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1.
Inj Epidemiol ; 9(1): 2, 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34980268

RESUMO

BACKGROUND: Little is known about voluntary divestment of firearms among US firearm owners. Here, we aim to estimate the proportion of handgun owners who divest their handguns in the years following their initial acquisition; examine the timing, duration, and dynamics of those divestments; and describe characteristics of those who divest. METHODS: We use data from the Longitudinal Study of Handgun Ownership and Transfer, a cohort of registered voters in California with detailed information on 626,756 adults who became handgun owners during the 12-year study period, 2004-2016. For the current study, persons were followed from the time of their initial handgun acquisition until divestment, loss to follow-up, death, or the end of the study period. We describe the cumulative proportion who divest overall and by personal and area-level characteristics. We also estimate the proportion who reacquired handguns among persons who divested. RESULTS: Overall, 4.5% (95% CI 4.5-4.6) of handgun owners divested within 5 years of their first acquisition, with divestment relatively more common among women and among younger adults. Among those who divested, 36.6% (95% CI 35.8-37.5) reacquired a handgun within 5 years. CONCLUSIONS: Handgun divestment is rare, with the vast majority of new handgun owners retaining them for years.

2.
Epidemiology ; 33(1): 84-94, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34847085

RESUMO

Mendelian randomization (MR) is often used to estimate effects of time-varying exposures on health outcomes using observational data. However, MR studies typically use a single measurement of exposure and apply conventional instrumental variable (IV) methods designed to handle time-fixed exposures. As such, MR effect estimates for time-varying exposures are often biased, and interpretations are unclear. We describe the instrumental conditions required for IV estimation with a time-varying exposure, and the additional conditions required to causally interpret MR estimates as a point effect, a period effect or a lifetime effect depending on whether researchers have measurements at a single or multiple time points. We propose methods to incorporate time-varying exposures in MR analyses based on g-estimation of structural mean models, and demonstrate its application by estimating the period effect of alcohol intake, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol on intermediate coronary heart disease outcomes using data from the Framingham Heart Study. We use this data example to highlight the challenges of interpreting MR estimates as causal effects, and describe other extensions of structural mean models for more complex data scenarios.

4.
BMC Med Res Methodol ; 21(1): 258, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34823502

RESUMO

BACKGROUND: In many applications of instrumental variable (IV) methods, the treatments of interest are intrinsically time-varying and outcomes of interest are failure time outcomes. A common example is Mendelian randomization (MR), which uses genetic variants as proposed IVs. In this article, we present a novel application of g-estimation of structural nested cumulative failure models (SNCFTMs), which can accommodate multiple measures of a time-varying treatment when modelling a failure time outcome in an IV analysis. METHODS: A SNCFTM models the ratio of two conditional mean counterfactual outcomes at time k under two treatment strategies which differ only at an earlier time m. These models can be extended to accommodate inverse probability of censoring weights, and can be applied to case-control data. We also describe how the g-estimates of the SNCFTM parameters can be used to calculate marginal cumulative risks under nondynamic treatment strategies. We examine the performance of this method using simulated data, and present an application of these models by conducting an MR study of alcohol intake and endometrial cancer using longitudinal observational data from the Nurses' Health Study. RESULTS: Our simulations found that estimates from SNCFTMs which used an IV approach were similar to those obtained from SNCFTMs which adjusted for confounders, and similar to those obtained from the g-formula approach when the outcome was rare. In our data application, the cumulative risk of endometrial cancer from age 45 to age 72 under the "never drink" strategy (4.0%) was similar to that under the "always ½ drink per day" strategy (4.3%). CONCLUSIONS: SNCFTMs can be used to conduct MR and other IV analyses with time-varying treatments and failure time outcomes.

