Large gene panel sequencing in clinical diagnostics-results from 501 consecutive cases.

BACKGROUND: In addition to whole exomes, large gene panels of clinically associated genes are used as high-throughput sequencing tests in many clinical centers, but their clinical utility has been much less investigated. MATERIALS AND METHODS: Here we report the results of the 501 first unselected cases for whom TruSight One panel (Illumina Inc., San Diego, California) was sequenced as a clinical diagnostic test for a variety of indications in our department. The analysis was restricted to virtual subpanels based on referral forms, where doctors were asked to list candidate genes or select one from predefined larger panels. RESULTS: A probable or definite pathogenic finding was reported in 26.3% of cases. In 238 samples for whom 1 to 9 genes were requested for analysis, the diagnostic yield was significantly higher compared to other 263 cases for whom larger subpanels were requested (31.5% vs 21.7%, respectively, P = .016). Detected mutations included single nucleotide variants, small insertions and deletions, and larger copy number variants. Out of 157 reported mutations, 67 were previously undescribed. CONCLUSION: The clinical utility of large gene panel sequencing in the context of other genetic diagnostic tests is discussed in detail.

Physicians' knowledge, attitudes, and practice of pharmacologic treatment of hypertension.

OBJECTIVE: To explore how well physicians who treat hypertension know the indications and contraindications for particular antihypertensive therapies, and how closely their opinions and practice of hypertension treatment agree with national guidelines. METHODS: We surveyed by mail a stratified random sample of 10,000 US cardiologists, internists, and general/family practitioners. This survey explored their knowledge, attitudes, and practices with respect to the treatment of hypertension. Responses were compared with national guidelines and product labeling at the time of the survey. Results were stratified by physician specialty. RESULTS: A total of 1,023 physicians, or 10.2% of the sample, responded to the survey. Only 37.3% answered all four knowledge questions correctly, including 25.7% of general/family practitioners, 38.3% of internists, and 49.5% of cardiologists (p < 0.001). In their attitudes with respect to evaluating high blood pressure and establishing treatment goals, most respondents agreed with established guidelines. However, when asked how they would treat uncomplicated, mild hypertension, only 23% limited their selection to diuretics and beta-blockers in accordance with the guidelines. Cardiologists in particular were more likely than internists or general/family practitioners to choose other drug classes, such as angiotensin-converting enzyme Inhibitors or calcium-channel blockers. CONCLUSIONS: The results of our survey suggest that national efforts to educate physicians about the increasingly complex armamentarium for hypertension, and to persuade them to base their prescribing on the results of randomized, controlled trials of primary prevention, must be continued.

Using medication history to measure confounding by indication in assessing calcium channel blockers and other antihypertensive therapy.

Reported findings of elevated risk of adverse events associated with calcium channel blocker use in hypertensives may be due partly to unmeasured confounding by indication. To determine if such confounding occurs, we conducted a retrospective cohort analysis of 77 196 Pennsylvania Medicaid recipients aged 18 to 61 who were treated with antihypertensive medication between 1990 and 1992. All diagnoses and dispensed prescriptions during the year prior to study entry were examined. Prior recipients of multitherapy (n = 18 763) were more likely to have had previously diagnosed risk factors (OR = 1.31 [95% CI, 1.30-1.33]) than subjects with prior monotherapy (n = 11141). New initiators (n = 47292) were less likely to have had previously diagnosed risk factors (OR = 0.48 (95% CI, 0.47-0.49)) than previous users (n = 29904). The likelihood of being prescribed calcium channel blocker rather than other monotherapy was significantly higher for subjects diagnosed during the previous week with arteriosclerotic cardiovascular disease OR = 7.78 (95% CI, 2.72-22.28), P < 0.0001; angina OR = 2.92 (95% CI, 1.77-4.83), (P < 0.0001); diabetes OR = 1.49 (95% CI, 1.07-2.06), (P = 0.0004); and hypertension OR = 1.57 (95% CI 1.35-1.82), (P < 0.0001). Calcium channel blockers were selectively prescribed to subjects at elevated risk of adverse events. Confounding by indication was found in this large indigent population. Unmeasured confounding may contribute to overestimated relative risk of adverse events associated with calcium channel blocker therapy vs diuretics or beta-blockers. At least 1 full year of subjects' medical and prescription drug history should be examined prior to study entry; shorter observation periods will miss clinically relevant information about risk.

