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

Dietary garlic and hip osteoarthritis: evidence of a protective effect and putative mechanism of action

Background Patterns of food intake and prevalent osteoarthritis of the hand, hip, and knee were studied using the twin design to limit the effect of confounding factors. Compounds found in associated food groups were further studied in vitro. Methods Cross-sectional study conducted in a large population-based volunteer cohort of twins. Food intake was evaluated using the Food Frequency Questionnaire; OA was determined using plain radiographs. Analyses were adjusted for age, BMI and physical activity. Subsequent in vitro studies examined the effects of allium-derived compounds on the expression of matrix-degrading proteases in SW1353 chondrosarcoma cells. Results Data were available, depending on phenotype, for 654-1082 of 1086 female twins (median age 58.9 years; range 46-77). Trends in dietary analysis revealed a specific pattern of dietary intake, that high in fruit and vegetables, showed an inverse association with hip OA (p = 0.022). Consumption of 'non-citrus fruit' (p = 0.015) and 'alliums' (p = 0.029) had the strongest protective effect. Alliums contain diallyl disulphide which was shown to abrogate cytokine-induced matrix metalloproteinase expression. Conclusions Studies of diet are notorious for their confounding by lifestyle effects. While taking account of BMI, the data show an independent effect of a diet high in fruit and vegetables, suggesting it to be protective against radiographic hip OA. Furthermore, diallyl disulphide, a compound found in garlic and other alliums, represses the expression of matrix-degrading proteases in chondrocyte-like cells, providing a potential mechanism of action

Increasing student engagement through virtual interactions: how?

Our ongoing research is focusing on identifying and taxonomising the elements and the factors that affect learner engagement with virtual worlds when hybrid virtual learning models are used. Our main hypothesis links learner engagement with interactions, both in the virtual world and in the physical classroom. In order to examine this subject, there is an elaboration on and consideration of aspects such as the learners’ prior experiences in the use of virtual worlds, their preconceptions about using them as a learning tool and the impact that the instructional designers’ choices have on enhancing the opportunities for interactions. In this paper, we examine the impact that the orientation process has on university students who study computer science and have almost no experience in the use of virtual worlds. Our findings suggest that the orientation process contributed positively to students’ smooth induction and that resulted in having meaningful and engaging interactions. Furthermore, students’ simultaneous coexistence in both environments eliminated the drawbacks of each educational approach and broadened the network of interactions

An educational game for teaching clinical practice guidelines to Internal Medicine residents: development, feasibility and acceptability

<p>Abstract</p> <p>Background</p> <p>Adherence to Clinical Practice Guidelines (CPGs) remains suboptimal among internal medicine trainees. Educational games are of growing interest and have the potential to improve adherence to CPGs. The objectives of this study were to develop an educational game to teach CPGs in Internal Medicine residency programs and to evaluate its feasibility and acceptability.</p> <p>Methods</p> <p>We developed the Guide-O-Game^©in the format of a TV game show with questions based on recommendations of CPGs. The development of the Guide-O-Game^©consisted of the creation of a multimedia interactive tool, the development of recommendation-based questions, and the definition of the game's rules. We evaluated its feasibility through pilot testing and its acceptability through a qualitative process.</p> <p>Results</p> <p>The multimedia interactive tool uses a Macromedia Flash web application and consists of a manager interface and a user interface. The user interface allows the choice of two game styles. We created so far 16 sets of questions relating to 9 CPGs. The pilot testing proved that the game was feasible. The qualitative evaluation showed that residents considered the game to be acceptable.</p> <p>Conclusion</p> <p>We developed an educational game to teach CPGs to Internal Medicine residents that is both feasible and acceptable. Future work should evaluate its impact on educational outcomes.</p

Correlation of breast cancer risk factors with HER-2/neu protein overexpression according to menopausal and estrogen receptor status

