Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population.

BACKGROUND AND OBJECTIVES: Allelic variants in UMOD, the gene coding for uromodulin, are associated with rare tubulointerstitial kidney disorders and risk of CKD and hypertension in the general population. The factors associated with uromodulin excretion in the normal population remain largely unknown, and were therefore explored in this study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Urinary uromodulin excretion was measured using a validated ELISA in two population-based cohorts that included more than 6500 individuals. The Swiss Kidney Project on Genes in Hypertension study (SKIPOGH) included 817 adults (mean age±SD, 45±17 years) who underwent renal ultrasonography and performed a 24-hour urine collection. The Cohorte Lausannoise study included 5706 adults (mean age, 53±11 years) with fresh spot morning urine samples. We calculated eGFRs using the CKD-Epidemiology Collaboration formula and by 24-hour creatinine clearance. RESULTS: In both studies, positive associations were found between uromodulin and urinary sodium, chloride, and potassium excretion and osmolality. In SKIPOGH, 24-hour uromodulin excretion (median, 41 [interquartile range, 29-57] mg/24 h) was positively associated with kidney length and volume and with creatinine excretion and urine volume. It was negatively associated with age and diabetes. Both spot uromodulin concentration and 24-hour uromodulin excretion were linearly and positively associated (multivariate analyses) with eGFR<90 ml/min per 1.73 m(2). CONCLUSION: Age, creatinine excretion, diabetes, and urinary volume are independent clinical correlates of urinary uromodulin excretion. The associations of uromodulin excretion with markers of tubular functions and kidney dimensions suggest that it may reflect tubule activity in the general population.

Little evidence for association between the TGFBR1*6A variant and colorectal cancer: a family-based association study on non-syndromic family members from Australia and Spain.

Genome-wide linkage studies have identified the 9q22 chromosomal region as linked with colorectal cancer (CRC) predisposition. A candidate gene in this region is transforming growth factor beta receptor 1 (TGFBR1). Investigation of TGFBR1 has focused on the common genetic variant rs11466445, a short exonic deletion of nine base pairs which results in truncation of a stretch of nine alanine residues to six alanine residues in the gene product. While the six alanine (*6A) allele has been reported to be associated with increased risk of CRC in some population based study groups this association remains the subject of robust debate. To date, reports have been limited to population-based case-control association studies, or case-control studies of CRC families selecting one affected individual per family. No study has yet taken advantage of all the genetic information provided by multiplex CRC families. Methods: We have tested for an association between rs11466445 and risk of CRC using several family-based statistical tests in a new study group comprising members of non-syndromic high risk CRC families sourced from three familial cancer centres, two in Australia and one in Spain. Results: We report a finding of a nominally significant result using the pedigree-based association test approach (PBAT; p = 0.028), while other family-based tests were non-significant, but with a p-value < 0.10 in each instance. These other tests included the Generalised Disequilibrium Test (GDT; p = 0.085), parent of origin GDT Generalised Disequilibrium Test (GDT-PO; p = 0.081) and empirical Family-Based Association Test (FBAT; p = 0.096, additive model). Related-person case-control testing using the 'More Powerful' Quasi-Likelihood Score Test did not provide any evidence for association (M-QL5; p = 0.41). Conclusions: After conservatively taking into account considerations for multiple hypothesis testing, we find little evidence for an association between the TGFBR1*6A allele and CRC risk in these families. The weak support for an increase in risk in CRC predisposed families is in agreement with recent meta-analyses of case-control studies, which estimate only a modest increase in sporadic CRC risk among 6*A allele carriers.

ContinuousMultimodal Global Optimization with Differential Evolution-Based Methods

Metaheuristic methods have become increasingly popular approaches in solving global optimization problems. From a practical viewpoint, it is often desirable to perform multimodal optimization which, enables the search of more than one optimal solution to the task at hand. Population-based metaheuristic methods offer a natural basis for multimodal optimization. The topic has received increasing interest especially in the evolutionary computation community. Several niching approaches have been suggested to allow multimodal optimization using evolutionary algorithms. Most global optimization approaches, including metaheuristics, contain global and local search phases. The requirement to locate several optima sets additional requirements for the design of algorithms to be effective in both respects in the context of multimodal optimization. In this thesis, several different multimodal optimization algorithms are studied in regard to how their implementation in the global and local search phases affect their performance in different problems. The study concentrates especially on variations of the Differential Evolution algorithm and their capabilities in multimodal optimization. To separate the global and local search search phases, three multimodal optimization algorithms are proposed, two of which hybridize the Differential Evolution with a local search method. As the theoretical background behind the operation of metaheuristics is not generally thoroughly understood, the research relies heavily on experimental studies in finding out the properties of different approaches. To achieve reliable experimental information, the experimental environment must be carefully chosen to contain appropriate and adequately varying problems. The available selection of multimodal test problems is, however, rather limited, and no general framework exists. As a part of this thesis, such a framework for generating tunable test functions for evaluating different methods of multimodal optimization experimentally is provided and used for testing the algorithms. The results demonstrate that an efficient local phase is essential for creating efficient multimodal optimization algorithms. Adding a suitable global phase has the potential to boost the performance significantly, but the weak local phase may invalidate the advantages gained from the global phase.

