Statistical Genetic Approaches to Investigate Genotype-by-Environment Interaction: Review and Novel Extension of Models.

Statistical genetic models of genotype-by-environment (G×E) interaction can be divided into two general classes, one on G×E interaction in response to dichotomous environments (e.g., sex, disease-affection status, or presence/absence of an exposure) and the other in response to continuous environments (e.g., physical activity, nutritional measurements, or continuous socioeconomic measures). Here we develop a novel model to jointly account for dichotomous and continuous environments. We develop the model in terms of a joint genotype-by-sex (for the dichotomous environment) and genotype-by-social determinants of health (SDoH; for the continuous environment). Using this model, we show how a depression variable, as measured by the Beck Depression Inventory-II survey instrument, is not only underlain by genetic effects (as has been reported elsewhere) but is also significantly determined by joint G×Sex and G×SDoH interaction effects. This model has numerous applications leading to potentially transformative research on the genetic and environmental determinants underlying complex diseases.

Metabolic syndrome traits exhibit genotype-by-environment interaction in relation to socioeconomic status in the Mexican American family heart study.

Background: Socioeconomic Status (SES) is a potent environmental determinant of health. To our knowledge, no assessment of genotype-environment interaction has been conducted to consider the joint effects of socioeconomic status and genetics on risk for metabolic disease. We analyzed data from the Mexican American Family Studies (MAFS) to evaluate the hypothesis that genotype-by-environment interaction (GxE) is an essential determinant of variation in risk factors for metabolic syndrome (MS). Methods: We employed a maximum likelihood estimation of the decomposition of variance components to detect GxE interaction. After excluding individuals with diabetes and individuals on medication for diabetes, hypertension, or dyslipidemia, we analyzed 12 MS risk factors: fasting glucose (FG), fasting insulin (FI), 2-h glucose (2G), 2-h insulin (2I), body mass index (BMI), waist circumference (WC), leptin (LP), high-density lipoprotein-cholesterol (HDL-C), triglycerides (TG), total serum cholesterol (TSC), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Our SES variable used a combined score of Duncan's socioeconomic index and education years. Heterogeneity in the additive genetic variance across the SES continuum and a departure from unity in the genetic correlation coefficient were taken as evidence of GxE interaction. Hypothesis tests were conducted using standard likelihood ratio tests. Results: We found evidence of GxE for fasting glucose, 2-h glucose, 2-h insulin, BMI, and triglycerides. The genetic effects underlying the insulin/glucose metabolism component of MS are upregulated at the lower end of the SES spectrum. We also determined that the household variance for systolic blood pressure decreased with increasing SES. Conclusion: These results show a significant change in the GxE interaction underlying the major components of MS in response to changes in socioeconomic status. Further mRNA sequencing studies will identify genes and canonical gene pathways to support our molecular-level hypotheses.

Frailty index in the Colonias of the Rio Grande Valley: health related quality of life and resilience.

Background: Frailty is characterized by an accumulation of deficits that lead to vulnerability to adverse health outcomes. The Frailty Index (FI) quantifies frailty by measuring deficits that increase susceptibility to stressors. This study focused on a population of Mexican Americans living in vulnerable communities in the Rio Grande Valley of south Texas. We used a Frailty Index developed based on common health-related data--the Patient Health Questionnaire (PHQ-9) and a Health-related Quality of Life survey (Duke Health Profile). Quality of life, resilience, and frailty are interrelated and influenced by chronic illness, mental illness, poverty, cognitive impairment, and community support. Methods: We used Logistic regression analysis, factor component analysis, receiver operating characteristic curves, and odds ratios to identify potential associations between clinical variables and candidate predictor variables and seven physiological health variables, and two survey instruments. We analyzed data obtained from participants (894) that live in two Colonias located on the Texas-Mexico border. We calculated the FI with seven physiological variables, PHQ-9 score, and the 11 domain-specific Duke Profile scores, for a total of 19 health deficits. We then dichotomized FI (>0.25) and determined ROC curves through model selection to determine best predictors of frailty. Results: Females (n = 622) had a higher starting frailty, and males (n = 272) had a significantly greater change rate with age. Women score higher in anxiety, depression, anxiety/depression, and pain. The frailty index and quality of life markers are strongly inversely related; poorer quality of life leads to greater frailty independent physiological health variables, the PHQ 9, sex, and age. Conclusion: The study highlights the importance of addressing modifiable mental health and social stressors to reduce frailty. Furthermore, it suggests that factors supporting resilience and well-being, such as physical and mental health, social support, and perceived health, play a crucial role in frailty development. The findings have implications for interventions targeting vulnerable populations and emphasize the need for further research on the relationship between health-related quality of life and frailty.

