Obesity's effect on asthma extends to diagnostic criteria.

BACKGROUND: The use of inflammatory biomarkers to delineate the type of lung inflammation present in asthmatic subjects is increasingly common. However, the effect of obesity on these markers is unknown. OBJECTIVES: We aimed to determine the effect of obesity on conventional markers of inflammation in asthmatic subjects. METHODS: We performed secondary analysis of data from 652 subjects previously enrolled in 2 Asthma Clinical Research Network trials. We performed linear correlations between biomarkers and logistic regression analysis to determine the predictive value of IgE levels, blood eosinophil counts, and fraction of exhaled nitric oxide values in relationship to sputum eosinophil counts (>2%), as well as to determine whether cut points existed that would maximize the sensitivity and specificity for predicting sputum eosinophilia in the 3 weight groups. RESULTS: Overall, statistically significant but relatively weak correlations were observed among all 4 markers of inflammation. Within obese subjects, the only significant correlation found was between IgE levels and blood eosinophil counts (r = 0.33, P < .001); furthermore, all other correlations between inflammatory markers were approximately 0, including correlations with sputum eosinophil counts. In addition, the predictive value of each biomarker alone or in combination was poor in obese subjects. In fact, in obese subjects none of the biomarkers of inflammation significantly predicted the presence of high sputum eosinophil counts. Obese asthmatic subjects have lower cut points for IgE levels (268 IU), fraction of exhaled nitric oxide values (14.5 ppb), and blood eosinophil counts (96 cells/µL) than all other groups. CONCLUSIONS: In obese asthmatic subjects conventional biomarkers of inflammation are poorly predictive of eosinophilic airway inflammation. As such, biomarkers currently used to delineate eosinophilic inflammation in asthmatic subjects should be approached with caution in these subjects.

The association between body mass index and gastroesophageal reflux disease in the World Trade Center Health Program General Responder Cohort.

BACKGROUND: There is increasing concern about the obesity epidemic in the United States. Obesity is a potential risk factor for a number of chronic diseases, including gastroesophageal reflux disease (GERD). This analysis examined whether body mass index (BMI) was associated with physician-diagnosed GERD in World Trade Center (WTC) general responders. METHODS: 19,819 WTC general responders were included in the study. Cox proportional hazards regression models were used to compare time to GERD diagnosis among three BMI groups (normal (<25 kg/m(2) ), overweight (≥25 and <30 kg/m(2) ), and obese (≥30 kg/m(2) )). RESULTS: Among the responders, 43% were overweight and 42% were obese. The hazard ratio for normal versus overweight was 0.81 (95% Confidence Interval (CI), 0.75-0.88); normal versus obese 0.71 (95%CI, 0.66, 0.77); and overweight versus obese 0.88 (95%CI, 0.83-0.92). CONCLUSION: GERD diagnoses rates were higher in overweight and obese WTC responders. Am. J. Ind. Med. 59:761-766, 2016. © 2016 Wiley Periodicals, Inc.

Sex differences in asthma and gastroesophageal reflux disease incidence among the World Trade Center Health Program General Responder Cohort.

BACKGROUND: Asthma and gastroesophageal reflux disease (GERD) are two common conditions among the responders to the WTC attacks. This study examined whether the cumulative incidence rates of asthma and GERD differed by sex among 24,022 and 23,557 WTC responders, respectively. METHODS: Cox proportional hazards regression was used to examine the sex difference in the rate of onset of physician-diagnosed asthma or GERD, from 9/12/2001 through 12/31/2015. RESULTS: The cumulative incidence of asthma reached 23% for women and 17% for men by the end of 2015, and the cumulative incidence of GERD reached 45% for women and 38% for men. Comparing women to men, the hazard ratio was 1.48 (95% confidence interval (CI): 1.27, 1.74) for asthma, and 1.25 (95% CI: 1.13, 1.38) for GERD. CONCLUSIONS: WTC general responders have a substantial burden of asthma and GERD, with higher incidence in women. Am. J. Ind. Med. 59:815-822, 2016. © 2016 Wiley Periodicals, Inc.

Predictors of response to tiotropium versus salmeterol in asthmatic adults.

BACKGROUND: Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described. OBJECTIVE: We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response. METHODS: Data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute's Asthma Clinical Research Network's Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV1, morning peak expiratory flow (PEF), and asthma control days (ACDs). RESULTS: Although approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n = 90 and 78, respectively) and ACDs (n = 49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (n = 104) than salmeterol (n = 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P < .001) and morning PEF (odds ratio, 2.12; 95% CI, 1.12-4.01; P = 0.021), as did a decreased FEV1/forced vital capacity ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in FEV1/forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not. CONCLUSION: Although these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy.

