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Context: The present study builds on our prior work that demonstrated an association between pharmacogenetic interactions and 90-day readmission. Objective: Evaluate aggregate contribution of social determinants, comorbidity, and gene-x-drug interactions to moderate 90-day hospital readmission. Study Design and Analysis: Non-concurrent cohort study; Multivariable logistic regression Setting: Hospital/integrated healthcare delivery system in northern Illinois Population Studied: 19,999 adults tracked from 2010 through 2020 who underwent testing with a 13-gene pharmacogenetic panel Outcome Measure: 90-day hospital readmission (primary outcome) Results: Univariate logistic regression analyses demonstrated that strongest associations with 90 day hospital readmissions were the number of medications prescribed within 30 days of a first hospital admission that had Clinical Pharmacogenomics Implementation Consortium (CPIC) guidance (CPIC medications) (5+ CPIC medications, odds ratio (OR) = 7.66, 95% confidence interval 5.45-10.77) (p < 0.0001), major comorbidities (5+ comorbidities, OR 3.36, 2.61-4.32) (p < 0.0001), age (65 + years, OR = 2.35, 1.77-3.12) (p < 0.0001), unemployment (OR = 2.19, 1.88-2.64) (p < 0.0001), Black/African-American race (OR 2.12, 1.47-3.07) (p < 0.0001), median household income (OR = 1.63, 1.03-2.58) (p = 0.035), male gender (OR = 1.47, 1.21-1.80) (p = 0.0001), and one or more gene-x-drug interaction (defined as a prescribed CPIC medication for a patient with a corresponding actionable pharmacogenetic variant) (OR = 1.41, 1.18-1.70). Health insurance was not associated with risk of 90-day readmission. Race, income, employment status, and gene-x-drug interactions were robust in a multivariable logistic regression model. The odds of 90-day readmission for patients with one or more identified gene-x-drug interactions after adjustment for these covariates was attenuated by 10% (OR = 1.31, 1.08-1.59) (p = 0.006). Although the interaction between race and gene-x-drug interactions was not statistically significant, White patients were more likely to have a gene-x-drug interaction (35.2%) than Black/African-American patients (25.9%) who were not readmitted (p < 0.0001). Conclusions: These results highlight the major contribution of social determinants and medical complexity to risk for hospital readmission, and that these determinants may modify the effect of gene-x-drug interactions on rehospitalization risk.
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Readmisión del Paciente , Farmacogenética , Adulto , Humanos , Masculino , Estados Unidos , Anciano , Estudios de Cohortes , Determinantes Sociales de la Salud , Estudios Retrospectivos , Factores de Riesgo , Interacciones FarmacológicasRESUMEN
BACKGROUND: The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population. METHODS: In this prospective longitudinal observational study, we collected data from participants who were self-reporting test results and symptoms in the ZOE COVID app (previously known as the COVID Symptoms Study App). Eligible participants were aged 16-99 years, based in the UK, with a body-mass index between 15 and 55 kg/m2, had received at least two doses of any SARS-CoV-2 vaccine, were symptomatic, and logged a positive symptomatic PCR or lateral flow result for SARS-CoV-2 during the study period. The primary outcome was the likelihood of developing a given symptom (of the 32 monitored in the app) or hospital admission within 7 days before or after the positive test in participants infected during omicron prevalence compared with those infected during delta prevalence. FINDINGS: Between June 1, 2021, and Jan 17, 2022, we identified 63 002 participants who tested positive for SARS-CoV-2 and reported symptoms in the ZOE app. These patients were matched 1:1 for age, sex, and vaccination dose, across two periods (June 1 to Nov 27, 2021, delta prevalent at >70%; n=4990, and Dec 20, 2021, to Jan 17, 2022, omicron prevalent at >70%; n=4990). Loss of smell was less common in participants infected during omicron prevalence than during delta prevalence (16·7% vs 52·7%, odds ratio [OR] 0·17; 95% CI 0·16-0·19, p<0·001). Sore throat was more common during omicron prevalence than during delta prevalence (70·5% vs 60·8%, 1·55; 1·43-1·69, p<0·001). There was a lower rate of hospital admission during omicron prevalence than during delta prevalence (1·9% vs 2·6%, OR 0·75; 95% CI 0·57-0·98, p=0·03). INTERPRETATION: The prevalence of symptoms that characterise an omicron infection differs from those of the delta SARS-CoV-2 variant, apparently with less involvement of the lower respiratory tract and reduced probability of hospital admission. Our data indicate a shorter period of illness and potentially of infectiousness which should impact work-health policies and public health advice. FUNDING: Wellcome Trust, ZOE, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, and Medical Research Council.
