A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.

Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases.

The Relative Ability of Comorbidity Ascertainment Methodologies to Predict In-Hospital Mortality Among Hospitalized Community-acquired Pneumonia Patients.

BACKGROUND: Despite widespread use of comorbidities for population health descriptions and risk adjustment, the ideal method for ascertaining comorbidities is not known. We sought to compare the relative value of several methodologies by which comorbidities may be ascertained. METHODS: This is an observational study of 1596 patients admitted to the University of Chicago for community-acquired pneumonia from 1998 to 2012. We collected data via chart abstraction, administrative data, and patient report, then performed logistic regression analyses, specifying comorbidities as independent variables and in-hospital mortality as the dependent variable. Finally, we compared area under the curve (AUC) statistics to determine the relative ability of each method of comorbidity ascertainment to predict in-hospital mortality. RESULTS: Chart review (AUC, 0.72) and administrative data (Charlson AUC, 0.83; Elixhauser AUC, 0.84) predicted in-hospital mortality with greater fidelity than patient report (AUC, 0.61). However, multivariate logistic regression analyses demonstrated that individual comorbidity derivation via chart review had the strongest relationship with in-hospital mortality. This is consistent with prior literature suggesting that administrative data have inherent, paradoxical biases with important implications for risk adjustment based solely on administrative data. CONCLUSIONS: Although comorbidities derived through administrative data did produce an AUC greater than chart review, our analyses suggest a coding bias in several comorbidities with a paradoxically protective effect. Therefore, chart review, while labor and resource intensive, may be the ideal method for ascertainment of clinically relevant comorbidities.

Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability.

Many factors affect the risks for neurodevelopmental maladies such as autism spectrum disorders (ASD) and intellectual disability (ID). To compare environmental, phenotypic, socioeconomic and state-policy factors in a unified geospatial framework, we analyzed the spatial incidence patterns of ASD and ID using an insurance claims dataset covering nearly one third of the US population. Following epidemiologic evidence, we used the rate of congenital malformations of the reproductive system as a surrogate for environmental exposure of parents to unmeasured developmental risk factors, including toxins. Adjusted for gender, ethnic, socioeconomic, and geopolitical factors, the ASD incidence rates were strongly linked to population-normalized rates of congenital malformations of the reproductive system in males (an increase in ASD incidence by 283% for every percent increase in incidence of malformations, 95% CI: [91%, 576%], p<6×10(-5)). Such congenital malformations were barely significant for ID (94% increase, 95% CI: [1%, 250%], p = 0.0384). Other congenital malformations in males (excluding those affecting the reproductive system) appeared to significantly affect both phenotypes: 31.8% ASD rate increase (CI: [12%, 52%], p<6×10(-5)), and 43% ID rate increase (CI: [23%, 67%], p<6×10(-5)). Furthermore, the state-mandated rigor of diagnosis of ASD by a pediatrician or clinician for consideration in the special education system was predictive of a considerable decrease in ASD and ID incidence rates (98.6%, CI: [28%, 99.99%], p = 0.02475 and 99% CI: [68%, 99.99%], p = 0.00637 respectively). Thus, the observed spatial variability of both ID and ASD rates is associated with environmental and state-level regulatory factors; the magnitude of influence of compound environmental predictors was approximately three times greater than that of state-level incentives. The estimated county-level random effects exhibited marked spatial clustering, strongly indicating existence of as yet unidentified localized factors driving apparent disease incidence. Finally, we found that the rates of ASD and ID at the county level were weakly but significantly correlated (Pearson product-moment correlation 0.0589, p = 0.00101), while for females the correlation was much stronger (0.197, p<2.26×10(-16)).

The Impact of Principal Diagnosis on Readmission Risk among Patients Hospitalized for Community-Acquired Pneumonia.

Coding variation distorts performance/outcome statistics not eliminated by risk adjustment. Among 1596 community-acquired pneumonia patients hospitalized from 1998 to 2012 identified using an evidence-based algorithm, the authors measured the association of principal diagnosis (PD) with 30-day readmission, stratified by Pneumonia Severity Index risk class. The 152 readmitted patients were more ill (Pneumonia Severity Index class V 38.8% versus 25.8%) and less likely to have a pneumonia PD (52.6% versus 69.9%). Among patients with PDs of pneumonia, respiratory failure, sepsis, and aspiration, mortality/readmission rates were 3.9/8.5%, 28.8/14.0%, 24.7/19.6%, and 9.0/15.0%, respectively. The nonpneumonia PDs were associated with a greater risk of adjusted 30-day readmission: respiratory failure odds ratio (OR) 1.89 (95% confidence interval [CI], 1.13-3.15), sepsis OR 2.54 (95% CI, 1.52-4.26), and possibly aspiration OR 1.73 (95% CI, 0.88-3.41). With increasing use of alternative PDs among pneumonia patients, quality reporting must account for variations in condition coding practices. Rigorous risk adjustment does not eliminate the need for accurate, consistent case definition in producing valid quality measures.

Discerning asthma endotypes through comorbidity mapping.