Hemoglobin A1c testing is associated with improved pancreas utilization for transplant.

CONTEXT: Aging, higher prevalence of diabetes, worsening obesity, and hyperglycemia among potential donors increase the likelihood that pancreata will be declined by transplant centers. Hemoglobin A1c testing, also known as glycated hemoglobin testing, identifies a donor's average blood glucose concentration for the preceding 2 to 3 months and is the standard test for identifying prolonged periods of hyperglycemia. OBJECTIVE: To compare pancreas utilization rates before and after implementation of hemoglobin A1c testing. DESIGN: A retrospective study of data from the New York Organ Donor Network was conducted. Potential donors were defined as standard criteria donors who had no history of diabetes and were not seropositive for hepatitis B or C. Criteria for "ideal" potential pancreas donors were based on age, body mass index, lipase level, and terminal creatinine level. Potential donors who did not meet the criteria for ideal donors were considered "expanded" potential pancreas donors. Pancreas utilization rate was defined as the number of pancreata transplanted divided by the number of potential pancreas donors. RESULTS: Of 779 standard criteria donors, 691 (89%) were potential pancreas donors: 251 ideal (36%) and 440 expanded (64%) donors. In 2005 and 2006, before hemoglobin A1c testing, pancreas utilization rates were 21% and 18%, respectively. In 2008, 2009, and 2010, after hemoglobin A1c testing was incorporated, utilization rates were 27%, 28%, and 32%, respectively. Utilization of ideal donors increased from 33% to 51% (P= .003), and utilization of expanded donors increased from 11% to 17% (P= .05). Pancreas utilization increased 51.0%, and pancreas discards decreased 50.8% with the implementation of hemoglobin A1c testing. CONCLUSION: Hemoglobin A1c testing may increase utilization of ideal and expanded criteria pancreata.

The digital rectal examination (DRE) remains important - outcomes from a contemporary cohort of men undergoing an initial 12-18 core prostate needle biopsy.

INTRODUCTION: Indications for prostate needle biopsy (PNB) include elevated serum prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE). We evaluated a contemporary cohort of men undergoing PNB to determine cancer detection rates when stratified by DRE status. MATERIALS AND METHODS: The charts of 806 men who underwent a PNB were reviewed. Serum PSA was categorized as normal or abnormal according to age-specific criteria. A normal DRE was defined as a smooth, age-appropriate, asymmetric, or uniformly enlarged prostate. An abnormal DRE was defined by either a nodule or induration. Sensitivity, specificity, and predictive values were determined for an abnormal DRE and the diagnosis of prostate cancer. RESULTS: Within the cohort, 516 patients (64%) had a normal and 290 (36%) an abnormal DRE. Three hundred six (38%) men were diagnosed with prostate cancer of which 136 (44%) had an abnormal DRE. Fourteen percent of patients with prostate cancer had an isolated DRE abnormality. Furthermore, when specifically considering these 136 men with an abnormal DRE and prostate cancer, 43 (31%) had a normal age-specific PSA value. No differences in cancer detection rate were noted when stratifying by type of DRE abnormality. In this select cohort of patients undergoing prostate biopsy, an abnormal DRE had a sensitivity of 44%, specificity of 68%, positive predictive value (PPV) of 46%, and a negative predictive value (NPV) of 67% for detecting prostate cancer on biopsy. CONCLUSION: Almost 50% of men in our cohort diagnosed with prostate cancer had an abnormal DRE. While only 14% of all patients with prostate cancer had an isolated DRE abnormality, 31% of these men had normal age-specific PSA values. Such observations underscore the importance of the DRE for prostate cancer screening.

Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial.

CONTEXT: No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms. OBJECTIVE: To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma. DESIGN, SETTING, AND PARTICIPANTS: A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. INTERVENTIONS: For physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use. MAIN OUTCOME MEASURE: The primary outcome was time to treatment failure. RESULTS: There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3). CONCLUSION: Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00495157.

Identifying risk factors in renal allografts before transplant: machine-measured renal resistance and posttransplant allograft survival.