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COVID-19 , SARS-CoV-2 , COVID-19/epidemiología , Vacunas contra la COVID-19 , Hospitales , Humanos , Prevalencia , Estudios Prospectivos , SARS-CoV-2/genéticaRESUMEN
Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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Sitios Genéticos , Fumar/genética , Bancos de Muestras Biológicas , Bases de Datos Factuales , Europa (Continente)/etnología , Exoma , Femenino , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Reino UnidoRESUMEN
This review has been withdrawn because it has been found to be in breach of the Cochrane Commercial Sponsorship policy clause 2: 'Individuals who are currently employed or where employed any time in the last three years by a company that has a real or potential financial interest in the outcome of the review (including but not limited to drug companies or medical device manufacturers); or who hold or have applied for a patent related to the review are prohibited from being Cochrane Review authors. In most cases, current or previous employment would be characterized by the affiliation statement made by the author at the title registration, protocol, or review stage of the review'.
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Cese del Hábito de Fumar , Biomarcadores , Terapia Combinada , Humanos , Dispositivos para Dejar de Fumar TabacoRESUMEN
INTRODUCTION: Pharmacogenomic studies have used genetic variants to identify smokers likely to respond to pharmacological treatments for smoking cessation. METHODS: We performed a systematic review and meta-analysis of primary and secondary analyses of trials of smoking cessation pharmacotherapies. Eligible were trials with data on a priori selected single nucleotide polymorphisms, replicated non-single nucleotide polymorphisms, and/or the nicotine metabolite ratio. We estimated the genotype × treatment interaction as the ratio of risk ratios (RRR) for treatment effects across genotype groups. RESULTS: We identified 18 trials (N = 9017 participants), including 40 active (bupropion, nicotine replacement therapy [NRT], varenicline, or combination therapies) versus placebo comparisons and 16 active versus active comparisons. There was statistical evidence of heterogeneity across rs16969968 genotypes in CHRNA5 with regard to both 6-month abstinence and end-of-treatment abstinence in non-Hispanic black smokers and end-of-treatment abstinence in non-Hispanic white smokers. There was also heterogeneity across rs1051730 genotypes in CHRNA3 with regard to end-of-treatment abstinence in non-Hispanic white smokers. There was no clear statistical evidence for other genotype-by-treatment combinations. Compared with placebo, NRT was more effective among non-Hispanic black smokers with rs16969968-GG with regard to both 6-month abstinence (RRR for GG vs. GA or AA, 3.51; 95% confidence interval [CI] = 1.19 to 10.30) and end-of-treatment abstinence (RRR for GG vs. GA or AA, 5.84; 95% CI = 1.89 to 18.10). Among non-Hispanic white smokers, NRT effectiveness relative to placebo was comparable across rs1051730 and rs169969960 genotypes. CONCLUSIONS: We did not identify widespread differential effects of smoking cessation pharmacotherapies based on genotype. The quality of the evidence is generally moderate. IMPLICATIONS: Although we identified some evidence of genotype × treatment interactions, the vast majority of analyses did not provide evidence of differential treatment response by genotype. Where we find some evidence, these results should be considered preliminary and interpreted with caution because of the small number of contributing trials per genotype comparison, the wide confidence intervals, and the moderate quality of evidence. Prospective trials and individual-patient data meta-analyses accounting for heterogeneity of treatment effects through modeling are needed to assess the clinical utility of genetically informed biomarkers to guide pharmacotherapy choice for smoking cessation.
