A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

A prospective study of dietary fat and risk of prostate cancer.

BACKGROUND: The strong correlation between national consumption of fat and national rate of mortality from prostate cancer has raised the hypothesis that dietary fat increases the risk of this malignancy. Case-control and cohort studies have not consistently supported this hypothesis. PURPOSE: We examined prospectively the relationship between prostate cancer and dietary fat, including specific fatty acids and dietary sources of fat. We examined the relationship of fat consumption to the incidence of advanced prostate cancer (stages C, D, or fatal cases) and to the total incidence of prostate cancer. METHODS: We used data from the Health Professionals Follow-up Study, which is a prospective cohort of 51529 U.S. men, aged 40 through 75, who completed a validated food-frequency questionnaire in 1986. We sent follow-up questionnaires to the entire cohort in 1988 and 1990 to document new cases of a variety of diseases and to update exposure information. As of January 31, 1990, 300 new cases of prostate cancer, including 126 advanced cases, were documented in 47855 participants initially free of diagnosed cancer. The Mantel-Haenszel summary estimator was used to adjust for age and other potentially confounding variables. Multiple logistic regression was used to estimate relative risks (RRs) when controlling simultaneously for more than two covariates. RESULTS: Total fat consumption was directly related to risk of advanced prostate cancer (age- and energy-adjusted RR = 1.79, with 95% confidence interval [CI] = 1.04-3.07, for high versus low quintile of intake; P [trend] = .06). This association was due primarily to animal fat (RR = 1.63; 95% CI = 0.95-2.78; P [trend] = .08), but not vegetable fat. Red meat represented the food group with the strongest positive association with advanced cancer (RR = 2.64; 95% CI = 1.21-5.77; P = .02). Fat from dairy products (with the exception of butter) or fish was unrelated to risk. Saturated fat, monounsaturated fat, and alpha-linolenic acid, but not linoleic acid, were associated with advanced prostate cancer risk; only the association with alpha-linolenic acid persisted when saturated fat, monounsaturated fat, linoleic acid, and alpha-linolenic acid were modeled simultaneously (multivariate RR = 3.43; 95% CI = 1.67-7.04; P [trend] = .002). CONCLUSION: The results support the hypothesis that animal fat, especially fat from red meat, is associated with an elevated risk of advanced prostate cancer. IMPLICATIONS: These findings support recommendations to lower intake of meat to reduce the risk of prostate cancer. The potential roles of carcinogens formed in cooking animal fat and of alpha-linolenic acid in the progression of prostate cancer need to be explored.

Incremental costs of enrolling cancer patients in clinical trials: a population-based study.

BACKGROUND: Payment for care provided as part of clinical research has become less predictable as a result of managed care. Because little is known at present about how entry into cancer trials affects the cost of care for cancer patients, we conducted a matched case-control comparison of the incremental medical costs attributable to participation in cancer treatment trials. METHODS: Case patients were residents of Olmsted County, MN, who entered phase II or phase III cancer treatment trials at the Mayo Clinic from 1988 through 1994. Control patients were patients who did not enter trials but who were eligible on the basis of tumor registry matching and medical record review. Sixty-one matched pairs were followed for up to 5 years after the date of trial entry for case patients or from an equivalent date for control patients. Hospital, physician, and ancillary service costs were estimated from a population-based cost database developed at the Mayo Clinic. RESULTS: Trial enrollees incurred modestly (no more than 10%) higher costs over various follow-up periods. The mean cumulative 5-year cost in 1995 inflation-adjusted U.S. dollars among trial enrollees after adjustment for censoring was $46424 compared with $44 133 for control patients. After 1 year, trial enrollee costs were $24645 compared with $23 964 for control patients. CONCLUSIONS: This study suggests that cancer chemotherapy trials may not imply budget-breaking costs. Cancer itself is a high-cost illness. Clinical protocols may add relatively little to that cost.

Health Concept and Knowledge Management: Twenty-five Years of Evolution.

OBJECTIVES: The fields of health terminology, classification, ontology, and related information models have evolved dramatically over the past 25 years. Our objective was to review notable trends, described emerging or enabling technologies, and highlight major terminology systems during the interval. METHODS: We review the progression in health terminology systems informed by our own experiences as part of the community involved in this work, reinforced with literature review and citation. RESULTS: The transformation in size, scope, complexity, and adoption of health terminological systems and information models has been tremendous, on the scale of orders of magnitude. CONCLUSION: The present "big science" era of inference and discovery in biomedicine would not have been possible or scalable absent the growth and maturation of health terminology systems and information models over the past 25 years.

