less of total hemoglobin remained indistinguishable in patients with T2D. Patients treated with sulfonylureas compared with DPP-4 inhibitors had a small increased consensus hazard ratio of myocardial infarction (1.12; 95% CI, 1.02-1.24) and eye disorders (1.15; 95% CI, 1.11-1.19) in the meta-analysis. Hazard of observing kidney disorders after treatment with sulfonylureas, DPP-4 inhibitors, or thiazolidinediones was equally likely. Conclusions and Relevance: The examined drug classes did not differ in lowering HbA1c and in hazards of kidney disorders in patients with T2D treated with metformin as a first-line therapy. Sulfonylureas had a small, higher observed hazard of myocardial infarction and eye disorders compared with DPP-4 inhibitors in the meta-analysis. The OHDSI collaborative network can be used to conduct a large international study examining the effectiveness of second-line treatment choices made in clinical management of T2D.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hemoglobina A Glicada/análise , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/uso terapêutico , Estudos de Coortes , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Humanos , Masculino , Compostos de Sulfonilureia/efeitos adversos , Tiazolidinedionas/efeitos adversos
20.
PLoS One ; 12(12): e0188377, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29232365

RESUMO

BACKGROUND: A recent comprehensive report on healthcare quality in Italy published by the Organization of Economic Co-operation and Development (OECD) recommended that regular monitoring of quality of primary care by means of compliance with standards of care for chronic diseases is performed. A previous ecological study demonstrated that compliance with standards of care could be reliably estimated on regional level using administrative databases. This study compares estimates based on administrative data with estimates based on GP records for the same persons, to understand whether ecological fallacy played a role in the results of the previous study. METHODS: We compared estimates of compliance with diagnostic and therapeutic standards of care for type 2 diabetes (T2DM), hypertension and ischaemic heart disease (IHD) from administrative data (IAD) with estimates from medical records (MR) for the same persons registered with 24 GP's in 2012. Data were linked at an individual level. RESULTS: 32,688 persons entered the study, 12,673 having at least one of the three diseases according to at least one data source. Patients not detected by IAD were many, for all three conditions: adding MR increased the number of cases of T2DM, hypertension, and IHD by +40%, +42%, and +104%, respectively. IAD had imperfect sensitivity in detecting population compliance with therapies (adding MR increased the estimate, from +11.5% for statins to +14.7% for antithrombotics), and, more substantially, with diagnostic recommendations (adding MR increased the estimate, from +23.7% in glycated hemoglobin tests, to +50.5% in electrocardiogram). Patients not detected by IAD were less compliant with respect to those that IAD correctly identified (from -4.8 percentage points in proportion of IHD patients compliant with a yearly glycated hemoglobin test, to -40.1 points in the proportion of T2DM patients compliant with the same recommendation). IAD overestimated indicators of compliance with therapeutic standards (significant differences ranged from 3.3. to 3.6 percentage points) and underestimated indicators of compliance with diagnostic standards (significant differences ranged from -2.3 to -14.1 percentage points). CONCLUSION: IAD overestimated the percentage of patients compliant with therapeutic standards by less than 6 percentage points, and underestimated the percentage of patients compliant with diagnostic standards by a maximum of 14 percentage points. Therefore, both discussions at local level between GP's and local health unit managers and discussions at central level between national and regional policy makers can be informed by indicators of compliance estimated by IAD, which, based on those results, have the ability of signalling critical or excellent clusters. However, this study found that estimates are partly flawed, because a high number of patients with chronic diseases are not detected by IAD, patients detected are not representative of the whole population of patients, and some categories of diagnostic tests are markedly underrecorded in IAD (up to 50% in the case of electrocardiograms). Those results call to caution when interpreting IAD estimates. Audits based on medical records, on the local level, and an interpretation taking into account information external to IAD, on the central level, are needed to assess a more comprehensive compliance with standards.


Assuntos
Doença Crônica/terapia , Fidelidade a Diretrizes , Diabetes Mellitus Tipo 2/terapia , Feminino , Humanos , Hipertensão/terapia , Itália , Masculino , Isquemia Miocárdica/terapia
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