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Marcadores Genéticos/genética , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Cese del Hábito de Fumar/métodos , Fumar/tratamiento farmacológico , Fumar/genética , Dispositivos para Dejar de Fumar Tabaco , Bupropión/farmacología , Bupropión/uso terapéutico , Ensayos Clínicos como Asunto/métodos , Femenino , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple/efectos de los fármacos , Polimorfismo de Nucleótido Simple/genética , Estudios Prospectivos , Agentes para el Cese del Hábito de Fumar/farmacología , Dispositivos para Dejar de Fumar Tabaco/tendencias , Vareniclina/farmacología , Vareniclina/uso terapéuticoRESUMEN
Introduction: Human genetic research has succeeded in definitively identifying multiple genetic variants associated with risk for nicotine dependence and heavy smoking. To build on these advances, and to aid in reducing the prevalence of smoking and its consequent health harms, the next frontier is to identify genetic predictors of successful smoking cessation and also of the efficacy of smoking cessation treatments ("pharmacogenomics"). More broadly, additional biomarkers that can be quantified from biosamples also promise to aid "Precision Medicine" and the personalization of treatment, both pharmacological and behavioral. Aims and Methods: To motivate ongoing and future efforts, here we review several compelling genetic and biomarker findings related to smoking cessation and treatment. Results: These Key results involve genetic variants in the nicotinic receptor subunit gene CHRNA5, variants in the nicotine metabolism gene CYP2A6, and the nicotine metabolite ratio. We also summarize reports of epigenetic changes related to smoking behavior. Conclusions: The results to date demonstrate the value and utility of data generated from biosamples in clinical treatment trial settings. This article cross-references a companion paper in this issue that provides practical guidance on how to incorporate biosample collection into a planned clinical trial and discusses avenues for harmonizing data and fostering consortium-based, collaborative research on the pharmacogenomics of smoking cessation. Implications: Evidence is emerging that certain genotypes and biomarkers are associated with smoking cessation success and efficacy of smoking cessation treatments. We review key findings that open potential avenues for personalizing smoking cessation treatment according to an individual's genetic or metabolic profile. These results provide important incentive for smoking cessation researchers to collect biosamples and perform genotyping in research studies and clinical trials.
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Ensayos Clínicos como Asunto/métodos , Epigénesis Genética/genética , Metabolómica/métodos , Cese del Hábito de Fumar/métodos , Fumar/genética , Fumar/metabolismo , Biomarcadores/metabolismo , Genotipo , Humanos , Farmacogenética/métodos , Medicina de Precisión/métodos , Fumar/terapiaRESUMEN
Implications: This article outlines a framework for the consistent integration of biological data/samples into smoking cessation pharmacotherapy trials, aligned with the objectives of the recently unveiled Precision Medicine Initiative. Our goal is to encourage and provide support for treatment researchers to consider biosample collection and genotyping their existing samples as well as integrating genetic analyses into their study design in order to realize precision medicine in treatment of nicotine dependence.
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Genómica/métodos , Medicina de Precisión/métodos , Cese del Hábito de Fumar/métodos , Fumar/genética , Fumar/terapia , Ensayos Clínicos como Asunto/métodos , Humanos , Medicina de Precisión/psicología , Fumar/psicología , Cese del Hábito de Fumar/psicología , Dispositivos para Dejar de Fumar Tabaco , Tabaquismo/genética , Tabaquismo/psicología , Tabaquismo/terapiaRESUMEN
BACKGROUND: Smoking cessation therapies are not effective for all smokers, and researchers are interested in identifying those subgroups of individuals (e.g. based on genotype) who respond best to specific treatments. OBJECTIVES: To assess whether quit rates vary by genetically informed biomarkers within pharmacotherapy treatment arms and as compared with placebo. To assess the effects of pharmacotherapies for smoking cessation in subgroups of smokers defined by genotype for identified genome-wide significant polymorphisms. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group specialised register, clinical trial registries, and genetics databases for trials of pharmacotherapies for smoking cessation from inception until 16 August 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that recruited adult smokers and reported pharmacogenomic analyses from trials of smoking cessation pharmacotherapies versus controls. Eligible trials included those with data on a priori genome-wide significant (P < 5 × 10-8) single-nucleotide polymorphisms (SNPs), replicated non-SNPs, and/or the nicotine metabolite ratio (NMR), hereafter collectively described as biomarkers. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary outcome was smoking abstinence at six months after treatment. The secondary outcome was abstinence at end of treatment (EOT). We conducted two types of meta-analyses- one in which we assessed smoking cessation of active treatment versus placebo within genotype groups, and another in which we compared smoking cessation across genotype groups within treatment arms. We carried out analyses separately in non-Hispanic whites (NHWs) and non-Hispanic blacks (NHBs). We assessed heterogeneity between genotype groups using T², I², and Cochrane Q statistics. MAIN RESULTS: Analyses included 18 trials including 9017 participants, of whom 6924 were NHW and 2093 NHB participants. Data were available for the following biomarkers: nine SNPs (rs1051730 (CHRNA3); rs16969968, rs588765, and rs2036527 (CHRNA5); rs3733829 and rs7937 (in EGLN2, near CYP2A6); rs1329650 and rs1028936 (LOC100188947); and rs215605 (PDE1C)), two variable number tandem repeats (VNTRs; DRD4 and SLC6A4), and the NMR. Included data produced a total of 40 active versus placebo comparisons, 16 active versus active comparisons, and 64 between-genotype comparisons within treatment arms.For those meta-analyses showing statistically significant heterogeneity between genotype groups, we found the quality of evidence (GRADE) to be generally moderate. We downgraded quality most often because of imprecision or risk of bias due to potential selection bias in genotyping trial participants. Comparisons of relative treatment effects by genotypeFor six-month abstinence, we found statistically significant heterogeneity between genotypes (rs16969968) for nicotine replacement therapy (NRT) versus placebo at six months for NHB participants (P = 0.03; n = 2 trials), but not for other biomarkers or treatment comparisons. Six-month abstinence was increased in the active NRT group as compared to placebo among participants with a GG genotype (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.07 to 2.03), but not in the combined group of participants with a GA or AA genotype (RR 0.43, 95% CI 0.15 to 1.26; ratio of risk ratios (RRR) GG vs GA or AA of 3.51, 95% CI 1.19 to 10.3). Comparisons of treatment effects between genotype groups within pharmacotherapy randomisation armsFor those receiving active NRT, treatment was more effective in achieving six-month abstinence among individuals with a slow NMR than among those with a normal NMR among NHW and NHB combined participants (normal NMR vs slow NMR: RR 0.54, 95% CI 0.37 to 0.78; n = 2 trials). We found no such differences in treatment effects between genotypes at six months for any of the other biomarkers among individuals who received pharmacotherapy or placebo. AUTHORS' CONCLUSIONS: We did not identify widespread differential treatment effects of pharmacotherapy based on genotype. Some genotype groups within certain ethnic groups may benefit more from NRT or may benefit less from the combination of bupropion with NRT. The reader should interpret these results with caution because none of the statistically significant meta-analyses included more than two trials per genotype comparison, many confidence intervals were wide, and the quality of this evidence (GRADE) was generally moderate. Although we found evidence of superior NRT efficacy for NMR slow versus normal metabolisers, because of the lack of heterogeneity between NMR groups, we cannot conclude that NRT is more effective for slow metabolisers. Access to additional data from multiple trials is needed, particularly for comparisons of different pharmacotherapies.
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Genotipo , Cese del Hábito de Fumar/métodos , Fumar/tratamiento farmacológico , Fumar/genética , Dispositivos para Dejar de Fumar Tabaco , Adulto , Marcadores Genéticos , Humanos , Polimorfismo de Nucleótido Simple , Ensayos Clínicos Controlados Aleatorios como Asunto , Cese del Hábito de Fumar/estadística & datos numéricos , Factores de TiempoRESUMEN