Web-Based Extension Studies in Medical Calculation

Nordic forum for nursing teachers. Wednesday - Friday 9-11 November 2011 Ounasvaara Campus School of Heath Care and Sports Rovaniemi University of Applied Sciences

Promoting Healthy Lifestyles with Personalized, APOE Genotype Based Health Information: The Effects on Psychological-, Health Behavioral and Clinical Factors

There is an increasing demand for individualized, genotype-based health advice. The general population-based dietary recommendations do not always motivate people to change their life-style, and partly following this, cardiovascular diseases (CVD) are a major cause of death in worldwide. Using genotype-based nutrition and health information (e.g. nutrigenetics) in health education is a relatively new approach, although genetic variation is known to cause individual differences in response to dietary factors. Response to changes in dietary fat quality varies, for example, among different APOE genotypes. Research in this field is challenging, because several non-modifiable (genetic, age, sex) and modifiable (e.g. lifestyle, dietary, physical activity) factors together and with interaction affect the risk of life-style related diseases (e.g. CVD). The other challenge is the psychological factors (e.g. anxiety, threat, stress, motivation, attitude), which also have an effect on health behavior. The genotype-based information is always a very sensitive topic, because it can also cause some negative consequences and feelings (e.g. depression, increased anxiety). The aim of this series of studies was firstly to study how individual, genotype-based health information affects an individual’s health form three aspects, and secondly whether this could be one method in the future to prevent lifestyle-related diseases, such as CVD. The first study concentrated on the psychological effects; the focus of the second study was on health behavior effects, and the third study concentrated on clinical effects. In the fourth study of this series, the focus was on all these three aspects and their associations with each other. The genetic risk and health information was the APOE gene and its effects on CVD. To study the effect of APOE genotype-based health information in prevention of CVD, a total of 151 volunteers attended the baseline assessments (T0), of which 122 healthy adults (aged 20 – 67 y) passed the inclusion criteria and started the one-year intervention. The participants (n = 122) were randomized into a control group (n = 61) and an intervention group (n = 61). There were 21 participants in the intervention Ɛ4+ group (including APOE genotypes 3/4 and 4/4) and 40 participants in the intervention Ɛ4- group (including APOE genotypes 2/3 and 3/3). The control group included 61 participants (including APOE genotypes 3/4, 4/4, 2/3, 3/3 and 2/2). The baseline (T0) and follow-up assessments (T1, T2, T3) included detailed measurements of psychological (threat and anxiety experience, stage of change), and behavioral (dietary fat quality, consumption of vegetables, - high fat/sugar foods and –alcohol, physical activity and health and taste attitudes) and clinical factors (total-, LDL- HDL cholesterol, triglycerides, blood pressure, blood glucose (0h and 2h), body mass index, waist circumference and body fat percentage). During the intervention six different communication sessions (lectures on healthy lifestyle and nutrigenomics, health messages by mail, and personal discussion with the doctor) were arranged. The intervention groups (Ɛ4+ and Ɛ4-) received their APOE genotype information and health message at the beginning of the intervention. The control group received their APOE genotype information after the intervention. For the analyses in this dissertation, the results for 106/107 participants were analyzed. In the intervention, there were 16 participants in the high-risk (Ɛ4+) group and 35 in the low-risk (Ɛ4-) group. The control group had 55 participants in studies III-IV and 56 participants in studies I-II. The intervention had both short-term (≤ 6 months) and long-term (12 months) effects on health behavior and clinical factors. The short-term effects were found in dietary fat quality and waist circumference. Dietary fat quality improved more in the Ɛ4+ group than the Ɛ4- and the control groups as the personal, genotype-based health information and waist circumference lowered more in the Ɛ4+ group compared with the control group. Both these changes differed significantly between the Ɛ4+ and control groups (p<0.05). A long-term effect was found in triglyceride values (p<0.05), which lowered more in Ɛ4+ compared with the control group during the intervention. Short-term effects were also found in the threat experience, which increased mostly in the Ɛ4+ group after the genetic feedback (p<0.05), but it decreased after 12 months, although remaining at a higher level compared to the baseline (T0). In addition, Study IV found that changes in the psychological factors (anxiety and threat experience, motivation), health and taste attitudes, and health behaviors (dietary, alcohol consumption, and physical activity) did not directly explain the changes in triglyceride values and waist circumference. However, change caused by a threat experience may have affected the change in triglycerides through total- and HDL cholesterol. In conclusion, this dissertation study has given some indications that individual, genotypebased health information could be one potential option in the future to prevent lifestyle-related diseases in public health care. The results of this study imply that personal genetic information, based on APOE, may have positive effects on dietary fat quality and some cardiovascular risk markers (e.g., improvement in triglyceride values and waist circumference). This study also suggests that psychological factors (e.g. anxiety and threat experience) may not be an obstacle for healthy people to use genotype-based health information to promote healthy lifestyles. However, even in the case of very personal health information, in order to achieve a permanent health behavior change, it is important to include attitudes and other psychological factors (e.g. motivation), as well as intensive repetition and a longer intervention duration. This research will serve as a basis for future studies and its information can be used to develop targeted interventions, including health information based on genotyping that would aim at preventing lifestyle diseases. People’s interest in personalized health advices has increased, while also the costs of genetic screening have decreased. Therefore, generally speaking, it can be assumed that genetic screening as a part of the prevention of lifestyle-related diseases may become more common in the future. In consequence, more research is required about how to make genetic screening a practical tool in public health care, and how to efficiently achieve long-term changes.