Genetic variation among 82 pharmacogenes: The PGRNseq data from the eMERGE network.

Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

Harmonization of detailed clinical models with clinical study data standards.

INTRODUCTION: This article is part of the Focus Theme of METHODS of Information in Medicine on "Managing Interoperability and Complexity in Health Systems". BACKGROUND: Data sharing and integration between the clinical research data management system and the electronic health record system remains a challenging issue. To approach the issue, there is emerging interest in utilizing the Detailed Clinical Model (DCM) approach across a variety of contexts. The Intermountain Healthcare Clinical Element Models (CEMs) have been adopted by the Office of the National Coordinator awarded Strategic Health IT Advanced Research Projects for normalization (SHARPn) project for normalizing patient data from the electronic health records (EHR). OBJECTIVE: The objective of the present study is to describe our preliminary efforts toward harmonization of the SHARPn CEMs with CDISC (Clinical Data Interchange Standards Consortium) clinical study data standards. METHODS: We were focused on three generic domains: demographics, lab tests, and medications. We performed a panel review on each data element extracted from the CDISC templates and SHARPn CEMs. RESULTS: We have identified a set of data elements that are common to the context of both clinical study and broad secondary use of EHR data and discussed outstanding harmonization issues. CONCLUSIONS: We consider that the outcomes would be useful for defining new requirements for the DCM modeling community and ultimately facilitating the semantic interoperability between systems for both clinical study and broad secondary use domains.

Sex hormones and lipoproteins in men.

PURPOSE: To clarify the conflicting evidence of an association between endogenous sex hormones and lipoprotein metabolism in men, we examined the relationship between sex hormone levels, total cholesterol, and high-density lipoprotein cholesterol (HDL-C), taking into account the coronary artery disease (CAD) status of the subjects. PATIENTS AND METHODS: Sex hormone levels, total cholesterol, and HDL-C were measured in 67 men with CAD from among 191 consecutive male patients between the ages of 25 and 75 undergoing coronary angiography, in 26 men without angiographic evidence of CAD, and in 55 men who were clinically free of CAD. RESULTS: There was a consistently positive correlation between total estradiol or calculated free estradiol and both total cholesterol and HDL-C, which persisted after adjustment for potential confounders. Total cholesterol was associated with total testosterone after controlling for age, adiposity, and the presence or absence of CAD, but not with calculated free testosterone. No association was noted between total testosterone or calculated free testosterone and HDL-C. A significant interaction was observed between estradiol and testosterone with respect to total cholesterol. CONCLUSION: This study demonstrates an association between sex hormone levels and lipoprotein metabolism, specifically between estradiol levels and both total cholesterol and HDL-C. Unlike most previous investigators, we were able both to control for the CAD status of our subjects and to consider unbound, biologically active hormone levels. In addition, we documented a complex interaction between endogenous testosterone and estradiol in relation to lipoprotein levels; this association should be considered in future studies.

Sex hormones and coronary artery disease.

Previous investigators have found an increased risk of coronary heart disease in men with high levels of circulating estrogens. To elucidate further this relationship, a case-control study of atherosclerotic coronary artery disease (ASCAD) and sex hormones was undertaken in male patients. Hormone levels in men with severe ASCAD documented at angiography were compared with those in men found to be virtually free from disease and with those in a group of control subjects without signs or symptoms of ASCAD. Significantly lower total testosterone levels were observed among men with severe ASCAD compared with either control group; the free testosterone level was significantly lower than in angiographically disease-free control subjects. The same pattern of hormone levels persisted after control of covariates. Epidemiologic analysis demonstrated a fivefold decrease in risk for severe ASCAD between the lowest and the highest quartile of total testosterone. No overall pattern of association was seen between ASCAD and free or total estrogens.

Effect of several recruitment strategies on response rates at baseline in a prospective cohort investigation. The Olmsted County Study of Urinary Symptoms and Health Status among Men.