The number of validated biomarkers of tobacco smoke exposure is limited, and none exist for tobacco-related cancer. Additional biomarkers for smoke, effects on cellular systems in vivo are needed to improve early detection of lung cancer, and to assist the Food and Drug Administration in regulating exposures to tobacco products. We assessed the effects of smoking on the gene expression using human cell cultures and blood from a cross-sectional study. We profiled global transcriptional changes in cultured smokers' peripheral blood mononuclear cells (PBMCs) treated with cigarette smoke condensate (CSC) in vitro (n = 7) and from well-characterized smokers' blood (n = 36). ANOVA with adjustment for covariates and Pearson correlation were used for statistical analysis in this study. CSC in vitro altered the expression of 1 178 genes (177 genes with > 1.5-fold-change) at P < 0.05. In vivo, PBMCs of heavy and light smokers differed for 614 genes (29 with > 1.5-fold-change) at P < 0.05 (309 remaining significant after adjustment for age, race, and gender). Forty-one genes were persistently altered both in vitro and in vivo, 22 having the same expression pattern reported for non-small cell lung cancer. Our data provides evidence that persistent alterations of gene expression in vitro and in vivo may relate to carcinogenic effects of cigarette smoke, and the identified genes may serve as potential biomarkers for cancer. The use of an in vitro model to corroborate results from human studies provides a novel way to understand human exposure and effect. © 2015 Wiley Periodicals, Inc.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Perfilación de la Expresión Génica/métodos , Neoplasias Pulmonares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Fumar/genética , Células Cultivadas , Estudios Transversales , ADN/sangre , Detección Precoz del Cáncer , Femenino , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Humo/efectos adversos , Nicotiana/efectos adversosRESUMEN
BACKGROUND: Early in medical education, physicians must develop competencies needed for tobacco dependence treatment. OBJECTIVE: To assess the effect of a multi-modal tobacco dependence treatment curriculum on medical students' counseling skills. DESIGN: A group-randomized controlled trial (2010-2014) included ten U.S. medical schools that were randomized to receive either multi-modal tobacco treatment education (MME) or traditional tobacco treatment education (TE). SETTING/PARTICIPANTS: Students from the classes of 2012 and 2014 at ten medical schools participated. Students from the class of 2012 (N = 1345) completed objective structured clinical examinations (OSCEs), and 50 % (N = 660) were randomly selected for pre-intervention evaluation. A total of 72.9 % of eligible students (N = 1096) from the class of 2014 completed an OSCE and 69.7 % (N = 1047) completed pre and post surveys. INTERVENTIONS: The MME included a Web-based course, a role-play classroom demonstration, and a clerkship booster session. Clerkship preceptors in MME schools participated in an academic detailing module and were encouraged to be role models for third-year students. MEASUREMENTS: The primary outcome was student tobacco treatment skills using the 5As measured by an objective structured clinical examination (OSCE) scored on a 33-item behavior checklist. Secondary outcomes were student self-reported skills for performing 5As and pharmacotherapy counseling. RESULTS: Although the difference was not statistically significant, MME students completed more tobacco counseling behaviors on the OSCE checklist (mean 8.7 [SE 0.6] vs. mean 8.0 [SE 0.6], p = 0.52) than TE students. Several of the individual Assist and Arrange items were significantly more likely to have been completed by MME students, including suggesting behavioral strategies (11.8 % vs. 4.5 %, p < 0.001) and providing information regarding quitline (21.0 % vs. 3.8 %, p < 0.001). MME students reported higher self-efficacy for Assist, Arrange, and Pharmacotherapy counseling items (ps ≤0.05). LIMITATIONS: Inclusion of only ten schools limits generalizability. CONCLUSIONS: Subsequent interventions should incorporate lessons learned from this first randomized controlled trial of a multi-modal longitudinal tobacco treatment curriculum in multiple U.S. medical schools. NIH Trial Registry Number: NCT01905618.
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Educación de Pregrado en Medicina/métodos , Cese del Hábito de Fumar/métodos , Tabaquismo/rehabilitación , Prácticas Clínicas , Competencia Clínica , Instrucción por Computador/métodos , Consejo/educación , Curriculum , Humanos , Evaluación de Resultado en la Atención de Salud , Autoeficacia , Estudiantes de Medicina , Estados UnidosRESUMEN
Cigarette smoking has been implicated in causing many cancers and cancer deaths. There is mounting evidence indicating that smoking negatively impacts cancer treatment efficacy and overall survival. The NCCN Guidelines for Smoking Cessation have been created to emphasize the importance of smoking cessation and establish an evidence-based standard of care in all patients with cancer. These guidelines provide recommendations to address smoking in patients and outlines behavioral and pharmacologic interventions for smoking cessation throughout the continuum of oncology care.