Enhancement of renal allograft function and survival in an era where expanded criteria donors are increasingly used requires validated selection criteria. The goal of this retrospective study was to evaluate the significance of pretransplant donor and allograft parameters to identify risk factors that can be used in a model to predict 1-year allograft outcomes. Donor demographic factors, donor type, and allograft parameters such as biopsy results and machine-measured renal resistance were correlated with 1-year graft outcome. The Kaplan-Meier method was used to estimate graft survival using the categorical predictors of donor type, donor age, and machine measured renal resistance at 1.5, 3, and 5 hours. The log-rank test was used to test the difference in survival curves between cohorts. The Cox regression analysis was used to estimate hazard ratios for machine-measured renal resistance, donor age, donor terminal creatinine level, donor's estimated glomerular filtration rate, cold ischemia time, and percent glomerulosclerosis. The data show that machine-measured renal resistance at 3 and 5 hours has a statistically significant inverse relationship to 1-year graft survival. All other risk factors had no correlation with 1-year graft survival. The machine-measured renal resistance at 3 hours is the earliest significant predictor of 1-year allograft outcome.

The kinetics of cardiopulmonary bypass: a dual-platform proteomics study of plasma biomarkers in pediatric patients undergoing cardiopulmonary bypass.

This study was designed to investigate the expression kinetics and patterns of plasma biomarkers throughout the pediatric cardiopulmonary bypass (CPB) procedure to help predict those patients most at risk for complications. This study sampled plasma from pediatric CPB patients at five time points before, during, and after CPB. A dual-platform proteomics approach was then utilized which incorporated two-dimensional difference gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption ionization-time-of-flight/time-of-flight tandem mass spectrometry, and multi-analyte profile (MAP) assays to identify changes in expression of plasma protein biomarkers and characterize the patterns of these changes. A combined total of 134 proteins were identified with significant changes between the two platforms, with 53 coming from 2D-DIGE, 90 from MAP, and nine proteins that were identified using both methods. The proteins were then divided into 12 major groups based on the expression patterns, and two of the most clinically relevant proteins having the greatest changes in expression were selected from each group to use as "predictor biomarkers." A potential model for prediction of patient outcome was then generated using these 24 proteins. The patterns of biomarker expression during pediatric CPB may provide insight into the prediction, prevention, or treatment of complications resulting from CPB, thereby helping to improve the outcomes of pediatric CPB patients and reduce the incidence of complications.

A large subgroup of mild-to-moderate asthma is persistently noneosinophilic.

RATIONALE: Airway eosinophilia is typical of asthma, and many controller treatments target eosinophilic disease. Asthma is clinically heterogeneous, however, and a subgroup of people with asthma do not have airway eosinophilia. The size of this subgroup is uncertain because prior studies have not examined repeated measures of sputum cytology to determine when people with asthma have intermittent versus persistent sputum eosinophila and when they are persistently noneosinophilic. OBJECTIVES: To determine the prevalence and clinical characteristics of the noneosinophilic asthma phenotype. METHODS: We analyzed sputum cytology data from 995 subjects with asthma enrolled in clinical trials in the Asthma Clinical Research Network where they had undergone sputum induction and measures of sputum cytology, often repeatedly, and assessment of responses to standardized asthma treatments. MEASUREMENTS AND MAIN RESULTS: In cross-sectional analyses, sputum eosinophilia (≥2% eosinophils) was found in only 36% of subjects with asthma not taking an inhaled corticosteroid (ICS) and 17% of ICS-treated subjects with asthma; an absence of eosinophilia was noted frequently, even in subjects with asthma whose disease was suboptimally controlled. In repeated measures analyses of people with asthma not taking an ICS, 22% of subjects had sputum eosinophilia on every occasion (persistent eosinophilia); 31% had eosinophilia on at least one occasion (intermittent eosinophilia); and 47% had no eosinophilia on every occasion (persistently noneosinophilic). Two weeks of combined antiinflammatory therapy caused significant improvements in airflow obstruction in eosinophilic asthma, but not in persistently noneosinophilic asthma. In contrast, bronchodilator responses to albuterol were similar in eosinophilic and noneosinophilic asthma. CONCLUSIONS: Approximately half of patients with mild-to-moderate asthma have persistently noneosinophilic disease, a disease phenotype that responds poorly to currently available antiinflammatory therapy.

The impact of race on organ donation authorization discussed in the context of liver transplantation.

