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Implementing a training resource for large-scale genomic data analysis in the All of Us Researcher Workbench.

A lack of representation in genomic research and limited access to computational training create barriers for many researchers seeking to analyze large-scale genetic datasets. The All of Us Research Program provides an unprecedented opportunity to address these gaps by offering genomic data from a broad range of participants, but its impact depends on equipping researchers with the necessary skills to use it effectively. The All of Us Biomedical Researcher (BR) Scholars Program at Baylor College of Medicine aims to break down these barriers by providing early-career researchers with hands-on training in computational genomics through the All of Us Evenings with Genetics Research Program. The year-long program begins with the faculty summit, an in-person computational boot camp that introduces scholars to foundational skills for using the All of Us dataset via a cloud-based research environment. The genomics tutorials focus on genome-wide association studies (GWASs), utilizing Jupyter Notebooks and the Hail computing framework to provide an accessible and scalable approach to large-scale data analysis. Scholars engage in hands-on exercises covering data preparation, quality control, association testing, and result interpretation. By the end of the summit, participants will have successfully conducted a GWAS, visualized key findings, and gained confidence in computational resource management. This initiative expands access to genomic research by equipping early-career researchers from a variety of backgrounds with the tools and knowledge to analyze All of Us data. By lowering barriers to entry and promoting the study of representative populations, the program fosters innovation in precision medicine and advances equity in genomic research.

Humans↗

Aspartic acid at position 57 of the HLA-DQ beta chain is protective against future development of insulin-dependent (type 1) diabetes mellitus.

Insulin-dependent (Type I) diabetes mellitus is a chronic autoimmune disease. From studies in discordant twins and multiplex families a long prediabetic period has been reported. In a population-based program started in 1983, fifteen individuals at possible risk for future Type I diabetes were followed for up to 74 months. Two individuals (13%) developed Type I diabetes. These probands were characterized by the presence of high-level cytoplasmic islet cell antibodies (ICA), complement-fixing ICA, and an impaired first-phase insulin response after intravenous glucose load. Both were homozygous for a high-risk immunogenetic marker of Type I diabetes, i.e., non-Asp at codon 57 of the HLA-DQ beta chain. In all other subjects studied, the immunogenetic marker that confers "dominant resistance", aspartic acid at codon 57, was found. On the basis of our data we conclude that a combination of assays which determine ICA, first-phase insulin release, and HLA-DQB1 polymorphisms will identify individuals with a high probability of developing Type I diabetes at the population level. Conversely, HLA haplotypes positive for aspartic acid seem to confer resistance to the disease.

Adult↗

Informing policy and service development at the interfaces between acute and aged care.

This paper argues that policies to address the interfaces between acute care and aged care should view older people as members of the wider Australian population entitled to a range of health services under Medicare rather than focusing only on supposed "bed blockers". In seeking to explain the current level of policy interest in this area, three areas are canvassed: pressures on acute hospital care, particularly those attributed to population ageing; shrinking provision of residential aged care; and the proliferation of post acute services. If policy development is to maintain a wider rather than narrower perspective, attention needs to be given to improving collection and analysis of critical data that are currently unavailable, to developing system-wide funding arrangements for post acute care, and to reassessing what constitutes appropriate hospital activity for younger and older age groups alike.

Acute Disease↗

Pharmacokinetic variability of nimodipine disposition after single and multiple oral dosing to hypertensive renal failure patients: parametric and nonparametric population analysis.