BACKGROUND: Several researchers have claimed that classification of tumours on the basis of HER-2/neu overexpression or amplification may define a subset of breast cancer in which the net effect of a risk factor could be rather more obvious and its impact on breast cancer development more clear. We decided to investigate, in a group of patients from a geographical area with a low incidence of breast cancer, whether HER-2/neu positive tumours are correlated with established or suspected risk factors for breast cancer and thus to identify distinct subgroups of high risk women. METHODS: This study analysed data from patients who attended the Breast Unit at the University Hospital of Heraklion, Crete, Greece between 1996 and 2002. 384 women with primary invasive breast cancer were compared with 566 screened women who were referred to the Unit and had not developed breast neoplasm by the time the data were analysed. Risk factor data were obtained from each subject by personal interviews using a structured questionnaire. The detection and scoring of the HER-2/neu protein, estrogen and progesterone receptor expression were performed using immunochemistry. Odds ratios and 95% confidence intervals were determined by chi-square test and logistic regression analysis. Case-case odds ratios were calculated in order to measure the risk heterogeneity between HER-2/neu+ and HER-2/neu-tumours. Separate analyses were performed for premenopausal and postmenopausal women and according to estrogen receptor status. RESULTS: In multivariate analysis without HER-2/neu stratification, an increased breast cancer risk was associated with only four of the factors examined: use of oral contraceptives (OR = 4.40, 95%C.I: 1.46–13.28), use of HRT (OR = 7.34, 95%C.I: 2.03–26.53), an age at first full pregnancy more than 23 years (OR = 1.91, 95%C.I: 1.29–2.83) and body mass index more than 29 kg/m(2 )(OR = 3.13, 95%C.I: 2.02–4.84). Additionally, a history of abortion or miscarriage (OR = 0.56, 95%C.I: 0.38–0.82) was correlated with a decreased risk of breast cancer. In the case to case comparison only BMI >29 kg/m(2 )revealed a relative connection that was stronger with positive than with negative HER-2/neu tumours (ratio of OR's = 2.23, 95%C.I: 1.20–4.15, p = 0.011). This may indicate evidence of heterogeneity of a rather significant degree for this factor. In the ER negative group an age at first full pregnancy >23 years and a BMI >29 kg/m(2 )were associated with an increased risk in both HER-2/neu groups, but the association was significantly stronger for the latter factor in the positive HER-2/neu tumours (ratio of OR's = 2.46, 95%CI: 0.97–6.21). CONCLUSIONS: Our study did not confirm that the established or putative hormonal breast cancer risk factors differ regarding their relations with HER-2/neu+ versus HER-2/neu-breast tumours, with the exception of increased BMI. Further innovative studies with larger sample sizes are needed to examine how the status of these potentially modifiable breast cancer risk factors interacts with biological markers such as HER-2/neu oncoprotein

Modelling the Dynamics of Feral Alfalfa Populations and Its Management Implications

BACKGROUND: Feral populations of cultivated crops can pose challenges to novel trait confinement within agricultural landscapes. Simulation models can be helpful in investigating the underlying dynamics of feral populations and determining suitable management options. METHODOLOGY/PRINCIPAL FINDINGS: We developed a stage-structured matrix population model for roadside feral alfalfa populations occurring in southern Manitoba, Canada. The model accounted for the existence of density-dependence and recruitment subsidy in feral populations. We used the model to investigate the long-term dynamics of feral alfalfa populations, and to evaluate the effectiveness of simulated management strategies such as herbicide application and mowing in controlling feral alfalfa. Results suggest that alfalfa populations occurring in roadside habitats can be persistent and less likely to go extinct under current roadverge management scenarios. Management attempts focused on controlling adult plants alone can be counterproductive due to the presence of density-dependent effects. Targeted herbicide application, which can achieve complete control of seedlings, rosettes and established plants, will be an effective strategy, but the seedbank population may contribute to new recruits. In regions where roadside mowing is regularly practiced, devising a timely mowing strategy (early- to mid-August for southern Manitoba), one that can totally prevent seed production, will be a feasible option for managing feral alfalfa populations. CONCLUSIONS/SIGNIFICANCE: Feral alfalfa populations can be persistent in roadside habitats. Timely mowing or regular targeted herbicide application will be effective in managing feral alfalfa populations and limit feral-population-mediated gene flow in alfalfa. However, in the context of novel trait confinement, the extent to which feral alfalfa populations need to be managed will be dictated by the tolerance levels established by specific production systems for specific traits. The modelling framework outlined in this paper could be applied to other perennial herbaceous plants with similar life-history characteristics

Payer leverage and hospital compliance with a benchmark: a population-based observational study

<p>Abstract</p> <p>Background</p> <p>Since 1976, Medicare has linked reimbursement for hospitals performing organ transplants to the attainment of certain benchmarks, including transplant volume. While Medicare is a stakeholder in all transplant services, its role in renal transplantation is likely greater, given its coverage of end-stage renal disease. Thus, Medicare's transplant experience allows us to examine the role of payer leverage in motivating hospital benchmark compliance.</p> <p>Methods</p> <p>Nationally representative discharge data for kidney (<it>n </it>= 29,272), liver (<it>n </it>= 7,988), heart (<it>n </it>= 3,530), and lung (<it>n </it>= 1,880) transplants from the Nationwide Inpatient Sample (1993 – 2003) were employed. Logistic regression techniques with robust variance estimators were used to examine the relationship between hospital volume compliance and Medicare market share; generalized estimating equations were used to explore the association between patient-level operative mortality and hospital volume compliance.</p> <p>Results</p> <p>Medicare's transplant market share varied by organ [57%, 28%, 27%, and 18% for kidney, lung, heart, and liver transplants, respectively (<it>P </it>< 0.001)]. Volume-based benchmark compliance varied by transplant type [85%, 75%, 44%, and 39% for kidney, liver, heart, and lung transplants, respectively (<it>P </it>< 0.001)], despite a lower odds of operative mortality at compliant hospitals. Adjusting for organ supply, high market leverage was independently associated with compliance at hospitals transplanting kidneys (OR, 143.00; 95% CI, 18.53 – 1103.49), hearts (OR, 2.84; 95% CI, 1.51 – 5.34), and lungs (OR, 3.24; 95% CI, 1.57 – 6.67).</p> <p>Conclusion</p> <p>These data highlight the influence of payer leverage–an important contextual factor in value-based purchasing initiatives. For uncommon diagnoses, these data suggest that at least 30% of a provider's patients might need to be "at risk" for an incentive to motivate compliance.</p