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Oncología Médica , Cese del Hábito de Fumar , Humanos , Oncología Médica/normas , Cese del Hábito de Fumar/estadística & datos numéricosRESUMEN
OBJECTIVE: Physicians play a critical role in addressing tobacco dependence, yet report limited training. Tobacco dependence treatment curricula for medical students could improve performance in this area. This study identified student and medical school tobacco treatment curricula characteristics associated with intentions and use of the 5As for tobacco treatment among 3rd year U.S. medical students. METHODS: Third year medical students (N=1065, 49.3% male) from 10 U.S. medical schools completed a survey in 2009-2010 assessing student characteristics, including demographics, tobacco treatment knowledge, and self-efficacy. Tobacco curricula characteristics assessed included amount and type of classroom instruction, frequency of tobacco treatment observation, instruction, and perception of preceptors as role models. RESULTS: Greater tobacco treatment knowledge, self-efficacy, and curriculum-specific variables were associated with 5A intentions, while younger age, tobacco treatment self-efficacy, intentions, and each curriculum-specific variable were associated with greater 5A behaviors. When controlling for important student variables, greater frequency of receiving 5A instruction (OR=1.07; 95%CI 1.01-1.12) and perception of preceptors as excellent role models in tobacco treatment (OR=1.35; 95%CI 1.04-1.75) were significant curriculum predictors of 5A intentions. Greater 5A instruction (B=.06 (.03); p<.05) and observation of tobacco treatment (B=.35 (.02); p<.001) were significant curriculum predictors of greater 5A behaviors. CONCLUSIONS: Greater exposure to tobacco treatment teaching during medical school is associated with both greater intentions to use and practice tobacco 5As. Clerkship preceptors, or those physicians who provide training to medical students, may be particularly influential when they personally model and instruct students in tobacco dependence treatment.
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Competencia Clínica , Curriculum , Educación de Pregrado en Medicina , Tabaquismo/terapia , Adulto , Prácticas Clínicas , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Autoeficacia , Cese del Hábito de Fumar/métodos , Cese del Hábito de Fumar/estadística & datos numéricos , Estados Unidos , Adulto JovenRESUMEN
Genomic research has generated much new knowledge into mechanisms of human disease, with the potential to catalyze novel drug discovery and development, prenatal and neonatal screening, clinical pharmacogenomics, more sensitive risk prediction, and enhanced diagnostics. Genomic medicine, however, has been limited by critical evidence gaps, especially those related to clinical utility and applicability to diverse populations. Genomic medicine may have the greatest impact on health care if it is integrated into primary care, where most health care is received and where evidence supports the value of personalized medicine grounded in continuous healing relationships. Redesigned primary care is the most relevant setting for clinically useful genomic medicine research. Taking insights gained from the activities of the Institute of Medicine (IOM) Roundtable on Translating Genomic-Based Research for Health, we apply lessons learned from the patient-centered medical home national experience to implement genomic medicine in a patient-centered, learning health care system.
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Genómica , National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division/organización & administración , Atención Dirigida al Paciente , Medicina de Precisión , Humanos , Investigación Biomédica Traslacional , Estados UnidosRESUMEN
INTRODUCTION: Rates of obesity are higher among more dependent smokers and 37%-65% of smokers seeking cessation treatment are overweight or obese. Overweight or obese smokers may possess metabolic and neurobiological features that contribute to difficulty achieving cessation using front-line nicotine replacement products. Attention to factors that facilitate effective cessation treatment in this vulnerable population is needed to significantly reduce mortality risk among overweight and obese smokers. METHOD: This secondary analysis of 2 large trials of transdermal nicotine replacement in general medical practices evaluated the hypothesis that higher body mass index (BMI) would moderate the efficacy of the nicotine patch. We examined the potential for gender to further moderate the relationship between BMI and treatment efficacy. RESULTS: In the placebo controlled trial (N = 1,621), 21-mg patch was no more effective than placebo for assisting biochemically verified point prevalence abstinence up to 1 year after quitting for women with higher BMI, but appeared to be effective for men at normal or high BMI (gender × BMI beta = -0.22, p = .004). We did not find differential long-term cessation outcomes among male or female smokers in the 15-mg patch trial (n = 705). However, we observed significantly higher rates of early lapse among women with higher BMI treated with nicotine patch across both trials. CONCLUSION: These results suggest that increased BMI may affect the efficacy of nicotine patch on reducing risk of early lapse in women. Additional research is needed to explore mechanisms of risk for decreased efficacy of this commonly used cessation aid.