Genotype-by-socioeconomic status interaction influences heart disease risk scores and carotid artery thickness in Mexican Americans: the predominant role of education in comparison to household income and socioeconomic index.

Background: Socioeconomic status (SES) is a potent environmental determinant of health. To our knowledge, no assessment of genotype-environment interaction has been conducted to consider the joint effects of socioeconomic status and genetics on risk for cardiovascular disease (CVD). We analyzed Mexican American Family Studies (MAFS) data to evaluate the hypothesis that genotype-by-environment interaction (GxE) is an important determinant of variation in CVD risk factors. Methods: We employed a linear mixed model to investigate GxE in Mexican American extended families. We studied two proxies for CVD [Pooled Cohort Equation Risk Scores/Framingham Risk Scores (FRS/PCRS) and carotid artery intima-media thickness (CA-IMT)] in relation to socioeconomic status as determined by Duncan's Socioeconomic Index (SEI), years of education, and household income. Results: We calculated heritability for FRS/PCRS and carotid artery intima-media thickness. There was evidence of GxE due to additive genetic variance heterogeneity and genetic correlation for FRS, PCRS, and CA-IMT measures for education (environment) but not for household income or SEI. Conclusion: The genetic effects underlying CVD are dynamically modulated at the lower end of the SES spectrum. There is a significant change in the genetic architecture underlying the major components of CVD in response to changes in education.

Gene-by-Environment Interaction in Non-Alcoholic Fatty Liver Disease and Depression: The Role of Hepatic Transaminases.

Non-alcoholic fatty liver disease (NAFLD) encompasses a range of liver conditions, from benign fatty accumulation to severe fibrosis. The global prevalence of NAFLD has risen to 25-30%, with variations across ethnic groups. NAFLD may advance to hepatocellular carcinoma, increases cardiovascular risk, is associated with chronic kidney disease, and is an independent metabolic disease risk factor. Assessment methods for liver health include liver biopsy, magnetic resonance imaging, ultrasound, and vibration-controlled transient elastography (VCTE by FibroScan). Hepatic transaminases are cost-effective and minimally invasive liver health assessment methods options. This study focuses on the interaction between genetic factors underlying the traits (hepatic transaminases and the FibroScan results) on the one hand and the environment (depression) on the other. We examined 525 individuals at risk for metabolic disorders. We utilized variance components models and likelihood-based statistical inference to examine potential GxE interactions in markers of NAFLD, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the AST/ALT ratio, and Vibration-Controlled Transient Elastography (VCTE by FibroScan). We calculated the Fibroscan-AST (FAST) score (a score that identifies the risk of progressive non-alcoholic steatohepatitis (NASH) and screened for depression using the Beck Depression Inventory-II (BDI-II). We identified significant G × E interactions for AST/ALT ratio × BDI-II, but not AST, ALT, or the FAST score. Our findings support that genetic factors play a role in hepatic transaminases, especially the AST/ALT ratio, with depression influencing this relationship. These insights contribute to understanding the complex interplay of genetics, environment, and liver health, potentially guiding future personalized interventions.

Case Report: Neurologic Presentation of West Nile Virus: Difficult Diagnosis.

West Nile virus infections have surged across the globe. South Texas, located on the path of bird migration, with Culex quinquefasciatus and other Culex species, and biotic primers that predispose the area to epidemics (floods, amplifying hosts, and lack of mosquito control and prevention) remains a highly endemic area for arbovirus spread. West Nile virus infection ranges from mild febrile illness to severe central nervous system involvement. The purpose of this report is to highlight complex presentations of WNV and how confounding presenting symptoms delay diagnosis. The secondary goal is to describe how pandemics, such as SARS-CoV-2, can overwhelm the system and result in medical decision bias errors.

Frailty Index in the Colonias on the US-Mexico Border: A Special Report.