Ambient air pollution and the prevalence of rhinoconjunctivitis in adolescents: A worldwide ecological analysis

Whether exposure to outdoor air pollution increases the prevalence of rhinoconjunctivitis in children is unclear. Using data from Phase Three of the International Study of Asthma and Allergies in childhood (ISAAC), we investigated associations of rhinoconjunctivitis prevalence in adolescents with model-based estimates of ozone, and satellite-based estimates of fine (diameter < 2.5 μm) particulate matter (PM2.5) and nitrogen dioxide (NO2). Information on rhinoconjunctivitis (defined as self-reported nose symptoms without a cold or flu accompanied by itchy watery eyes in the past 12 months) was available on 505,400 children aged 13–14 years, in 183 centres in 83 countries. Centre-level prevalence estimates were calculated and linked geographically with estimates of long-term average concentrations of NO2, ozone and PM2.5. Multi-level models were fitted adjusting for population density, climate, sex and gross national income. Information on parental smoking, truck traffic and cooking fuel was available for a restricted set of centres (77 in 36 countries). Between centres within countries, the estimated change in rhinoconjunctivitis prevalence per 100 children was 0.171 (95% confidence interval: − 0.013, 0.354) per 10% increase in PM2.5, 0.096 (− 0.003, 0.195) per 10% increase in NO2 and − 0.186 (− 0.390, 0.018) per 1 ppbV increase in ozone. Between countries, rhinoconjunctivitis prevalence was significantly negatively associated with both ozone and PM2.5. In the restricted dataset, the latter association became less negative following adjustment for parental smoking and open fires for cooking. In conclusion, there were no significant within-country associations of rhinoconjunctivitis prevalence with study pollutants. Negative between-country associations with PM2.5 and ozone require further investigation

Supportive interventions to improve physiological and psychological health outcomes among patients undergoing cystectomy: A systematic review

Background Our understanding of effective perioperative supportive interventions for patients undergoing cystectomy procedures and how these may affect short and long-term health outcomes is limited. Methods Randomised controlled trials involving any non-surgical, perioperative interventions designed to support or improve the patient experience for patients undergoing cystectomy procedures were reviewed. Comparison groups included those exposed to usual clinical care or standard procedure. Studies were excluded if they involved surgical procedure only, involved bowel preparation only or involved an alternative therapy such as aromatherapy. Any short and long-term outcomes reflecting the patient experience or related urological health outcomes were considered. Results 19 articles (representing 15 individual studies) were included for review. Heterogeneity in interventions and outcomes across studies meant meta-analyses were not possible. Participants were all patients with bladder cancer and interventions were delivered over different stages of the perioperative period. The overall quality of evidence and reporting was low and outcomes were predominantly measured in the short-term. However, the findings show potential for exercise therapy, pharmaceuticals, ERAS protocols, psychological/educational programmes, chewing gum and nutrition to benefit a broad range of physiological and psychological health outcomes. Conclusions Supportive interventions to date have taken many different forms with a range of potentially meaningful physiological and psychological health outcomes for cystectomy patients. Questions remain as to what magnitude of short-term health improvements would lead to clinically relevant changes in the overall patient experience of surgery and long-term recovery

Re-interpreting conventional interval estimates taking into account bias and extra-variation

BACKGROUND: The study design with the smallest bias for causal inference is a perfect randomized clinical trial. Since this design is often not feasible in epidemiologic studies, an important challenge is to model bias properly and take random and systematic variation properly into account. A value for a target parameter might be said to be "incompatible" with the data (under the model used) if the parameter's confidence interval excludes it. However, this "incompatibility" may be due to bias and/or extra-variation. DISCUSSION: We propose the following way of re-interpreting conventional results. Given a specified focal value for a target parameter (typically the null value, but possibly a non-null value like that representing a twofold risk), the difference between the focal value and the nearest boundary of the confidence interval for the parameter is calculated. This represents the maximum correction of the interval boundary, for bias and extra-variation, that would still leave the focal value outside the interval, so that the focal value remained "incompatible" with the data. We describe a short example application concerning a meta analysis of air versus pure oxygen resuscitation treatment in newborn infants. Some general guidelines are provided for how to assess the probability that the appropriate correction for a particular study would be greater than this maximum (e.g. using knowledge of the general effects of bias and extra-variation from published bias-adjusted results). SUMMARY: Although this approach does not yet provide a method, because the latter probability can not be objectively assessed, this paper aims to stimulate the re-interpretation of conventional confidence intervals, and more and better studies of the effects of different biases