Feasibility of using recipients of health promotional newsletters for post-marketing surveillance.

Achieving an adequate sample size is one of the major difficulties in performing post-marketing observational studies of health outcomes in persons taking specific drug preparations. We assessed the feasibility of recruiting participants for such a study of Cardizem CD from approximately 400,000 U.S. recipients of a health promotion newsletter. A three-page questionnaire was sent to a 2.5% random sample (n = 10,000) of recipients, stratified by geographic region. After two mailings, 2779 (28%) returned the questionnaire. Of the 2779 respondents, 2132 (77%) reported having high blood pressure. Eighty-seven percent indicated a willingness to participate in a long-term prospective study. In a multivariate model, calcium channel blocker (CCB) use was associated with a history of coronary heart disease, duration of hypertension medication use greater than 1 year, a rating of good or excellent hypertension care, higher systolic blood pressure, higher education level, family history of cardiovascular disease, and history of smoking. These results indicate that self-reported CCB users may be at greater risk of cardiovascular heart disease and that it is feasible to use health promotion newsletters as a source of participants in prospective studies of cardiovascular disease.

Selective use of calcium channel blockers to treat high-risk hypertensive patients.

PURPOSE: While hypertension treatment is aimed at reducing cardiovascular disease (CVD) risk, there are reports of association between calcium channel blockers (CCB) use and increased risk. However, these studies may be misleading if CCBs are used selectively in high-risk patients. METHODS: We conducted a knowledge, attitudes, and practice (KAP) survey by mail of a stratified random sample of 10,000 US cardiologists, internists, and family/general practitioners. Completed surveys were received from 1023 physicians, and population means and frequencies (+/-standard errors) were estimated RESULTS: While only 36.3 (+/-0.6)% of physicians use long-acting CCBs for mild hypertension without additional risk factors, use increases with moderate or severe hypertension and other risk factors, including history of myocardial infarction (48.4 (+/-0.6)%), family history of CVD (54.6 (+/-0.6)%), diabetes (57.3 (+/-0.6)%), and angina (63.8 (+/-0.5)%). Physicians use CCBs as initial therapy for 24.8 (+/-0.3)% of mildly and 33.1 (+/-0.3)% of moderately hypertensive patients, and add CCBs to the regimens of 39.0 (+/-0.3)% of moderately hypertensive patients not controlled on other antihypertensive therapy. In multiple regression analysis, the proportion of hypertensive patients treated with CCBs was significantly elevated among geriatricians and physicians who believe severity of hypertension is an indication for their use. CONCLUSION: These findings suggest that CCBs are used selectively for high-risk hypertensive patients. Copyright (c) 2000 John Wiley & Sons, Ltd.

Epidemiology in the pharmaceutical industry.

A survey assessing the practice of epidemiology in the pharmaceutical industry was sent to all member companies and research affiliates of the Pharmaceutical Research and Manufacturers of America (PhRMA) and to six non-member companies. Eighty-three companies were surveyed. Screening questions established whether or not a company employed epidemiologists, had an epidemiology department, or contracted work to epidemiologists outside the company. The survey included questions about organizational structure, functional role of epidemiologists, epidemiology department activities within the company, and collaboration with external partners. The response rate was 90.4%. Of the responding companies, 40% employed epidemiologists, 20% had epidemiology departments, and 36% utilized epidemiologists contracted outside the company. Eighty per cent of companies that employed epidemiologists also contracted epidemiology services outside of the company, while 6.7% of companies that did not employ epidemiologists utilized outside epidemiology services. Among all companies 42.7% employed or utilized epidemiologists. Differences were found in the extent to which large, medium and small pharmaceutical companies employ and utilize epidemiologists. The survey demonstrates that epidemiologists perform many roles within the pharmaceutical industry; that there are many potential opportunities for epidemiologists in this industry and that increased emphasis on safety will require more epidemiology training and recruitment efforts. Copyright (c) 2000 John Wiley & Sons, Ltd.