5.
JAMA ; 326(16): 1614-1621, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34698778

RESUMO

Importance: Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation. Objective: To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies. Design, Setting, and Participants: The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021. Findings: The STROBE-MR checklist is organized into 6 sections (Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information) and includes 20 main items and 30 subitems. It covers both 1-sample and 2-sample MR studies that assess 1 or multiple exposures and outcomes, and addresses MR studies that follow a genome-wide association study and are reported in the same article. The checklist asks authors to justify why MR is a helpful method to address the study question and state prespecified causal hypotheses. The measurement, quality, and selection of genetic variants must be described and attempts to assess validity of MR-specific assumptions should be well reported. An item on data sharing includes reporting when the data and statistical code required to replicate the analyses can be accessed. Conclusions and Relevance: STROBE-MR provides guidelines for reporting MR studies. Improved reporting of these studies could facilitate their evaluation by editors, peer reviewers, researchers, clinicians, and other readers, and enhance the interpretation of their results.


Assuntos
Lista de Checagem , Epidemiologia , Guias como Assunto , Análise da Randomização Mendeliana/métodos , Estudos Observacionais como Assunto , Viés , Estudo de Associação Genômica Ampla , Humanos , Disseminação de Informação , Projetos Piloto , Mídias Sociais
7.
Am J Epidemiol ; 190(11): 2280-2283, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34132326

RESUMO

Dimitris and Platt (Am J Epidemiol. 2021;190(11):2275-2279) take on the challenging topic of using "shocks" such as the severe acute respiratory system coronavirus 2 (SARS-CoV-2) pandemic as instrumental variables to study the effect of some exposure on some outcome. Evoking our recent lived experiences, they conclude that the assumptions necessary for an instrumental variable analysis will often be violated and therefore strongly caution against such analyses. Here, we build upon this warranted caution while acknowledging that such analyses will still be pursued and conducted. We discuss strategies for evaluating or reasoning about when such an analysis is clearly inappropriate for a given research question, as well as strategies for interpreting study findings with special attention to incorporating plausible sources of bias in any conclusions drawn from a given finding.


Assuntos
COVID-19 , Pandemias , Viés , Humanos , Pandemias/prevenção & controle , SARS-CoV-2
8.
Nat Med ; 27(4): 668-676, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33837377

RESUMO

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.


Assuntos
COVID-19/genética , Reposicionamento de Medicamentos , Análise da Randomização Mendeliana/métodos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/fisiologia , COVID-19/tratamento farmacológico , Estudo de Associação Genômica Ampla , Humanos , Subunidade beta de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/fisiologia , Locos de Características Quantitativas , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/fisiologia
10.
Epidemiology ; 32(1): 131, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33122568
11.
Paediatr Perinat Epidemiol ; 35(1): 130-142, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32779786

RESUMO

BACKGROUND: Mendelian randomisation (MR) designs apply instrumental variable techniques using genetic variants to study causal effects. MR is increasingly used to evaluate the role of maternal exposures during pregnancy on offspring health. OBJECTIVES: We review the application of MR to prenatal exposures and describe reporting of methodologic challenges in this area. DATA SOURCES: We searched PubMed, EMBASE, Medline Ovid, Cochrane Central, Web of Science, and Google Scholar. STUDY SELECTION AND DATA EXTRACTION: Eligible studies met the following criteria: (a) a maternal pregnancy exposure; (b) an outcome assessed in offspring of the pregnancy; and (c) a genetic variant or score proposed as an instrument or proxy for an exposure. SYNTHESIS: We quantified the frequency of reporting of MR conditions stated, techniques used to examine assumption plausibility, and reported limitations. RESULTS: Forty-three eligible studies were identified. When discussing challenges or limitations, the most common issues described were known potential biases in the broader MR literature, including population stratification (n = 29), weak instrument bias (n = 18), and certain types of pleiotropy (n = 30). Of 22 studies presenting point estimates for the effect of exposure, four defined their causal estimand. Twenty-four studies discussed issues unique to prenatal MR, including selection on pregnancy (n = 1) and pleiotropy via postnatal exposure (n = 10) or offspring genotype (n = 20). CONCLUSIONS: Prenatal MR studies frequently discuss issues that affect all MR studies, but rarely discuss problems specific to the prenatal context, including selection on pregnancy and effects of postnatal exposure. Future prenatal MR studies should report and attempt to falsify their assumptions, with particular attention to issues specific to prenatal MR. Further research is needed to evaluate the impacts of biases unique to prenatal MR in practice.