OBJECTIVES: To explore the contribution of renal failure to nimodipine overall pharmacokinetic variability after single and multiple oral dosing and to develop a population pharmacokinetic model by means of the nonparametric expectation maximization (NPEM2) algorithm based on sampled individual drug concentrations close to the estimated patients' C(SS)avs (NPEM2-C(SS)av). PATIENTS, MATERIALS AND METHODS: 24 hypertensive patients with normal and reduced renal function, without clinical and laboratory data for hepatic dysfunction, were enrolled in the study and their nimodipine plasma levels were analyzed by means of a parametric and nonparametric population pharmacokinetic modeling using a maximum a posteriori Bayesian (MAPB) estimator in an iterative two-stage Bayesian population modeling program and NPEM2-algorithm. RESULTS: Comparison of parameter dispersion revealed higher variability of nimodipine disposition after the first dose than at steady-state except for apparent volume of distribution at steady-state, V(SS)/F, whose variability increased from 98% to 223%. The most variable was mean residence time, MRT, whose coefficient of variation (CV) was 288% after the first dose and decreased by more than 2 times at steady-state, followed by terminal elimination half-life, t(1/2el), with CV = 171% after the first dosing and decreasing by more than 3 times at steady-state. Concerning the impact of renal failure on disposition parameters variability, patients with slightly to moderately reduced renal function, creatinine clearances between 51 to 80 and 25 to 50 ml/min, resp., stated higher variation than patients with more definitively altered renal function. The validation of NPEM2-C(SS)av population model was performed by using a set of 272 individual plasma drug concentrations, including trough levels as well as concentrations belonging to mono-exponential elimination phases after single and multiple dosing. Bayesian forecasting, using 4 trough levels per patient as Bayesian priors, revealed highly significant correlation between observed and population model predicted drug concentrations (r = 0.526, p < 0.0001). The predictive performance of NPEM2-C(SS)av population model was characterized by low bias (mean error = -0.48 microg/l, 95% CI = -0.99-0.04 microg/l), and good precision (root mean squared error = 4.32 microg/l, 95% CI = -2.53-11.17 microg/l). CONCLUSIONS: As predicted for high hepatic clearance drugs [Rowland 1985], nimodipine parameters variability decreased after reaching steady-state. NPEM2-C(SS)av population model demonstrated high accuracy and precision in predicting drug levels from terminal exponential phase including trough levels at steady-state.

Administration, Oral↗

Sentinel surveillance for HIV-1 among pregnant women in a developing country: 3 years' experience and comparison with a population serosurvey.

OBJECTIVES: To establish unlinked, anonymous sentinel surveillance for HIV-1 among pregnant women attending an antenatal clinic, to determine age-specific seroprevalences, to monitor trends and to compare seroprevalence with that detected by a population serosurvey. To establish the sustainability and costs of surveillance. DESIGN: Sentinel surveillance for HIV through serial collection of unlinked, anonymous seroprevalence data from antenatal care; comparison of sentinel data with those from a population serosurvey; financial and general audit of the sentinel surveillance. SETTING: A community antenatal clinic in a large urban centre, Mwanza Municipality, Tanzania, eastern Africa, between October 1988 and September 1991. PATIENTS: Pregnant women attending for antenatal care. MAIN OUTCOME MEASURE: Age-specific HIV-1 seroprevalences, trends over time, difference from age-specific population seroprevalences, sustainability and costs. RESULTS: Overall HIV-1 seroprevalence was 11.5% (95% confidence interval, 10.5-12.4); differences in age-specific prevalences were not significant. There was no clear evidence of change in seroprevalence over the study period in any age group, although there was some indication of a rise in some age groups in 1988-1989. Sentinel surveillance among pregnant women may have significantly underestimated population HIV-1 seroprevalence for women under the age of 35 years. HIV-1 surveillance proved feasible and sustainable. Additional recurrent costs were US$1.7 per specimen for unlinked anonymous testing and US$0.57 per woman for syphilis screening. CONCLUSIONS: HIV-1 seroprevalence did not change significantly over 3 years, probably implying a substantial incidence of HIV-1 infection. In this setting seroprevalence in pregnant women may have underestimated population seroprevalence in women aged under 35 years. With modest inputs and good organization unlinked anonymous HIV-1 sentinel surveillance of pregnant women can be introduced and sustained in an African setting. This may usefully be carried out in conjunction with syphilis screening.

AIDS Serodiagnosis↗

Profiling the health service needs of populations using diagnosis-based classification systems.

Managed care presents the challenge to deliver health care services to populations from a fixed pool of dollars and be accountable for doing so. From a health plan and a community perspective, it is critical to have classification systems that adequately describe the health service needs of the population. This article describes the design and structure of the National Association of Children's Hospitals and Related Institutions Classification of Congenital and Chronic Health Conditions and illustrates its management applications from its first testing on a full-service, paid claims database. Capabilities and limitations of diagnosis-based classification systems and the International Classification of Diseases, Ninth Edition, Clinical Modification diagnosis codes that underpin such systems are discussed.