Risque de cancer du poumon associé aux expositions environnementales de fumées de soudage : 2 études cas-témoins basées sur la population montréalaise.

Objectif : Examiner la relation entre une exposition professionnelle aux fumées de soudage au gaz et à l’arc et le risque de développer un cancer du poumon, chez des travailleurs provenant de différents milieux de travail et exposés à de nombreuses substances de différentes concentrations. Méthodes : Nous avons mené deux études cas-témoins basés sur la population montréalaise (1979-86 et 1996-2001), incluant respectivement 857 et 736 cas, ainsi que des témoins appariés selon la fréquence des cas, le sexe et le lieu de résidence. Un historique détaillé des emplois occupés fut obtenu par entrevue et évalué par une équipe d’experts afin d’estimer l’intensité, la durée ainsi que l’exposition cumulative à un grand nombre de substances. Les fumées de soudage au gaz et à l’arc sont parmi les substances évaluées et nous avons pu calculer un rapport de cote (RC) et son intervalle de confiance de 95% (IC 95%) pour le risque de cancer du poumon en utilisant la régression logistique et en ajustant pour l’historique de tabagisme et plusieurs autres covariables pertinentes. Des analyses subséquentes ont permis d’explorer d’autres voies, comme la modification des effets observés par le tabagisme. Résultats : Les résultats obtenus à partir des deux études étant assez similaires, nous avons donc pu les combiner pour former une seule étude. Aucune association statistiquement significative n’a été trouvée entre le cancer du poumon et les fumées de soudage au gaz (RC=1,13; IC 95%=0,90-1,42) et les fumées de soudage à l’arc (RC=1,01; IC 95%=0,80-1,26). Par contre, dans le sous-groupe des non-fumeurs et fumeurs très légers, nous avons trouvé un risque accru de cancer du poumon en relation avec les fumées de soudage au gaz (RC=2,78; IC 95%=1,66-4,65) et à l’arc (RC=2,20; IC 95%=1,32-3,70). En se concentrant sur ce sous-groupe, nous avons trouvé un risque encore plus élevé de développer un cancer du poumon pour ceux exposé à des doses plus substantielles, pour le soudage au gaz (RC=4,63; IC 95%=2,14-10,03) et à l’arc (RC=3,45; IC 95%=1,59-7,48). Discussion : Globalement, aucun excès de risque causé par une exposition aux fumées de soudage n’a été détecté, mais un excès a été trouvé chez les non-fumeurs et fumeurs légers uniquement et ce, pour les deux types de fumées de soudage. L’effet des fumées de soudage peut être voilé chez les fumeurs, ou bien les non-fumeurs pourraient être plus vulnérables.