Asthma is a heterogeneous, complex syndrome, and identifying asthma endotypes has been challenging. We hypothesize that distinct endotypes of asthma arise in disparate genetic variation and life-time environmental exposure backgrounds, and that disease comorbidity patterns serve as a surrogate for such genetic and exposure variations. Here, we computationally discover 22 distinct comorbid disease patterns among individuals with asthma (asthma comorbidity subgroups) using diagnosis records for >151 M US residents, and re-identify 11 of the 22 subgroups in the much smaller UK Biobank. GWASs to discern asthma risk loci for individuals within each subgroup and in all subgroups combined reveal 109 independent risk loci, of which 52 are replicated in multi-ancestry meta-analysis across different ethnicity subsamples in UK Biobank, US BioVU, and BioBank Japan. Fourteen loci confer asthma risk in multiple subgroups and in all subgroups combined. Importantly, another six loci confer asthma risk in only one subgroup. The strength of association between asthma and each of 44 health-related phenotypes also varies dramatically across subgroups. This work reveals subpopulations of asthma patients distinguished by comorbidity patterns, asthma risk loci, gene expression, and health-related phenotypes, and so reveals different asthma endotypes.

Obesity and asthma morbidity in a community-based adult cohort in a large urban area: the Chicago Initiative to Raise Asthma Health Equity (CHIRAH).

BACKGROUND: Urban minority populations experience increased rates of obesity and increased asthma prevalence and severity. Objective. The authors sought to determine whether obesity, as measured by body mass index (BMI), was associated with asthma quality of life or asthma-related emergency department (ED)/urgent care utilization in an urban, community-based sample of adults. METHODS: This is a cross-sectional analysis of 352 adult subjects (age 30.9 +/- 6.1, 77.8% females, forced expiratory volume in one second (FEV(1))% predicted = 87.0% +/- 18.5%) with physician-diagnosed asthma from a community-based Chicago cohort. Outcome variables included the Juniper Asthma Quality of Life Questionnaire (AQLQ) scores and health care utilization in the previous 12 months. Bivariate tests were used as appropriate to assess the relationship between BMI or obesity status and asthma outcome variables. Multivariate regression analyses were performed to predict asthma outcomes, controlling for demographics, income, depression score, and beta-agonist use. RESULTS: One hundred ninety-one (54.3%) adults were obese (BMI > 30 kg/m(2)). Participants with a higher BMI were older (p = .008), African American (p < .001), female (p = .002), or from lower income households (p = .002). BMI was inversely related to overall AQLQ scores (r = -.174, p = .001) as well as to individual domains. In multivariate models, BMI remained an independent predictor of AQLQ. Obese participants were more likely to have received ED/urgent care for asthma than nonobese subjects (odds ratio [OR] = 1.8, p = .036). CONCLUSIONS: In a community-based sample of urban asthmatic adults, obesity was related to worse asthma-specific quality of life and increased ED/urgent care utilization. However, compared to other variables measured such as depression, the contribution of obesity to lower AQLQ scores was relatively modest.

Ethnic disparities in asthma morbidity in Chicago.

RATIONALE: The role of ethnicity and socioeconomic status in explaining variations in asthma morbidity is unclear. OBJECTIVES: To describe the magnitude of ethnic disparities in asthma morbidity in Chicago and to determine whether differences in socioeconomic status explain these disparities. METHODS: We conducted a survey of 561 school-age children and 353 young adults with asthma and measured their self-reported ethnicity, socioeconomic status (using 11 variables), and asthma morbidity (symptom frequency, asthma-specific quality of life, and frequency of severe asthma exacerbations). MEASUREMENTS AND MAIN RESULTS: White children and adults had better asthma-specific quality of life and fewer severe asthma exacerbations compared to black and Hispanic children and adults. White children also had fewer days with asthma symptoms, but among adults there were no ethnic differences in the frequency of asthma symptoms. Socioeconomic status explained a large portion of the ethnic disparities in asthma quality of life but explained little of the disparities in other aspects of asthma morbidity. CONCLUSIONS: There are large disparities across ethnic groups in Chicago in asthma quality of life and in the frequency of severe exacerbations. Differences in socioeconomic status do not fully explain these disparities.

Characterizing community-based asthma knowledge in Chicago and its high risk neighborhoods.

The goal of this study was to characterize asthma knowledge in high risk neighborhoods compared to a random sample of residents in the Chicago area. The Chicago Community Asthma Survey-32 (CCAS-32) was administered to 1006 Chicago-area residents and 388 residents in 4 high-risk Chicago inner-city neighborhoods. There was a significant difference in asthma knowledge between groups. The general Chicago-area respondents have an average desirable response rate of 71.6% versus 64.7% for respondents in high-risk communities (p < 0.0001). For some aspects of asthma knowledge, e.g., nocturnal cough, cockroach allergen, and vaporizer use, general knowledge was similarly low. For other aspects, such as the need for asymptomatic asthma visits and chest tightness, there were larger gaps between residents of high risk communities and the general community. High-risk neighborhoods in Chicago had lower asthma knowledge compared to the general Chicago community. This discrepancy may be contributing to the disparities seen in asthma morbidity. Public health efforts to increase asthma knowledge in these high risk minority communities may help reduce these disparities. Important misconceptions exist about asthma triggers, signs and symptoms, especially among lower income African American communities, that should be addressed by physicians.