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Índice de Masa Corporal , Nicotina/administración & dosificación , Sobrepeso/tratamiento farmacológico , Cese del Hábito de Fumar/métodos , Fumar/tratamiento farmacológico , Dispositivos para Dejar de Fumar Tabaco , Administración Cutánea , Adulto , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Obesidad/tratamiento farmacológico , Obesidad/epidemiología , Sobrepeso/epidemiología , Fumar/epidemiología , Resultado del TratamientoRESUMEN
OBJECTIVES: To evaluate whether biases may influence the findings of whole-brain structural imaging literature. METHODS: Forty-seven whole-brain voxel-based meta-analyses including voxel-based morphometry (VBM) studies in neuropsychiatric conditions were included, for a total of 324 individual VBM studies. The total sample size, the overall number of foci, and different moderators were extracted both at the level of the individual studies and at the level of the meta-analyses. RESULTS: Sample size ranged from 12 to 545 (median n = 47) per VBM study. The median number of reported foci per study was six. VBM studies with larger sample sizes reported only slightly more abnormalities than smaller studies (2% increase in the number of foci per 10-patients increase in sample size). A similar pattern was seen in several analyses according to different moderator variables with some possible modulating evidence for the statistical threshold employed, publication year and number of coauthors. Whole-brain meta-analyses (median sample size n = 534) found fewer foci (median = 3) than single studies and overall they showed no significant increase in the number of foci with increasing sample size. Meta-analyses with ≥10 VBM studies reported a median of three foci and showed a significant increase with increasing sample size, while there was no relationship between sample size and number of foci (median = 5) in meta-analyses with <10 VBM studies. CONCLUSIONS: The number of foci reported in small VBM studies and even in meta-analyses with few studies may often be inflated. This picture is consistent with reporting biases affecting small studies.
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Sesgo , Encéfalo/patología , Trastornos Mentales/patología , Enfermedades del Sistema Nervioso/patología , Bases de Datos Factuales/estadística & datos numéricos , Femenino , Humanos , Masculino , Metaanálisis como Asunto , Tamaño de la MuestraRESUMEN
INTRODUCTION: Reactivity to smoking cues is an important factor in the motivation to smoke and has been associated with the dopamine receptor 4 variable number tandem repeat (DRD4 exon III VNTR) polymorphism. However, little is known about the associated neural mechanisms. METHODS: Non-treatment-seeking Caucasian smokers completed overnight abstinence and viewed smoking and neutral cues during 2 separate functional magnetic resonance imaging scans while wearing either a nicotine or placebo patch (order randomized) and were genotyped for the DRD4 VNTR. We conducted mixed-effects repeated-measures analyses of variance (within-subject factor: nicotine or placebo patch; between-subject factor: DRD4 long [L: ≥ 1 copy of ≥ 7 repeats] or short [S: 2 copies ≤ 6 repeats] genotype) of 6 a priori regions of interest. RESULTS: Relative to neutral cues, smoking cues elicited greater activity in bilateral ventral striatum and left amygdala during nicotine replacement and deactivation in these regions during nicotine deprivation. A patch × DRD4 interaction was observed in the left amygdala, an area associated with appetitive reinforcement and relapse risk, such that S allele carriers demonstrated greater activation on active patch than on placebo patch. CONCLUSIONS: Brain systems associated with reward salience may become primed and overreactive at nicotine replacement doses intended for the first step of smoking cessation and may become inhibited during nicotine withdrawal in DRD4 S but not in DRD4 L carriers. These findings are consistent with the role of these regions in drug reinforcement and suggest a differential influence of nicotine replacement on amygdala activation in the association of incentive salience with smoking stimuli across DRD4 genotypes.
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Señales (Psicología) , Repeticiones de Minisatélite , Nicotina/administración & dosificación , Receptores de Dopamina D4/genética , Adulto , Alelos , Amígdala del Cerebelo/efectos de los fármacos , Encéfalo/efectos de los fármacos , Exones , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Motivación , Nicotina/farmacología , Polimorfismo Genético , Fumar/genética , Población Blanca/genéticaRESUMEN
Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.