Epidemiologic survey response rates were studied in relation to maneuvers introduced to improve acceptance: (a) variation in invitation letters, (b) the use of a brochure with the recruitment mailing, and (c) options for interview location. The baseline population-based survey of a prospective cohort investigation of the natural history of benign prostatic hyperplasia was used. Invitations to participate were mailed to eligible, randomly selected men aged 40 to 79 years from the Olmsted County, Minnesota, population during 1989 to 1991. Of the 3874 men identified, 2119 (55%) participated. Overall, there was no difference in response rate according to invitation characteristics (chi 2(5) = 8.02, P = 0.16). Nevertheless, response rates varied with age (chi 2(7) = 30.9, P < 0.001) and home location (rural versus Rochester city; chi 2(1) = 76.9, P < 0.001). This suggests the innovations used to bolster acceptance did not materially improve response rates. Further, since response rates were highest for men aged 60 to 74 years, men with more symptoms and free time may have joined the cohort more often than others.

Validation of a new quality of life questionnaire for benign prostatic hyperplasia.

In planning a longitudinal study to characterize the natural history of benign prostatic hyperplasia (BPH), we validated a new disease-specific quality of life questionnaire in a pilot study. We studied 110 men in Rochester, Minnesota who spanned the severity of BPH, from men with no known BPH to men who underwent surgery for this condition. Baseline data were obtained on all men, and the 30 who underwent prostatectomy were re-interviewed to test responsiveness. Reproducibility was examined on the pre-post responses (10 weeks apart) of the 37 men with BPH who did not undergo prostatectomy. Six of twelve question domains were retained in the final questionnaire on the basis of their responsiveness to change, reproducibility, internal consistency, and validity. These were: urinary symptoms, degree of bother due to urinary symptoms, BPH-specific interference with activities, general psychological well-being, worries and concerns, and sexual satisfaction. Most of the more generic measures were deleted.

The natural history of prostatism: the effects of non-response bias.

BACKGROUND: In epidemiological studies, non-response may raise the question of generalizability to the target population. Most investigations have not been able to access data that could provide information about the potential impact of non-response bias. METHODS: A 55% response rate was realized at baseline for a prospective cohort investigation of the natural history of benign prostatic hyperplasia in Olmsted County, Minnesota, during 1989-1991 (the Olmsted County Study of Urinary Symptoms and Health Status Among Men). This prompted a preliminary study of potential non-response bias among full participants, partial participants and complete non-responders. The medical diagnostic index maintained by the Rochester Epidemiology Project was used to ascertain the prevalence of specific conditions in the 9 years prior to study inception. RESULTS: The age-adjusted period prevalence rate for benign prostatic hyperplasia (%) was 9.6 (95% confidence interval [CI]: 8.1-11.0) for full participants, 8.2 (95% CI: 5.8-10.6) for partial participants and 5.3 (95% CI: 3.6-6.9) for complete non-responders. Other urologic diagnoses followed the same pattern. However, age-adjusted prevalence rates for general medical examination history and major non-urologic morbidities were decidedly similar across response groups. CONCLUSIONS: These data suggest response may have been driven, in part, by concerns about urologic disease. However, the similarity in non-urologic diagnoses and general medical examinations provide some preliminary reassurance that the 55% response rate did not necessarily compromise generalizability.

Sexual function of men ages 40 to 79 years: the Olmsted County Study of Urinary Symptoms and Health Status Among Men.

OBJECTIVES: Knowledge of male sexual function is somewhat limited because of a lack of current population-based data. This study provides information on sexual function and satisfaction in a population-based sample of men. METHODS: Men aged 40 to 79 years (n = 2115) were selected randomly from the Olmsted County population for the baseline component of a prospective cohort study (the Olmsted County Study of Urinary Symptoms and Health Status Among Men) during 1989-1990. The men completed a self-administered questionnaire that included questions about sexual concerns, performance, satisfaction, drive, and erectile dysfunction. RESULTS: For all five sexual parameters queried, the prevalence of problems and dysfunction increased with age. A comparison of men aged 70 to 79 years with men aged 40 to 49 years suggested that older men were more worried about sexual function (46.6% vs 24.9%), had worsened performance compared with a year ago (30.1% vs 10.4%), expressed extreme dissatisfaction with sexual performance (10.7% vs 1.7%), had absent sexual drive (25.9% vs 0.6%), and reported complete erectile dysfunction when sexually stimulated (27.4% vs 0.3%). Logistic regression analyses suggested that sexual dissatisfaction was significantly associated with erectile dysfunction, decreased libido, and the interaction between erectile dysfunction and libido, but not age. CONCLUSIONS: These population-based cross-sectional data corroborate the previously reported age-related decrease in sexual function. The age-related increase in dissatisfaction could, however, be accounted for primarily by the age-related increase in erectile dysfunction, decreased libido, and the interaction between erectile dysfunction and decreased libido.