Changing impact of gastroesophageal reflux in medical and otolaryngology practice.

OBJECTIVES/HYPOTHESIS: A major trend in gastroesophageal reflux disease (GERD) is an observed increased prevalence of the problem, with an associated burden on health care resources. There are relatively few objective reports of increasing prevalence of this disease, and there are no epidemiologic reports that discuss changing practice strategies in managing the disease. The clinical problem is of critical importance to practicing otolaryngologists, who manage the impact of GERD on diseases affecting the ear, nose, and throat. The hypothesis of this thesis is that 1) GERD is an increasing problem affecting outpatient office visits over time, and 2) the disease is increasingly managed with prescription pharmacotherapy. STUDY DESIGN: Retrospective national medical database review using the National Ambulatory Medical Care Survey. METHODS: Twelve years of data (1990-2001) were examined with visits weighted to provide U.S. estimates of care. Average annual frequencies and visit rates were calculated for total visits and by age, sex, race, and physician specialty. Selected issues in GERD treatment were also examined, including prescriptions and physician/patient counseling regarding stress management, tobacco abuse, and diet modification. Trends were reported based on changes in care across three time periods to satisfy statistical significance: 1990 to 1993, 1994 to 1997, and 1998 to 2001. RESULTS: Between 1990 and 1993 and 1998 and 2001, there was a significant increase in U.S. ambulatory care visits for GERD, from a rate of 1.7 per 100 to 4.7 per 100. There were no significant changes in race, although there was a small trend toward increased GERD visits in the age group over 44 years old and in the male sex. Office visits to otolaryngologists increased from 89,000 to 421,000 between the time periods of 1990 to 1993 and 1998 to 2001. This also represented a percent increase in office encounters by otolaryngologists compared with visits by all specialties from 2.9% to 4.4%. Over the three time periods, there was a fall in prescriptions for histamine (H2) blockers from 58.1% to 20.7% of total prescriptions. Over the same three time periods, prescriptions of proton pump inhibitors increased from 13.2% to 64.6%. Physician recommendations for over the counter medications fell from 18.8% to 6.6%. Average annual counseling during ambulatory care visits for GERD was assessed for the period from 1998 to 2001 as follows: diet counseling was provided at 27.2% of encounters, tobacco cessation counseling was provided at 3.9%, and stress management was discussed at 3.9%. CONCLUSIONS: During the 1990s, there was a substantial increase in the use of ambulatory care services for GERD. Although much of this increase was among the primary care community, otolaryngologists appeared to have an increasingly prominent role in the management of this disease. There have also been dramatic changes in physician prescribing patterns for GERD, with the emergence of the predominant role of proton pump inhibitors. However, the use of physician counseling for lifestyle modification of factors known to affect GERD remains very low. The increasing impact of GERD on physician practice emphasizes the importance of both physician and patient education in the delivery of health care related to this disease.

Defining an episode of care for colonoscopy: work of the High Value Health Care Project characterizing episodes and costs of care.

Working with a group of key stakeholders, the authors developed an episode-based resource use measure focused on the use of colonoscopy. This measure is intended to identify differences in health care resource use in a short time frame surrounding the colonoscopy. The ultimate intent in the development of this measure was to pair it with a measure of quality so that both the cost and quality of care can be evaluated together. In initial testing, the authors found the use of general anesthesia with colonoscopy to be associated with higher episode costs. Eventually, when paired with quality measures, it is hoped this measure will provide actionable information for health care payers and providers to more efficiently provide colonoscopy services without compromising quality.

Asthma morbidity and treatment in the Chicago metropolitan area: one decade after national guidelines.

BACKGROUND: A number of studies have demonstrated disproportionate hospitalization and mortality rates in US urban areas. Yet, no published population-based studies have examined the burden of asthma on the residents of a particular urban area known to be at high risk for poor asthma outcomes. OBJECTIVES: To examine asthma morbidity and medical care in a population-based sample of adults and children with asthma residing in the greater Chicago, IL, metropolitan area and to explore social and demographic influences on morbidity and treatment. METHODS: A telephone survey of adults living in the Chicago metropolitan area was conducted from November 1999 through December 2000. RESULTS: The final sample included 152 adults and children with active asthma. Emergency department visits and hospitalizations for asthma in the previous year were reported by 25.7% and 6.6% of respondents, respectively. Of current medication users, 32.2% reported current regular use of controller medications. After adjusting for age, sex, income, education, and reported current pharmacotherapy, compared with white individuals, African American individuals remained 6.3 times more likely to have experienced an emergency department visit and 12.3 times more likely to have been hospitalized. CONCLUSIONS: These findings suggest that poorly controlled asthma remains a prevalent problem for persons with asthma in this metropolitan area and that a large gap remains between the goals of asthma therapy and appropriate treatment as defined by the National Asthma Education and Prevention Program. The reasons for disparate treatment and health outcomes by race/ethnicity and income need further study and intervention.