The incidence of epilepsy and unprovoked seizures in multiethnic, urban health maintenance organizations.

PURPOSE: Studies of the incidence of epilepsy are limited to a few populations in which new cases can be ascertained. Health maintenance organization (HmO) populations were studied to determine the incidence in a multiethnic, urban United States population. METHODS: Cases of initial unprovoked seizure disorder or epilepsy while enrolled in an HMO between 1988 and 1994 were ascertained. Ethnicity was obtained from the medical records and was part of a nested case-control study. RESULTS: There were 197 incidence cases of epilepsy and 275 of initial unprovoked seizure diagnosis. The incidence rate in the age range 0-64 years was 35.5 per 100,000 for epilepsy and 50.9 for initial unprovoked seizure. When compared with population-based studies, rates were slightly higher in children younger than 15, similar for the 15- to 24-year age group, but lower for ages 25-64 years. The ethnicity-specific odds ratios for initial unprovoked seizure, by using non-Hispanic white as the referent, were 1.04 (0.73-1.49) for African-American, 0.97 (0.64-1.48) for Hispanic, and 0.25 (0.08-0.84) for Asian-American. CONCLUSIONS: The lower rate in the HMO population is presumably due to a healthy-worker effect. The ethnicity-specific incidence rates do not differ in this population.

Mortality and survival for Minamata disease.

Analysis of mortality of 439 deaths that occurred among 1483 patients with Minamata disease (MD) in Kumamoto Prefecture, Japan was performed from the end of 1981. Causes of death and survival rates were studied by means of the standardized mortality ratio (SMR) and life-table technique. Of the 439 deaths (29.6%) in MD cases, the first death occurred in 1954. There was a first peak incidence in 1956 when MD was initially reported, however, the majority of deaths occurred after 1972 when a second and much larger peak was evident. In 1970 an important milestone occurred when the Public Nuisance Relief Law (an anti-pollution law) was enacted. Among its provisions, this law required and enabled verification of MD among people suspected of having been exposed. In contrast to the early cases, later cases of MD were older and their mean age-at-death was not different from that of the general population. The mortality rate for all causes of death was significantly higher in both sexes compared to the general population. Significantly lower survival rates were noted for older patients. The cause-specific mortality rates also showed significantly increased SMRs for liver diseases and nephritis-nephrosis-nephrotic syndrome in male patients, and for nephritis-nephrosis-nephrotic syndrome and other diseases in females. On the other hand, the SMR for senility without mention of psychosis was significantly lower than expected in both sexes.

Community exposure to hazardous waste disposal sites: assessing reporting bias.

A household health survey of residents living near two hazardous waste disposal sites in Calcasieu Parish, Louisiana was conducted in 1981-1982 as part of a comprehensive study of the effects of those sites on the environment and on the health of nearby residents. An unexposed community was included in the health survey for comparison. Due to media coverage and public concern about the sites, two potential indices of reporting bias, hypochondriasis and respondent's opinion about the environmental effects of waste sites, were included in the survey. Because air and water quality data showed little evidence that hazardous concentrations of chemicals were being released from the sites, questions were raised about the interpretation of the health survey data. The data were analyzed, therefore, for the association between symptom reports and the potential indices of reporting bias. Hypochondriasis scores were associated with symptom reports regardless of location of residence while an individual's opinion showed a different pattern by area of residence. Respondents living near one of the waste disposal sites who answered "yes" to the opinion question were 2-3 times more likely to report some types of symptoms than residents of the comparison community. In contrast, there was little difference in symptom reports between the exposed and comparison communities for those answering "no" to the opinion question. The usefulness of self-reported symptom data in studies of communities near hazardous waste disposal sites is discussed, and attention is called to the need to develop measures sensitive to reporting bias in epidemiologic studies.