Clinical classification and terminology: some history and current observations.

The evolution of health terminology has undergone glacial transition over time, although this pace has quickened recently. After a long history of near neglect, unimaginative structure, and factitious development, health terminologies are in an era of unprecedented importance, sophistication, and collaboration. The major highlights of this history are reviewed, together with important intellectual advances in health terminology development. The inescapable conclusion is that we are amidst a major revolution in the role and capabilities of health terminologies, entering an age of large-scale systems for health concept representation with international implications.

A framework for comprehensive health terminology systems in the United States: development guidelines, criteria for selection, and public policy implications. ANSI Healthcare Informatics Standards Board Vocabulary Working Group and the Computer-Based Patient Records Institute Working Group on Codes and Structures.

Health care in the United States has become an information-intensive industry, yet electronic health records represent patient data inconsistently for lack of clinical data standards. Classifications that have achieved common acceptance, such as the ICD-9-CM or ICD, aggregate heterogeneous patients into broad categories, which preclude their practical use in decision support, development of refined guidelines, or detailed comparison of patient outcomes or benchmarks. This document proposes a framework for the integration and maturation of clinical terminologies that would have practical applications in patient care, process management, outcome analysis, and decision support. Arising from the two working groups within the standards community--the ANSI (American National Standards Institute) Healthcare Informatics Standards Board Working Group and the Computer-based Patient Records Institute Working Group on Codes and Structures--it outlines policies regarding 1) functional characteristics of practical terminologies, 2) terminology models that can broaden their applications and contribute to their sustainability, 3) maintenance attributes that will enable terminologies to keep pace with rapidly changing health care knowledge and process, and 4) administrative issues that would facilitate their accessibility, adoption, and application to improve the quality and efficiency of American health care.

Embedded structures and representation of nursing knowledge.

Nursing Vocabulary Summit participants were challenged to consider whether reference terminology and information models might be a way to move toward better capture of data in electronic medical records. A requirement of such reference models is fidelity to representations of domain knowledge. This article discusses embedded structures in three different approaches to organizing domain knowledge: scientific reasoning, expertise, and standardized nursing languages. The concept of pressure ulcer is presented as an example of the various ways lexical elements used in relation to a specific concept are organized across systems. Different approaches to structuring information-the clinical information system, minimum data sets, and standardized messaging formats-are similarly discussed. Recommendations include identification of the polyhierarchies and categorical structures required within a reference terminology, systematic evaluations of the extent to which structured information accurately and completely represents domain knowledge, and modifications or extensions to existing multidisciplinary efforts.

Phase II evaluation of clinical coding schemes: completeness, taxonomy, mapping, definitions, and clarity. CPRI Work Group on Codes and Structures.

OBJECTIVE: To compare three potential sources of controlled clinical terminology (READ codes version 3.1, SNOMED International, and Unified Medical Language System (UMLS) version 1.6) relative to attributes of completeness, clinical taxonomy, administrative mapping, term definitions and clarity (duplicate coding rate). METHODS: The authors assembled 1929 source concept records from a variety of clinical information taken from four medical centers across the United States. The source data included medical as well as ample nursing terminology. The source records were coded in each scheme by an investigator and checked by the coding scheme owner. The codings were then scored by an independent panel of clinicians for acceptability. Codes were checked for definitions provided with the scheme. Codes for a random sample of source records were analyzed by an investigator for "parent" and "child" codes within the scheme. Parent and child pairs were scored by an independent panel of medical informatics specialists for clinical acceptability. Administrative and billing code mapping from the published scheme were reviewed for all coded records and analyzed by independent reviewers for accuracy. The investigator for each scheme exhaustively searched a sample of coded records for duplications. RESULTS: SNOMED was judged to be significantly more complete in coding the source material than the other schemes (SNOMED* 70%; READ 57%; UMLS 50%; *p < .00001). SNOMED also had a richer clinical taxonomy judged by the number of acceptable first-degree relatives per coded concept (SNOMED* 4.56, UMLS 3.17; READ 2.14, *p < .005). Only the UMLS provided any definitions; these were found for 49% of records which had a coding assignment. READ and UMLS had better administrative mappings (composite score: READ* 40.6%; UMLS* 36.1%; SNOMED 20.7%, *p < .00001), and SNOMED had substantially more duplications of coding assignments (duplication rate: READ 0%; UMLS 4.2%; SNOMED* 13.9%, *p < .004) associated with a loss of clarity. CONCLUSION: No major terminology source can lay claim to being the ideal resource for a computer-based patient record. However, based upon this analysis of releases for April 1995, SNOMED International is considerably more complete, has a compositional nature and a richer taxonomy. Is suffers from less clarity, resulting from a lack of syntax and evolutionary changes in its coding scheme. READ has greater clarity and better mapping to administrative schemes (ICD-10 and OPCS-4), is rapidly changing and is less complete. UMLS is a rich lexical resource, with mappings to many source vocabularies. It provides definitions for many of its terms. However, due to the varying granularities and purposes of its source schemes, it has limitations for representation of clinical concepts within a computer-based patient record.