Frailty is the age-related decline in well-being. The Frailty index (FI) measures the accumulation of health deficits and reflects biopsychosocial and cultural determinants of well-being. Frailty is measured as a static phenotype or as a Frailty Index comprising a ratio of suffered health deficits and total deficits. We report a Frailty Index calculated from routinely measured clinical variables gathered from residents of two Colonias (neighborhoods) in South Texas. A Colonia is a predominantly Hispanic, economically distressed, unincorporated neighborhood. We analyzed retrospective data from 894 patients that live in two Colonias located on the Texas-Mexico border. We calculated the FI with seven physiological variables, PHQ-9 score, and the 11 domain-specific Duke Profile scores, for a total of 19 possible health deficits. FI against age separately in males (n = 272) and females (n = 622) was regressed. Females had a significantly higher starting frailty, and males had a significantly greater change rate with age. FI against age for Cameron Park Colonia and Indian Hills Colonia was regressed. We calculated a significantly higher starting FI in Indian Hills and a significantly greater change rate in Cameron Park residents. Frailty's contributors are complex, especially in neighborhoods of poverty, immigration, low education level, and high prevalence of chronic disease. We report baseline Frailty Index data from two Colonias in South Texas and the clinical and research implications.

UniMóvil: A Mobile Health Clinic Providing Primary Care to the Colonias of the Rio Grande Valley, South Texas.

Background: We describe a mobile unit (UniMóvil) designed to improve poor healthcare access delivery to residents in two South Texas underserved Colonias. The interprofessional team measured seven clinical outcomes [obesity, diabetes, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C) levels, and depression], and using the Duke Health Profile, assessed the health-related quality of life (HrQoL). Methods: The investigators used previously reported disease prevalence, an implementation model, and community needs-assessments to design an outreach healthcare delivery model. A retrospective review of the cohort provides data used to determine potential predictors of clinical variables, 11 domains of HrQOL, and inter/intra Colonia differences. Results: The average age of patients was 45 years-old and females represented 67% of the population served. Results include a high prevalence of obesity (55.5%), hypertension (39%), diabetes (32.5%), and depression (19%), gender differences, and inter-Colonia differences. A generalized linear mixed model analysis provided associations between clinical outcomes and predictors (age, sex, BMI, PHQ-9 score, HbA1c, blood pressure, serum cholesterol, low HDL, triglycerides, and HrQOL domains). The HrQol domain of low self-perceived health, relates to obesity, diabetes, low HDL, and depression. Depression predicted all 11 domains of the HrQol. Conclusion: The prevalence of diabetes, hypertension, obesity, and depression remains epidemic. Mobile clinics increase access and address highly prevalent illnesses in the Colonias. The data collected can be used to address chronic disease and quality of life, focus care, and direct research in high-need underserved areas.

Mindfulness-oriented recovery enhancement for chronic pain and prescription opioid misuse: results from an early-stage randomized controlled trial.

OBJECTIVE: Opioid pharmacotherapy is now the leading treatment for chronic pain, a problem that affects nearly one third of the U.S. population. Given the dramatic rise in prescription opioid misuse and opioid-related mortality, novel behavioral interventions are needed. The purpose of this study was to conduct an early-stage randomized controlled trial of Mindfulness-Oriented Recovery Enhancement (MORE), a multimodal intervention designed to simultaneously target mechanisms underpinning chronic pain and opioid misuse. METHOD: Chronic pain patients (N = 115; mean age = 48 ± 14 years; 68% female) were randomized to 8 weeks of MORE or a support group (SG). Outcomes were measured at pre- and posttreatment, and at 3-month follow-up. The Brief Pain Inventory was used to assess changes in pain severity and interference. Changes in opioid use disorder status were measured by the Current Opioid Misuse Measure. Desire for opioids, stress, nonreactivity, reinterpretation of pain sensations, and reappraisal were also evaluated. RESULTS: MORE participants reported significantly greater reductions in pain severity (p = .038) and interference (p = .003) than SG participants, which were maintained by 3-month follow-up and mediated by increased nonreactivity and reinterpretation of pain sensations. Compared with SG participants, participants in MORE evidenced significantly less stress arousal (p = .034) and desire for opioids (p = .027), and were significantly more likely to no longer meet criteria for opioid use disorder immediately following treatment (p = .05); however, these effects were not sustained at follow-up. CONCLUSIONS: Findings demonstrate preliminary feasibility and efficacy of MORE as a treatment for co-occurring prescription opioid misuse and chronic pain. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Learning to walk before we run: what can medical education learn from the human body about integrated care.

True integration requires a shift in all levels of medical and allied health education; one that emphasizes team learning, practicing, and evaluating from the beginning of each students' educational experience whether that is as physician, nurse, psychologist, or any other health profession. Integration of healthcare services will not occur until medical education focuses, like the human body, on each system working inter-dependently and cohesively to maintain balance through continual change and adaptation. The human body develops and maintains homeostasis by a process of communication: true integrated care relies on learned interprofessionality and ensures shared responsibility and practice.