Inadequate organ donation limits transplantation for many in need of a life-saving organ. Race of donor families and requesting coordinators may impact the authorization rate for organ donation. We evaluated authorization rates for organ donation within the New York Organ Donor Network by race during 2009 and 2010. The donation authorization rate varied considerably according to the race of the donor. The authorization rate was 57% for Hispanic, 53% for Caucasian, 48% for African-American, and 23% for Asian donor families. Fifty-five percent of donor families agreed to donation when there was racial concordance between coordinator and donor. Donation authorization was 49% when a racial mis-match existed. When adjusted for coordinator training and experience, racial discordance had a lesser impact on authorization rates. Our findings suggest the need for education and communication strategies to overcome racial-associated perception during the organ donation process.

Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma.

BACKGROUND: Improvement in lung function after macrolide antibiotic therapy has been attributed to reduction in bronchial infection by specific bacteria. However, the airway might be populated by a more diverse microbiota, and clinical features of asthma might be associated with characteristics of the airway microbiota present. OBJECTIVE: We sought to determine whether relationships exist between the composition of the airway bacterial microbiota and clinical features of asthma using culture-independent tools capable of detecting the presence and relative abundance of most known bacteria. METHODS: In this pilot study bronchial epithelial brushings were collected from 65 adults with suboptimally controlled asthma participating in a multicenter study of the effects of clarithromycin on asthma control and 10 healthy control subjects. A combination of high-density 16S ribosomal RNA microarray and parallel clone library-sequencing analysis was used to profile the microbiota and examine relationships with clinical measurements. RESULTS: Compared with control subjects, 16S ribosomal RNA amplicon concentrations (a proxy for bacterial burden) and bacterial diversity were significantly higher among asthmatic patients. In multivariate analyses airway microbiota composition and diversity were significantly correlated with bronchial hyperresponsiveness. Specifically, the relative abundance of particular phylotypes, including members of the Comamonadaceae, Sphingomonadaceae, Oxalobacteraceae, and other bacterial families were highly correlated with the degree of bronchial hyperresponsiveness. CONCLUSION: The composition of bronchial airway microbiota is associated with the degree of bronchial hyperresponsiveness among patients with suboptimally controlled asthma. These findings support the need for further functional studies to examine the potential contribution of members of the airway microbiota in asthma pathogenesis.

A trial of clarithromycin for the treatment of suboptimally controlled asthma.

BACKGROUND: PCR studies have demonstrated evidence of Mycoplasma pneumoniae and Chlamydophila pneumoniae in the lower airways of patients with asthma. OBJECTIVE: To test the hypothesis that clarithromycin would improve asthma control in individuals with mild-to-moderate persistent asthma that was not well controlled despite treatment with low-dose inhaled corticosteroids. METHODS: Adults with an Asthma Control Questionnaire score ≥1.5 after a 4-week period of treatment with fluticasone propionate were entered into a PCR-stratified randomized, controlled trial to evaluate the effect of 16 weeks of either clarithromycin or placebo, added to fluticasone, on asthma control in individuals with or without lower airway PCR evidence of M pneumoniae or C pneumoniae. RESULTS: A total of 92 participants were randomized. Twelve (13%) subjects demonstrated PCR evidence of M pneumoniae or C pneumoniae in endobronchial biopsies; 80 were PCR-negative for both organisms. In PCR-positive participants, clarithromycin yielded a 0.4 ± 0.4 unit improvement in the Asthma Control Questionnaire score, with a 0.1 ± 0.3 unit improvement in those allocated to placebo. This between-group difference of 0.3 ± 0.5 (P = .6) was neither clinically nor statistically significant. In PCR-negative participants, a nonsignificant between-group difference of 0.2 ± 0.2 units (P = .3) was observed. Clarithromycin did not improve lung function or airway inflammation but did improve airway hyperresponsiveness, increasing the methacholine PC(20) by 1.2 ± 0.5 doubling doses (P = .02) in the study population. CONCLUSION: Adding clarithromycin to fluticasone in adults with mild-to-moderate persistent asthma that was suboptimally controlled by low-dose inhaled corticosteroids alone did not further improve asthma control. Although there was an improvement in airway hyperresponsiveness with clarithromycin, this benefit was not accompanied by improvements in other secondary outcomes.

Tiotropium bromide step-up therapy for adults with uncontrolled asthma.

BACKGROUND: Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed. METHODS: In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison). RESULTS: The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003). CONCLUSIONS: When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).

Aeroallergen sensitization correlates with PC(20) and exhaled nitric oxide in subjects with mild-to-moderate asthma.