The content coverage of clinical classifications. For The Computer-Based Patient Record Institute's Work Group on Codes & Structures.

BACKGROUND AND OBJECTIVE: Patient conditions and events are the core of patient record content. Computer-based records will require standard vocabularies to represent these data consistently, thereby facilitating clinical decision support, research, and efficient care delivery. To address whether existing major coding systems can serve this function, the authors evaluated major clinical classifications for their content coverage. METHODS: Clinical text from four medical centers was sampled from inpatient and outpatient settings. The resultant corpus of 14,247 words was parsed into 3,061 distinct concepts. These concepts were grouped into Diagnoses, Modifiers, Findings, Treatments and Procedures, and Other. Each concept was coded into ICD-9-CM, ICD-10, CPT, SNOMED III, Read V2, UMLS 1.3, and NANDA; a secondary reviewer ensured consistency. While coding, the information was scored: 0 = no match, 1 = fair match, 2 = complete match. RESULTS: ICD-9-CM had an overall mean score of 0.77 out of 2; its highest subscore was 1.61 for Diagnoses. ICD-10 scored 1.60 for Diagnoses, and 0.62 overall. The overall score of ICD-9-CM augmented by CPT was not materially improved at 0.82. The SNOMED International system demonstrated the highest score in every category, including Diagnoses (1.90), and had an overall score of 1.74. CONCLUSION: No classification captured all concepts, although SNOMED did notably the most complete job. The systems in major use in the United States, ICD-9-CM and CPT, fail to capture substantial clinical content. ICD-10 does not perform better than ICD-9-CM. The major clinical classifications in use today incompletely cover the clinical content of patient records; thus analytic conclusions that depend on these systems may be suspect.

Incidence and outcome of surgery for benign prostatic hyperplasia among residents of Rochester, Minnesota: 1980-87. A population-based study.

The incidence and outcome of surgery for benign prostatic hyperplasia (BPH) was studied in Rochester, Minnesota, during the period 1980-1987. Three hundred thirty Rochester men without a diagnosis of prostate or bladder cancer underwent prostatectomy for BPH for the first time. Mean and median ages were both seventy (range: 46-95). The incidence of initial prostatectomy for BPH among men forty-five years of age and older age-adjusted to the 1980 U.S. white male population was 642 cases per 100,000 persons per year (py). Among the 330 men undergoing initial prostatectomy for BPH, 14 (4.2%) had serious intraoperative complications, 32 (9.7%) were rehospitalized for urologic complications within thirty days of surgery, and 13 (3.9%) had other serious complications within thirty days after surgery, including 1 death (surgical mortality 0.3%). Forty-five patients (14%) required blood transfusions within thirty days of surgery. The likelihood of reoperation within six years of the initial surgery was 15.1 percent (95% CI 9.7, 20.6). Short- and long-term postoperative mortality was not statistically significantly different than expected based on age- and sex-specific mortality statistics for Rochester, Minnesota.

Urinary symptom and quality of life questions indicative of obstructive benign prostatic hyperplasia. Results of a pilot study.

In a pilot study of a urinary symptom and health-related quality-of-life questionnaire for benign prostatic hyperplasia (BPH), responses from 64 Mayo Clinic patients with cystoscopic evidence of obstructive BPH were compared with those of 14 men with no cystoscopic evidence of BPH and a community sample of 64 comparably aged men with no medical history of prostate enlargement. Questions which best discriminated between the groups were those dealing with urinary symptom frequency, bother due to urinary symptoms, and worry and concern about urinary problems. The results suggest that urinary-symptom-bother and worry due to urinary symptoms may be important additions to the more usual questions asked about urinary frequency in the identification of men with BPH. These findings are preliminary, however, and will be verified in an ongoing natural history study of BPH.