Assuntos
Variação Genética , Análise da Randomização Mendeliana , Viés , Causalidade , Feminino , Humanos , Gravidez
12.
Eur J Epidemiol ; 36(1): 69-79, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33247419

RESUMO

We aimed to study the effects of hypothetical interventions on systolic blood pressure (SBP) and smoking on risk of stroke and dementia using data from 15 years of follow-up in the Rotterdam Study. We used data from 4930 individuals, aged 55-80 years, with no prior history of stroke, dementia or cognitive impairment, followed for 15 years within the Rotterdam Study, a population-based cohort. We defined the following sustained interventions on SBP: (1) maintaining SBP below 120 mmHg, (2) maintaining SBP below 140 mmHg, (3) reducing SBP by 10% if above 140 mmHg, (4) reducing SBP by 20% if above 140 mmHg, and a combined intervention of quitting smoking with each of these SBP-lowering strategies. We considered incident stroke and incident dementia diagnoses as outcomes. We applied the parametric g-formula to adjust for baseline and time-varying confounding. The observed 15-year risk for stroke was 10.7%. Compared to no specified intervention (i.e., the "natural course"), all interventions that involved reducing SBP were associated with a stroke risk reduction of about 10% (e.g., reducing SBP by 20% if above 140 mmHg risk ratio: 0.89; 95% CI 0.76, 1). Jointly intervening on SBP and smoking status further decreased the risk of stroke (e.g., risk ratio: 0.83; 95% CI 0.71, 0.94). None of the specified interventions were associated with a substantive change in dementia risk. Our study suggests that a joint intervention on SBP and smoking cessation during later life may reduce stroke risk, while the potential for reducing dementia risk were not observed.


Assuntos
Pressão Sanguínea/fisiologia , Demência/fisiopatologia , Hipertensão/prevenção & controle , Acidente Vascular Cerebral/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Demência/epidemiologia , Feminino , Seguimentos , Cardiopatias/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Prevalência , Fatores de Risco , Comportamento de Redução do Risco , Acidente Vascular Cerebral/epidemiologia
13.
Neurology ; 95(10): e1322-e1332, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32753444

RESUMO

OBJECTIVE: Observational data can be used to attempt to emulate a target trial of statin use and estimate analogues of intention-to-treat and per protocol effects on dementia risk. METHODS: Using data from a prospective cohort study in the Netherlands, we conceptualized a sequence of "trials" in which eligible individuals ages 55-80 years were classified as statin initiators or noninitiators for every consecutive month between 1993 and 2007 and were followed until diagnosis of dementia, death, loss to follow-up, or the end of follow-up. We estimated 2 types of effects of statin use on dementia and a combined endpoint of dementia or death: the effect of initiation vs no initiation and the effect of sustained use vs no use. We estimated risk by statin treatment strategy over time via pooled logistic regression. We used inverse-probability weighting to account for treatment-confounder feedback in estimation of per-protocol effects. RESULTS: Of 233,526 eligible person-trials (6,373 individuals), there were 622 initiators and 232,904 noninitiators. Comparing statin initiation with no initiation, the 10-year risk differences (95% confidence interval) were -0.1% (-2.3% to 1.8%) for dementia and 0.3% (-2.7% to 3.3%) for dementia or death. Comparing sustained statin use vs no use, the 10-year risk differences were -2.2% (-5.2% to 1.6%) for dementia and -5.1% (-10.5% to -1.1%) for dementia or death. CONCLUSIONS: Individuals with sustained statin use, but not statin initiation alone, had reduced 10-year risks of dementia and dementia or death. Our results should be interpreted with caution due to the small number of initiators and events and potential for residual confounding.