Ambulatory Care↗

Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program.

BACKGROUND: Population-based data are unavailable concerning the predictive value of orthostatic hypotension on mortality in ambulatory elderly patients, particularly minority groups. METHODS AND RESULTS: With the use of data from the Honolulu Heart Program's fourth examination (1991 to 1993), orthostatic hypotension was assessed in relation to subsequent 4-year all-cause mortality among a cohort of 3522 Japanese American men 71 to 93 years old. Blood pressure was measured in the supine position and after 3 minutes of standing, with the use of standardized methods. Orthostatic hypotension was defined as a drop in systolic blood pressure (SBP) of >/=20 mm Hg or in diastolic blood pressure of >/=10 mm Hg. Overall prevalence of orthostatic hypotension was 6.9% and increased with age. There was a total of 473 deaths in the cohort over 4 years; of those who died, 52 had orthostatic hypotension. Four-year age-adjusted mortality rates in those with and without orthostatic hypotension were 56.6 and 38.6 per 1000 person-years, respectively. With the use of Cox proportional hazards models, after adjustment for age, smoking, diabetes mellitus, body mass index, physical activity, seated systolic blood pressure, antihypertensive medications, hematocrit, alcohol intake, and prevalent stroke, coronary heart disease and cancer, orthostatic hypotension was a significant independent predictor of 4-year all-cause mortality (relative risk 1.64, 95% CI 1.19 to 2.26). There was a significant linear association between change in systolic blood pressure from supine position to standing and 4-year mortality rates (test for linear trend, P<0.001), suggesting a dose-response relation. CONCLUSIONS: Orthostatic hypotension is relatively uncommon, may be a marker for physical frailty, and is a significant independent predictor of 4-year all-cause mortality in this cohort of elderly ambulatory men.

Aged↗

HLA gene and haplotype frequencies in the North American population: the National Marrow Donor Program Donor Registry.

BACKGROUND: As of May 1, 1995, the National Marrow Donor Program had a donor registry consisting of over 1.35 million HLA-typed volunteers recruited from most major cities and states in the United States. This registry represents the largest single HLA-typed pool of normal individuals in the world. METHODS: We analyzed the HLA-A, -B, -DR locus phenotypes of the National Marrow Donor Program donors in order to estimate gene and haplotype frequencies for major racial groups of the United States: Caucasian American, Asian American, African American, Latin American, and Native American. The large size of the database allowed us to calculate the frequencies of relatively rare antigens and haplotypes with more accuracy than previous studies. RESULTS: We observed 89,522 distinguishable HLA-A, -B phenotypes in 1,351,260 HLA-A, -B-typed donors and 302,867 distinguishable HLA-A, -B, -DR phenotypes in 406,503 HLA-A, -B, -DR-typed donors. Gene and haplotype frequencies differed remarkably among the five racial groups, with African Americans and Asian Americans having a large number of haplotypes that were specific to their racial groups, whereas Caucasian Americans, Latin Americans, and Native Americans shared a number of common haplotypes. CONCLUSIONS: These data represent an important resource for investigators in the fields of transplantation and population genetics. The gene and haplotype frequencies can be used to aid clinicians in advising patients about the probability of finding a match within a specific ethnic group, or to determine donor recruitment goals and strategies. The information is also a valuable resource for individuals who are interested in population genetics, selection and evolution of polymorphic human genes, and HLA-disease association.

Chi-Square Distribution↗

Birth characteristics associated with early intervention referral, evaluation for eligibility, and program eligibility in the first year of life.