BACKGROUND: Aeroallergen sensitization in adult asthmatic patients from a wide geographic area has not been correlated with patients' characteristics, markers of airways inflammation, and lung function. OBJECTIVE: We assessed data obtained from the Asthma Clinical Research Network trials to determine the relationship of aeroallergen sensitization to age, sex, ethnicity, and markers of inflammation and airways function. METHODS: Skin testing (14 epicutaneous) was performed on 1338 subjects with objectively diagnosed mild-to-moderate asthma from 11 Asthma Clinical Research Network studies. Skin testing used identical techniques and a quality assurance program to ensure uniformity across centers. RESULTS: Ninety-five percent of the subjects had at least 1 positive skin test response. Of these, 14% had positive reactions to 1 or 2 allergens and 81% had positive reactions to 3 or more allergens, and 2% of subjects reacted only to seasonal allergens, 26% only to perennial allergens, and 67% to both. Increasing IgE and exhaled nitric oxide values, decreasing PC(20) values, and minority ethnicity significantly correlated with the number of positive skin test responses. Subjects with late-onset asthma were less likely to be sensitized; nonetheless, 89% of subjects older than 60 years had positive responses. CONCLUSION: Ninety-five percent of patients with mild-to-moderate asthma might have an allergic component. Age does not significantly affect aeroallergen sensitization, but the pattern of allergic sensitization varies with ethnicity and geography. Measures used to characterize asthma, such as IgE, exhaled nitric oxide, and PC(20) values, are correlated with aeroallergen sensitization.

Modelling clinical trials in heterogeneous samples.

Individual variation in genetic, phenotypic and environmental factors could lead to significant differences in rates of drug metabolism, in clinical responses to drugs, and in drug side effects. The impact of population heterogeneity on treatment effect estimation and on assessment and application of clinical trial findings has been less than fully studied. In this paper, we studied the properties of models that reflect population heterogeneity of clinical trial samples by unmeasured covariates such as genetic susceptibility. The impact of heterogeneity on the estimation of treatment effect in a two-armed placebo or active-controlled clinical trial was quantified using logistic regression models. We also proposed a two-stage clinical trial, where the effects of individual drug-response-related covariates were estimated in a 'training data set' in the first stage of the trial. In the second stage of the trial, a subgroup of individuals with enhanced (or reduced) sensitivity to drug treatments in a heterogeneous risk cohort was identified based on information about their drug-related characteristics. Only these 'responders' were included in the subsequent efficacy test. Our simulation results showed that population heterogeneity could lead to biased estimation of treatment effect not only in the contaminated groups but also in the uncontaminated groups. A two-stage trial could greatly increase the power of an efficacy test over a 'full trial' even with fewer individuals enrolled in the trial; results would apply to a more highly specified population. The bigger the covariate effects, the more efficient the two-stage trial is compared to a 'full trial'.

The impact of population heterogeneity on risk estimation in genetic counseling.

BACKGROUND: Genetic counseling has been an important tool for evaluating and communicating disease susceptibility for decades, and it has been applied to predict risks for a wide class of hereditary disorders. Most diseases are complex in nature and are affected by multiple genes and environmental conditions; it is highly likely that DNA tests alone do not define all the genetic factors responsible for a disease, so that persons classified into the same risk group by DNA testing actually could have different disease susceptibilities. Ignorance of population heterogeneity may lead to biased risk estimates, whereas additional information on population heterogeneity may improve the precision of such estimates. METHODS: Although DNA tests are widely used, few studies have investigated the accuracy of the predicted risks. We examined the impact of population heterogeneity on predicted disease risks by simulation of three different heterogeneity scenarios and studied the precision and accuracy of the risks estimated from a logistic regression model that ignored population heterogeneity. Moreover, we also incorporated information about population heterogeneity into our original model and investigated the resulting improvement in the accuracy of risk estimation. RESULTS: We found that heterogeneity in one or more categories could lead to biased estimates not only in the "contaminated" categories but also in other homogeneous categories. Incorporating information about population heterogeneity into the original model greatly improved the accuracy of risk estimation. CONCLUSIONS: Our findings imply that without thorough knowledge about genetic basis of the disease, risks estimated from DNA tests may be misleading. Caution should be taken when evaluating the predicted risks obtained from genetic counseling. On the other hand, the improved accuracy of risk estimates after incorporating population heterogeneity information into the model did point out a promising direction for genetic counseling, since more and more new techniques are being invented and disease etiology is being better understood.