Asunto(s)
Análisis Mutacional de ADN/métodos , Genes Sintéticos , Variación Genética , Estudio de Asociación del Genoma Completo/métodos , Trombofilia/genética , Alelos , Secuencia de Bases , Femenino , Predisposición Genética a la Enfermedad , Genoma Humano , Genotipo , Haplotipos , Humanos , Masculino , Linaje , Estándares de Referencia , Medición de Riesgo , Alineación de Secuencia , Análisis de Secuencia de ADNRESUMEN
IMPORTANCE: Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. OBJECTIVES: To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. DESIGN, SETTING, AND PARTICIPANTS: An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. MAIN OUTCOMES AND MEASURES: Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. RESULTS: Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001). CONCLUSIONS AND RELEVANCE: In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.
Asunto(s)
Genoma Humano/genética , Mutación , Farmacogenética , Análisis de Secuencia de ADN/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genes BRCA1 , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Importance: Declining treatment negatively affects health outcomes among patients with cancer. Limited research has investigated national trends of and factors associated with treatment declination or its association with overall survival (OS) among patients with breast cancer. Objectives: To examine trends and racial and ethnic disparities in treatment declination and racial and ethnic OS differences stratified by treatment decision in US patients with breast cancer. Design, Setting, and Participants: This retrospective cross-sectional study used data for patients with breast cancer from the 2004 to 2020 National Cancer Database. Four treatment modalities were assessed: chemotherapy, hormone therapy (HT), radiotherapy, and surgery. The chemotherapy cohort included patients with stage I to IV disease. The HT cohort included patients with stage I to IV hormone receptor-positive disease. The radiotherapy and surgery cohorts included patients with stage I to III disease. Data were analyzed from March to November 2023. Exposure: Race and ethnicity and other sociodemographic and clinicopathologic characteristics. Main Outcomes and Measures: Treatment decision, categorized as received or declined, was modeled using logistic regression. OS was modeled using Cox regression. Models were controlled for year of initial diagnosis, age, sex, health insurance, median household income, facility type, Charlson-Deyo comorbidity score, histology, American Joint Committee on Cancer stage, molecular subtype, and tumor grade. Results: The study included 2â¯837â¯446 patients (mean [SD] age, 61.6 [13.4] years; 99.1% female), with 1.7% American Indian, Alaska Native, or other patients; 3.5% Asian or Pacific Islander patients; 11.2% Black patients; 5.6% Hispanic patients; and 78.0% White patients. Of 1â¯296â¯488 patients who were offered chemotherapy, 124â¯721 (9.6%) declined; 99â¯276 of 1â¯635â¯916 patients (6.1%) declined radiotherapy; 94â¯363 of 1â¯893â¯339 patients (5.0%) declined HT; and 15â¯846 of 2â¯590â¯963 patients (0.6%) declined surgery. Compared with White patients, American Indian, Alaska Native, or other patients (adjusted odds ratio [AOR], 1.47; 95% CI, 1.26-1.72), Asian or Pacific Islander patients (AOR, 1.29; 95% CI, 1.15-1.44), and Black patients (AOR, 2.01; 95% CI, 1.89-2.14) were more likely to decline surgery; American Indian, Alaska Native, or other patients (AOR, 1.13; 95% CI, 1.05-1.21) and Asian or Pacific Islander patients (AOR, 1.21; 95% CI, 1.16-1.27) were more likely to decline chemotherapy; and Black patients were more likely to decline radiotherapy (AOR, 1.05; 95% CI, 1.02-1.08). Asian or Pacific Islander patients (AOR, 0.81; 95% CI, 0.77-0.85), Black patients (AOR, 0.86; 95% CI, 0.83-0.89), and Hispanic patients (AOR, 0.66; 95% CI, 0.63-0.69) were less likely to decline HT. Furthermore, Black patients who declined chemotherapy had a higher mortality risk than White patients (adjusted hazard ratio [AHR], 1.07; 95% CI, 1.02-1.13), while there were no OS differences between Black and White patients who declined HT (AHR, 1.05; 95% CI, 0.97-1.13) or radiotherapy (AHR, 0.98; 95% CI, 0.92-1.04). Conclusions and Relevance: This cross-sectional study highlights racial and ethnic disparities in treatment declination and OS, suggesting the need for equity-focused interventions, such as patient education on treatment benefits and improved patient-clinician communication and shared decision-making, to reduce disparities and improve patient survival.