Prevalence of bone demineralization in the United States.

A study of the distribution and prevalence of bone demineralization in the US population is reported. Based on the HANES I Survey data that incorporated bone density examination of V-2 by the Goldsmith and Vose techniques in a national sample of 6030 adults, it was observed that (1) age-adjusted bone density differences between sexes were consistently found when controlling for race (the prevalence of low bone density was greater among females than males) and (2) whites of both sexes had higher prevalence of low density than blacks in most age-sex categories.

Low-back pain in industry. An old problem revisited.

Low-back pain is a major occupational health problem. Risk factors predisposing to the development of low-back pain are discussed. These include individual risk factors such as age, sex, anthropometry, musculoskeletal abnormalities, muscle strength and physical fitness, psychological factors, and previous attacks of low-back pain and workplace factors such as heavy work, lifting, bending, and slipping. Various programs for prevention are evaluated. These include selection of workers, education and training regarding lifting methods, design of lifting jobs, and fitness training. Limitations of the various studies of these programs are discussed. Preemployment strength testing and ergonomic job design together appear to offer the greatest promise.

Causes of death in Minamata disease: analysis of death certificates.

The causes of death in Minamata disease were analyzed and compared with those of control subjects. Of the 1422 Minamata disease patients in the Kumamoto Prefecture, 378 had died by the end of 1980. Of these 378, the first death occurred in 1954 with a peak incidence in 1956 when Minamata disease was officially reported for the first time. The number of deaths increased rapidly after 1972 with a second peak in 1976. The male:female ratio was 1.8:1 and the mean age-at-death was 67.2 years (SD = +/- 18.65). The mean age-at-death was younger in the cases of the initial outbreak than in those recently. There were, on the average, 2.8 causes of death per person. Of these cases, 157 (41.5%) had Minamata disease indicated on the death certificate, though 64 (16.9%) had Minamata disease coded as the underlying cause. Minamata disease and the noninflammatory diseases of the central nervous system (CNS) were the main underlying causes of death between 1954 and 1969, while, in the multiple cause data, pneumonia and non-ischemic heart disease were the most prevalent. Cerebrovascular diseases (18.0%) were the main underlying causes of death followed by malignant neoplasms (14.7%), cardiovascular diseases (14.1%) and Minamata disease (14.1%) in 1970 or later, while cardiovascular diseases (18.6%), Minamata disease (14.5%), cerebrovascular diseases (10.4%) and malignant neoplasms (7.1%) were the major multiple causes of death. As compared with the control, the proportions of deaths due to noninflammatory diseases of CNS and pneumonia were higher in the initial outbreak. Although the difference in the causes of death was less apparent recently, malignant neoplasms and hypertensive diseases tended to be lower. These results suggest that there is a need for a long-term follow-up of Minamata disease patients. The data also show the potential value of multiple causes of death coding in analyses of mortality.

Effects of cost-sharing on users of a state's health service program.

This study analyzed some of the effects of the introduction of cost-sharing on users of the state's health service program. The study population had previously received services at no charge and consisted of people with provider-determined medical need, and included, but was not limited to people in financial need. The study sample was selected from 3 years of program service records (1977-1980). Sampling was random and stratified by key variables. Time-series analysis as well as pre/post-policy comparisons were employed. Analysis of changes in the distributions of service user characteristics and in services provided indicated that use of services was not affected adversely and that lower-income, medically needy people were not deterred from using services following the introduction of cost-sharing. Limitations to the study are reviewed, and implications of using cost-sharing in programs such as Medicaid are considered.

Increased reporting of menstrual symptoms among women who used induced abortion.

A mail survey was conducted among 3,222 Japanese women 20 to 44 years of age to determine and compare the characteristics of menstruation among women with and without a history of induced abortion. Women with prior abortion consistently reported an excess of symptoms in all age groups. While it is not yet known whether induced abortion results in a physiologic change in the uterus, it is suggested that a psychic component may be present by which women with prior abortion perceive their menses differently than nonabortion respondents.