“Population Characteristics, Fishery and Post larval distribution of Macrobrachium rosenbergii (de Man) and M. idella (Hilgendorf) of Vembanad lake”

Macrobrachium rosenbergii (de Man) and M.ide77a (Hilgendorf) form two commercially important Palaemonid prawns of the Vembanad lake (9 28' and 10 10’ N and 76 13' and 76 31' E). Both of them were known to have contributed to a very lucrative fishery during the sixties, however, in recent years these natural resources have badly depleted owing to the impact of many man made alterations brought about in the ecosystem such as habitat reduction, physical obstruction imposed in the migratory pathway of these species, pollution hazards, etc,. Changed environmental conditions and increased fishing pressures caused persistent alterations in the stock size of these prawns during the past so many years, however, no serious attempt was made to monitor the stock size from time to time and also to bring out the resource characteristics. Though, the morphotypic differentiation in grow out male population of M.rosenbergii has been documented, no similar studies were conducted with regard to natural male and female population. Based on the data collected during fishery cruise surveys conducted in Vembanad lake from March '94 to February '96, population characteristics. postlarval distribution, fishery and population dynamics of M.rosenbergii and M.ide77a of the lake were studied in detail.

Sexual abuse and alcohol use among women in metropolitan Sao Paulo, Brazil: a general population study

OBJECTIVE:The present study aimed at estimating the prevalence of lifetime sexual abuse among women and at investigating its association with alcohol consumption.METHOD:Population-based survey conducted through a representative and stratified cluster sample of metropolitan São Paulo. GENACIS questionnaire was used. Sample unit was the home, and all residents aged 18 years and over were interviewed. The outcome was lifetime sexual abuse. The univariate statistical analysis used the Rao-Scott test. Logistic regression was used for the multivariate analysis.RESULTS:The final sample totalized 1,216 women aged 18 years and over; the response rate was 75.0%. Most women were married (56.6%) and had less than 12 years of formal education (59.0%); 46.2% were aged between 25 and 44 years, and 44.4% had a low income. Of the respondents, 7.5% reported having suffered lifetime sexual abuse. Multiple logistic regression model showed an association between lifetime sexual abuse and being a heavy drinker (OR = 4.97) and being a former drinker (OR = 2.04).CONCLUSIONS:There are few population studies in Brazil investigating sexual abuse and its relation to alcohol use. Although the prevalence of lifetime sexual abuse in the present study was smaller than that observed in other studies, it is a highly expressive percentage on account of its social and economic impact, as well as its potential effect on the health system.

Brazilian psychiatric brain bank: a new contribution tool to network studies

There is an urgent need for expanding the number of brain banks serving psychiatric research. We describe here the Psychiatric Disorders arm of the Brain Bank of the Brazilian Aging Brain Study Group (Psy-BBBABSG), which is focused in bipolar disorder (BD) and obsessive compulsive disorder (OCD). Our protocol was designed to minimize limitations faced by previous initiatives, and to enable design-based neurostereological analyses. The Psy-BBBABSG first milestone is the collection of 10 brains each of BD and OCD patients, and matched controls. The brains are sourced from a population-based autopsy service. The clinical and psychiatric assessments were done by an expert team including psychiatrists, through an informant. One hemisphere was perfused-fixed to render an optimal fixation for conducting neurostereological studies. The other hemisphere was comprehensively dissected and frozen for molecular studies. In 20 months, we collected 36 brains. A final report was completed for 14 cases: 3 BDs, 4 major depressive disorders, 1 substance use disorder, 1 mood disorder NOS, 3 obsessive compulsive spectrum symptoms, 1 OCD and 1 schizophrenia. The majority were male (64%), and the average age at death was 67.2 +/- 9.0 years. The average postmortem interval was 16 h. Three matched controls were collected. The pilot stage confirmed that the protocols are well fitted to reach our goals. Our unique autopsy source makes possible to collect a fairly number of high quality cases in a short time. Such a collection offers an additional to the international research community to advance the understanding on neuropsychiatric diseases.

Sleep quality, the neglected outcome variable in clinical studies focusing on locomotor system; a construct validation study

In addition to general health and pain, sleep is highly relevant to judging the well-being of an individual. Of these three important outcome variables, however, sleep is neglected in most outcome studies.Sleep is a very important resource for recovery from daily stresses and strains, and any alteration of sleep will likely affect mental and physical health, especially during disease. Sleep assessment therefore should be standard in all population-based or clinical studies focusing on the locomotor system. Yet current sleep assessment tools are either too long or too specific for general use.