OBJECTIVES: The Individual with Disabilities Education Act mandates Early Intervention (EI) services for infants and toddlers with developmental delay. We assessed the percentage of infants at risk for developmental delay due to characteristics present at birth who were referred to Massachusetts EI within 1 year of birth, evaluated for eligibility, and eligible for services. In addition, we identified birth characteristics that independently predicted 0-1 year program referral, evaluation, and eligibility. METHODS: The Pregnancy to Early Life Longitudinal (PELL) data system linked birth certificate, hospital discharge, and EI program data of 219,037 infants born in Massachusetts, 1998-2000. Multivariate logistic regressions identified independent infant predictors of referral, evaluation, and eligibility. RESULTS: Of 219,037 births, 14,852 (6.8%) were referred to EI within 1 year. Birthweight<1200 g (OR=9.7, 95% CI 3.3-12.9) and birthweight 1200-1499 g (OR=7.4, 95% CI 5.8-9.5) strongly predicted referral. Referral was high (88%) among infants with two or more birth risks. Among referrals, 88% were evaluated for eligibility. The strongest predictor of evaluation was triplet birth (OR=4.3, 95% CI 1.6-11.8). Among infants evaluated, 85% were determined to be eligible. CONCLUSION: EI referral and evaluation are high among infants born at risk for delay in Massachusetts. Some characteristics not included in the state's high-risk definition (e.g. birthweight 1200-1499 g) were identified that predicted referral. Most referrals were eligible for services. Results demonstrate the value to states of using linked population and program data for program evaluation.

Confidence Intervals↗

Is infection a major risk factor for preeclampsia?

Recently in an open population-based program composed of 15 354 pregnant women in Colombia we applied a biopsychosocial risk model, which permitted us to identify pregnant women at high risk of preeclampsia. 1443 (9.4%) of patients at high risk for developing preeclampsia received 450 mg of linoleic acid, and 1.5 g/day of calcium. Bacteriuria was identified in 1766 (11.5%) and vaginal infections in 2150 (14.0%) of the pregnant women. These women received oral antibiotics for 10 days. The incidence of low birthweight, preterm delivery and preeclampsia were reduced by 53% (6.2% vs 13.2%), 64.7% (1.8% vs 5.1%), and 52.5% (3.8% vs 8.0%) respectively, when compared with the incidence of the preceding five years. We believe that these dramatic reductions were due to early identification of risk factors, administration of nutritional supplements and principally by treatment of asymptomatic infections. Unfortunately, because of the study design it is not possible to confirm that infection was the major risk factor for preeclampsia in our population. However, we hypothesize that chronic subclinical infections may cause increased maternal cytokine levels sufficient to affect vascular endothelial function, and so prime individuals for the subsequent development of preeclampsia. This hypothesis can be tested in a more appropriately designed clinical trial to assess whether there is a relationship between infection, inflammation and preeclampsia.

Anti-Bacterial Agents↗

[Cost dynamics, demographic development and medical progress].

The drastic increase in the proportion of the elderly in the Germany population in the coming 30 to 40 years and the rapid technological progress in medicine form a vast potential for a rise of health care expenditures as a fraction of gross national product. Three possible strategies to cope with this development are discussed. It is shown that the predominant strategy of stabilizing the rate of contribution to the sickness funds will soon lead to a sharp rationing even of life-prolonging medical services. As an alternative, a strategy of "freedom of choice" is presented.

Aged↗

HIV-1 subtype E incidence and sexually transmitted diseases in a cohort of military conscripts in northern Thailand.

OBJECTIVES: To determine the rate of and risk factors for HIV-1 seroconversion and describe sexually transmitted disease (STD) prevalence rates for young men in northern Thailand. METHODS: Data were collected from self-administered questionnaires and serologic testing at enrollment in a prospective study in 1991 and at follow-up after 6, 17, and 23 months on a cohort of 1115 men selected by lottery for military conscription. RESULTS: A total of 14 men seroconverted to HIV-1 envelope subtype E. The overall HIV-1 incidence rate was 1.1 (95% confidence interval [CI], 0.6-1.8) per 100 person-years (PY) of follow-up. However, the rate was 2.0/100 PY for conscripts from the upper northern subregion of Thailand compared with 0.5/100 PY from other regions (adjusted rate ratio [RR] = 2.69; 95% CI, 0.8-12.2). On multivariate analyses, the behavioral factors associated with HIV-1 seroconversion were frequency of sex with female sex workers (FSWs; p = .04), receptive anal sex (adjusted RR = 6.73; 95% CI, 1.8-21.7), and large amount of alcohol consumption (adjusted RR = 3.12; 95% CI, 1.0-10.9). Genital ulceration was the STD most strongly associated with seroconversion. The prevalence of serologic reactivity to syphilis, Haemophilus ducreyi, and herpes simplex virus type 2 increased with greater frequency of sex with FSWs and was generally higher for men from the upper north. CONCLUSION: Young men in northern Thailand are at high risk for HIV-1, primarily through sex with FSWs; and other STDs are highly associated with HIV-1 incidence. As HIV-1 infection extends into the general population, intervention programs are needed to address the problem of sexual transmission apart from commercial sex venues.