Assuntos
Demência/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade
14.
N Engl J Med ; 382(23): 2220-2229, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32492303

RESUMO

BACKGROUND: Research has consistently identified firearm availability as a risk factor for suicide. However, existing studies are relatively small in scale, estimates vary widely, and no study appears to have tracked risks from commencement of firearm ownership. METHODS: We identified handgun acquisitions and deaths in a cohort of 26.3 million male and female residents of California, 21 years old or older, who had not previously acquired handguns. Cohort members were followed for up to 12 years 2 months (from October 18, 2004, to December 31, 2016). We used survival analysis to estimate the relationship between handgun ownership and both all-cause mortality and suicide (by firearm and by other methods) among men and women. The analysis allowed the baseline hazard to vary according to neighborhood and was adjusted for age, race and ethnic group, and ownership of long guns (i.e., rifles or shotguns). RESULTS: A total of 676,425 cohort members acquired one or more handguns, and 1,457,981 died; 17,894 died by suicide, of which 6691 were suicides by firearm. Rates of suicide by any method were higher among handgun owners, with an adjusted hazard ratio of 3.34 for all male owners as compared with male nonowners (95% confidence interval [CI], 3.13 to 3.56) and 7.16 for female owners as compared with female nonowners (95% CI, 6.22 to 8.24). These rates were driven by much higher rates of suicide by firearm among both male and female handgun owners, with a hazard ratio of 7.82 for men (95% CI, 7.26 to 8.43) and 35.15 for women (95% CI, 29.56 to 41.79). Handgun owners did not have higher rates of suicide by other methods or higher all-cause mortality. The risk of suicide by firearm among handgun owners peaked immediately after the first acquisition, but 52% of all suicides by firearm among handgun owners occurred more than 1 year after acquisition. CONCLUSIONS: Handgun ownership is associated with a greatly elevated and enduring risk of suicide by firearm. (Funded by the Fund for a Safer Future and others.).


Assuntos
Armas de Fogo , Violência com Arma de Fogo/estatística & dados numéricos , Suicídio/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Causas de Morte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Propriedade , Fatores de Risco , Suicídio/prevenção & controle , Análise de Sobrevida , Adulto Jovem
15.
Eur J Epidemiol ; 35(7): 619-630, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32445007

RESUMO

In this paper we study approaches for dealing with treatment when developing a clinical prediction model. Analogous to the estimand framework recently proposed by the European Medicines Agency for clinical trials, we propose a 'predictimand' framework of different questions that may be of interest when predicting risk in relation to treatment started after baseline. We provide a formal definition of the estimands matching these questions, give examples of settings in which each is useful and discuss appropriate estimators including their assumptions. We illustrate the impact of the predictimand choice in a dataset of patients with end-stage kidney disease. We argue that clearly defining the estimand is equally important in prediction research as in causal inference.


Assuntos
Regras de Decisão Clínica , Ensaios Clínicos como Assunto/métodos , Projetos de Pesquisa , Ensaios Clínicos como Assunto/normas , Interpretação Estatística de Dados , Humanos , Modelos Estatísticos
16.
Inj Prev ; 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409621

RESUMO

BACKGROUND: Strong and consistent associations between access to firearms and suicide have been found in ecologic and individual-level observational studies. For adolescents, a seminal case-control study estimated that living in a home with (vs without) a firearm was associated with a fourfold increase in the risk of death by suicide. METHODS: We use data from a nationally representative study of 10 123 US adolescents aged 13-18 years to (1) measure how much adolescents who live in a home with a firearm differ from those who do not in ways related to their risk of suicide, and (2) incorporate these differences into an updated effect estimate of the risk of adolescent suicide attributable to living in a home with firearms. RESULTS: Almost one-third (30.7%) of adolescents reported living in a home with firearms. Relative to those who did not, adolescents reporting living in a home with a firearm were slightly more likely to be male, older and reside in the South and rural areas, but few differences were identified for mental health characteristics. The effect size found by Brent and colleagues appeared robust to sources of possible residual confounding: updated relative risks remained above 4.0 across most sensitivity analyses and at least 3.1 in even the most conservative estimates. CONCLUSIONS: Although unmeasured confounding and other biases may nonetheless remain, our updated estimates reinforce the suggestion that adolescents' risk of suicide was increased threefold to fourfold if they had lived in homes with a firearm compared with if they had not.