Management options for patients with chronic back pain without an etiology.

The treatment and management of low back pain is complex when there is no specific etiology such as cancer, fracture, or herniated disc. An organized approach to management that follows evidence based guidelines will facilitate care in a problem that reflects a lifetime prevalence of over 70 percent. The purpose of this review is to present a guideline to care for a common disabling process with a very heterogeneous etiology.

Evaluation and diagnosis of low back pain.

The diagnosis of low back pain is complicated by the varying presentations and complex nature of pain and the nonstandardized approach by physicians to clinical decision making. Only a few physicians use evidence-based guidelines to assist with clinical decision making. This article reviews a systematic approach to the evaluation and diagnosis of low back pain.

Surgical treatment of low back pain.

There is a need for quality trials that study optimal selection and timing of surgical treatment options. Studies are needed of cost-effectiveness and effect on long-term improvement. Until data from such studies are available, primary physicians should follow the guidelines on conservative management and aggressively evaluate the red flags of low back pain, immediately refer for neurologic deficit and bowel or bladder compromise, and focus treatment on modalities with high-quality evidence-based information. Patients who do not improve can be referred to surgeons with experience and expertise in discectomies.

The disability evaluation and low back pain.

In the United States an estimated 11 million persons are unable to work, with 8.1 million unable to work to their full capacity. Primary care physicians are often called on for the evaluation and determination of patients with claims for disability. Knowledge of the system for disability determination and a systematic approach facilitates the process. This article focuses on the requirements of the Social Security Administration, under federal law tasked to administer the Social Security Disability Insurance program and the Supplemental Security Income program, and offers an approach to the evaluation of patients with claims of disability.

Contributors of black men's success in admission to and graduation from medical school.

PURPOSE: To determine characteristics and individual experiences that contribute to black men's success in being admitted to and graduating from medical school. METHOD: In 2010, one of the authors, a black man, interviewed 10 black male medical students enrolled at Florida State University College of Medicine and 3 black male physicians associated with that school, using consensual qualitative research methodology to analyze the data. The investigators recorded and transcribed the interviews, coded them to determine themes, and identified an overarching theoretical construct. RESULTS: The authors identified six broad contributors to successful admission to and completion of medical school: social support, education, exposure to the field of medicine, group identity, faith, and social responsibility. The six categories were subsequently grouped into four major themes: educational experiences, exposure to medicine, psychosocial-cultural experiences, and personal attributes and individual perceptions. The metaphor of a table (success) with four legs (four major themes) illustrates the complex dynamics that contribute to success. CONCLUSIONS: The success of black men and the factors that contribute to that success guided this study. The results reinforced the conclusion that success for black men is achieved via a balance between educational experiences, exposure to medicine, psychosocial-cultural experiences, and personal attributes and individual perceptions. This information can be used by medical schools to strengthen their outreach programs, provide a theoretical construct for discussion and research, and generate questions for future quantitative studies.

Toward a common framework for rural background.

BACKGROUND AND OBJECTIVES: To develop a standardized framework to discuss rural background, a review of the literature to identify studies regarding the association of rural background with primary care and/or rural health practice was conducted. The various definitions of rural background were collated and from this data a framework for the conceptualization of rural background is proposed. METHODS: The Medline database from 1966-2009 was searched to find citations that included a rural background definition as a variable for rural intent to practice, rural career choice, or rural practice. Studies that included medical school admission outcomes of US medical schools were included if there was (1) a definition of rural background noted, (2) a research-based question, and (3) a defined outcome of rural practice intent or practice in rural area. RESULTS: A full text review was completed for all 45 articles identified. After applying the inclusion and exclusion criteria to the full length articles, there were 15 articles included in the review. The five most common definitions of rural background were (1) a positive answer to the question "Did you grow up in a rural area"? (2) a rural county of birth, (3) grew up in a town of less than 10,000 persons, (4) graduation from a high school located in a town of less than 10,000 persons, and (5) self-declared rural county of residence. CONCLUSIONS: There are multiple terms used in research to elucidate the conceptualization of rural background. Based on a definition of rural as the "anchor," we propose the use of the five most common definitions of rural background as "rural connectors" that can be used to buttress the definition of rural background. The framework of rural connectors can then be used to more closely define rural background.