Adult↗

Operational problems of an iron supplementation programme for pregnant women: an assessment of UNRWA experience.

Assessed is a large-scale iron supplementation programme for the 70 000 pregnant refugee women cared for by the United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA). For this purpose, a retrospective survey of 1267 antenatal records was conducted in health centres located in the West Bank, Gaza, Syrian Arab Republic, Jordan, and Lebanon. The following operational problems were identified: late entry to antenatal care; high drop-out rate from antenatal care; low compliance in follow-up haemoglobin examinations; and misdirected continued testing of women who were not anaemic at registration. Routine iron supplementation of all pregnant women should be considered only in those countries where severe anaemia is prevalent and should always be coupled with additional interventions that are effective at improving iron deficiency anaemia in a given population. In most countries attention should be directed towards changing dietary habits to enhance the availability of local foodstuffs that are rich in iron. One initial haemoglobin test may help in focusing on the relatively few initially anaemic subjects who need further attention. Repeated testing during pregnancy is unwarranted.

Adult↗

Implementation of a cancer prevention program for working class, multiethnic populations.

BACKGROUND: This paper describes the implementation of the Healthy Directions-Health Centers intervention and examines the characteristics of participants associated with completion of intervention activities. Healthy Directions-Health Centers was designed to address social contextual factors relevant to cancer prevention interventions for working class, multi-ethnic populations. METHODS: Ten community health centers were paired and randomly assigned to intervention or control. Patients who resided in low income, multi-ethnic neighborhoods were approached for participation. This study targeted fruit and vegetable consumption, red meat consumption, multi-vitamin intake, and physical activity. The intervention components consisted of: (1) a brief study endorsement from a clinician; (2) an in-person counseling session with a health advisor; (3) four follow-up telephone counseling sessions; and (4) multiple distributions of tailored materials. RESULTS: Among the 1,088 intervention group participants, 978 participants (90%) completed at least five out of six intervention activities. Participants who missed clinical appointments were less likely to complete all components of the intervention. Participant characteristics that predicted receipt of clinician endorsement differed from characteristics that predicted completion of health advisor activities. Low acculturation did not present a barrier to delivery of the intervention once the participant was enrolled. CONCLUSIONS: Collection and reporting on process evaluation results can help explain variations in program implementation.

Community Health Centers↗

The macro determinants of health expenditure in the United States and Canada: assessing the impact of income, age distribution and time.

This paper examines the determinants of real per capita health expenditures in order to assess the impact of age distribution, income and time using American state-level data for the period 1980-1998 and Canadian province-level data for the period 1975-2000. Ageing population distributions and income explain a relatively small portion of health expenditures when the impact of time effects, which is a partial proxy for technological change, is controlled for. However, the impact of age is of more concern given that cost increases are concentrated in the last few years of life and there may be cohort effects as the "Baby-Boom" generation ages. There is an urgent need to better understand the exact mechanisms driving health expenditure increases given that time accounts for approximately two-thirds of health expenditure increases and that its effect is non-linear.

Age Distribution↗

Assessment of routine surveillance data as a tool to investigate measles outbreaks in Mozambique.