18.
Epidemiology ; 31(1): 65-74, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31790379

RESUMO

BACKGROUND: Investigators often support the validity of Mendelian randomization (MR) studies, an instrumental variable approach proposing genetic variants as instruments, via. subject matter knowledge. However, the instrumental variable model implies certain inequalities, offering an empirical method of falsifying (but not verifying) the underlying assumptions. Although these inequalities are said to detect only extreme assumption violations in practice, to our knowledge they have not been used in settings with multiple proposed instruments. METHODS: We applied the instrumental inequalities to an MR analysis of the effect of maternal pregnancy vitamin D on offspring psychiatric outcomes, proposing four independent maternal genetic variants as instruments. We assessed whether the proposed instruments satisfied the instrumental inequalities separately and jointly and explored the instrumental inequalities' properties via simulations. RESULTS: The instrumental inequalities were satisfied (i.e., we did not falsify the MR model) when considering each variant separately. However, the inequalities were violated when considering four variants jointly and for some combinations of two or three variants (two of 36 two-variant combinations and 18 of 24 three-variant combinations). In simulations, the inequalities detected structural biases more often when assessing proposed instruments jointly, although falsification in the absence of structural bias remained rare. CONCLUSIONS: The instrumental inequalities detected violations of the MR assumptions for genetic variants jointly proposed as instruments in our study, although the instrumental inequalities were satisfied when considering each proposed instrument separately. We discuss how investigators can assess instrumental inequalities to eliminate clearly invalid analyses in settings with many proposed instruments and provide appropriate code.


Assuntos
Análise da Randomização Mendeliana , Viés , Humanos , Análise da Randomização Mendeliana/instrumentação
20.
Inj Prev ; 26(2): 153-158, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31662345

RESUMO

BACKGROUND: Virtually all existing evidence linking access to firearms to elevated risks of mortality and morbidity comes from ecological and case-control studies. To improve understanding of the health risks and benefits of firearm ownership, we launched a cohort study: the Longitudinal Study of Handgun Ownership and Transfer (LongSHOT). METHODS: Using probabilistic matching techniques we linked three sources of individual-level, state-wide data in California: official voter registration records, an archive of lawful handgun transactions and all-cause mortality data. There were nearly 28.8 million unique voter registrants, 5.5 million handgun transfers and 3.1 million deaths during the study period (18 October 2004 to 31 December 2016). The linkage relied on several identifying variables (first, middle and last names; date of birth; sex; residential address) that were available in all three data sets, deploying them in a series of bespoke algorithms. RESULTS: Assembly of the LongSHOT cohort commenced in January 2016 and was completed in March 2019. Approximately three-quarters of matches identified were exact matches on all link variables. The cohort consists of 28.8 million adult residents of California followed for up to 12.2 years. A total of 1.2 million cohort members purchased at least one handgun during the study period, and 1.6 million died. CONCLUSIONS: Three steps taken early may be particularly useful in enhancing the efficiency of large-scale data linkage: thorough data cleaning; assessment of the suitability of off-the-shelf data linkage packages relative to bespoke coding; and careful consideration of the minimum sample size and matching precision needed to support rigorous investigation of the study questions.


Assuntos
Armas de Fogo/estatística & dados numéricos , Propriedade/estatística & dados numéricos , Adulto , California , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Armazenamento e Recuperação da Informação/métodos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
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