BACKGROUND: Measles remains a major public health problem in Mozambique despite significant efforts to control the disease. Currently, health authorities base their outbreak control on data from the routine surveillance system while vaccine coverage and efficacy are calculated based on mathematical projections of the target population. The aim of this work was to assess the quality of the measles reporting system during two outbreaks that occurred in Maputo City (1998) and in Manica Province (2002). METHODS: Retrospectively, we collected data from the routine surveillance system, i.e. register books at health facilities and weekly provincial and national epidemiological reports. To test whether the provinces registered an outbreak, the distribution of measles cases was compared to an endemic level established based on cases reported in previous years. RESULTS: There was a significant under-notification of measles cases from the health facilities to the province and national level. Register books, the primary sources of information for the measles surveillance system, were found to be incomplete for two main variables: "age" and "vaccination status". CONCLUSION: The Mozambican surveillance system is based on poor quality records, receives the notification of only a fraction of the total number of measles in the country and may result in failures do detect epidemics. The measles reporting system does not provide the data needed by Expanded Program on Immunisation managers to make evidence-based decisions, nor does it allow in-depth analysis to monitor measles epidemiology in the country. The progress of Mozambique to the next stage of measles elimination will require an improvement of the routine surveillance system and a stronger Health Information System.

Adolescent↗

Diabetes mellitus in managed care: complications and resource utilization.

OBJECTIVES: To implement a diabetes mellitus surveillance system designed to use administrative data and to demonstrate how it can be used by managed care organizations (MCOs) with different administrative data systems to estimate the prevalence of diabetic complications and describe utilization of services in persons with and without complications and comorbidities. STUDY DESIGN, PATIENTS, AND METHODS: We identified individuals with diabetes mellitus in 3 MCOs in 1993 using 4 sources of computerized data records: inpatient, pharmacy, outpatient, and laboratory. The presence of diabetes mellitus complications and cardiovascular comorbidities were determined using diagnostic and procedural codes. Use of healthcare resources by persons with and without complications and comorbidities was determined from computerized administrative data. RESULTS: The most prevalent complication or comorbidity was cardiovascular disease (45%-53%), followed by eye disease (20%-34%), lower extremity disease (8%-20%), and renal disease (3%-6%). The presence of multiple complications was common and ranged from 14% to 34% in the 3 MCO populations. Compared with persons with none, persons with 2 or more complications or comorbidities used moderately more primary care services (1.3-1.9 times more) and markedly more specialty care services (5.8-6.3 times more), emergency department visits (3.3-5.5 times more), and hospitals stays (3.3-11.9 times more). CONCLUSIONS: Diabetic complications were common and had a large impact on patients' use of healthcare services. Within MCOs, administrative databases are useful tools for estimating and monitoring the prevalence of diabetic complications and the use of healthcare resources associated with these complications.

Comorbidity↗

Customary diet, anthropometry, and dyslipoproteinemia in selected North American populations. The Lipid Research Clinics Program Prevalence Study.

The intake of nutrients, determined by 24 hr diet recall, and body measurements were obtained in 8250 free-living white study participants divided into 20 to 49 and 50 + age groups for males and female nonusers and users of gonadal hormones. They were classified into dyslipoproteinemia (DLP) phenotypes: hyperHDL, hypoHDL, IIA, hpypoLDL, IV, and normal. The dyslipoproteinemia DLP phenotypes, compared with the normal, had biologically meaningful differences in nutrient intake and indexes of obesity that were most marked for males aged 20 to 49 years as shown in the table (below). Those with the hyperHDL phenotype were thinner and ingested more energy and more alcohol and less carbohydrate as percent kilocalories (%kcal). Individuals classified as hypoHDL were fatter and tended to ingest less energy and less alcohol as %kcal. Persons with the type II phenotype were fatter and ingested less energy. Those with hypoLDL tended to be thinner and ingested more energy. Individuals with the type IV phenotype were fatter, ingested less energy and carbohydrate and more alcohol as %kcal. Similar trends were observed in female nonusers of hormones aged 20 to 49 and to a lesser extent in the 50 + age groups and in female users of hormones. Dietary protein, cholesterol, total fat, and polyunsaturated and saturated fatty acids had no consistent associations with DLP phenotype, and sucrose and starch had no association independent of total carbohydrate. This is the first evidence of an association of customary diet and DLP phenotypes in the free-living population. Equating energy intake with energy expenditure, persons with the high-risk phenotypes, IIA, IV, and hypoHDL, compared with the normal, had decreased energy expenditure and were fatter, whereas those with the low-risk phenotypes, hyperHDL and hypoLDL, had increased energy expenditure and were thinner.

Adult↗