The course of chronic and recurrent low back pain in the general population

Using latent class analysis (LCA), a previous study on patients attending primary care identified four courses of low back pain (LBP) over the subsequent 6 months. To date, no studies have used longitudinal pain recordings to examine the "natural" course of recurrent and chronic LBP in a population-based sample of individuals. This study examines the course of LBP in the general population and elaborates on the stability and criterion-related validity of the clusters derived. A random sample of 400 individuals reporting LBP in a population-based study was asked to complete a comprehensive questionnaire at the start and end of the year's survey, and 52 weekly pain diaries in between. The latter were analyzed using LCA. 305 individuals returned more than 50% of the diaries. Four clusters were identified (severe persistent, moderate persistent, mild persistent, and fluctuating). The clusters differed significantly with regards to pain and disability. Assessment of cluster stability showed that a considerable proportion of patients in the "fluctuating" group changed their classification over time. Three of the four clusters describing the typical course of pain matched the clusters described previously for patients in primary care. Due to the population-based design, this study achieves, for the first time, a close insight into the "natural" course of chronic and recurrent low back pain, including individuals that did not necessarily visit the general practitioner. The findings will help to understand better the nature of this pain in the general population.

Heritability, determinants and reference values of renal length: a family-based population study

OBJECTIVES: In this population-based study, reference values were generated for renal length, and the heritability and factors associated with kidney length were assessed. METHODS: Anthropometric parameters and renal ultrasound measurements were assessed in randomly selected nuclear families of European ancestry (Switzerland). The adjusted narrow sense heritability of kidney size parameters was estimated by maximum likelihood assuming multivariate normality after power transformation. Gender-specific reference centiles were generated for renal length according to body height in the subset of non-diabetic non-obese participants with normal renal function. RESULTS: We included 374 men and 419 women (mean ± SD, age 47 ± 18 and 48 ± 17 years, BMI 26.2 ± 4 and 24.5 ± 5 kg/m(2), respectively) from 205 families. Renal length was 11.4 ± 0.8 cm in men and 10.7 ± 0.8 cm in women; there was no difference between right and left renal length. Body height, weight and estimated glomerular filtration rate (eGFR) were positively associated with renal length, kidney function negatively, age quadratically, whereas gender and hypertension were not. The adjusted heritability estimates of renal length and volume were 47.3 ± 8.5 % and 45.5 ± 8.8 %, respectively (P < 0.001). CONCLUSION: The significant heritability of renal length and volume highlights the familial aggregation of this trait, independently of age and body size. Population-based references for renal length provide a useful guide for clinicians. KEY POINTS: • Renal length and volume are heritable traits, independent of age and size. • Based on a European population, gender-specific reference values/percentiles are provided for renal length. • Renal length correlates positively with body length and weight. • There was no difference between right and left renal lengths in this study. • This negates general teaching that the left kidney is larger and longer.

Simulation-based cost-utility analysis of population screening-based alendronate use in Switzerland

A simulation model adopting a health system perspective showed population-based screening with DXA, followed by alendronate treatment of persons with osteoporosis, or with anamnestic fracture and osteopenia, to be cost-effective in Swiss postmenopausal women from age 70, but not in men. INTRODUCTION: We assessed the cost-effectiveness of a population-based screen-and-treat strategy for osteoporosis (DXA followed by alendronate treatment if osteoporotic, or osteopenic in the presence of fracture), compared to no intervention, from the perspective of the Swiss health care system. METHODS: A published Markov model assessed by first-order Monte Carlo simulation was refined to reflect the diagnostic process and treatment effects. Women and men entered the model at age 50. Main screening ages were 65, 75, and 85 years. Age at bone densitometry was flexible for persons fracturing before the main screening age. Realistic assumptions were made with respect to persistence with intended 5 years of alendronate treatment. The main outcome was cost per quality-adjusted life year (QALY) gained. RESULTS: In women, costs per QALY were Swiss francs (CHF) 71,000, CHF 35,000, and CHF 28,000 for the main screening ages of 65, 75, and 85 years. The threshold of CHF 50,000 per QALY was reached between main screening ages 65 and 75 years. Population-based screening was not cost-effective in men. CONCLUSION: Population-based DXA screening, followed by alendronate treatment in the presence of osteoporosis, or of fracture and osteopenia, is a cost-effective option in Swiss postmenopausal women after age 70.

Epidemiological, social, diagnostic and economic evaluation of population screening for genital chlamydial infection

OBJECTIVES: To investigate epidemiological, social, diagnostic and economic aspects of chlamydia screening in non-genitourinary medicine settings. METHODS: Linked studies around a cross-sectional population-based survey of adult men and women invited to collect urine and (for women) vulvovaginal swab specimens at home and mail these to a laboratory for testing for Chlamydia trachomatis. Specimens were used in laboratory evaluations of an amplified enzyme immunoassay (PCE EIA) and two nucleic acid amplification tests [Cobas polymerase chain reaction (PCR), Becton Dickinson strand displacement amplification (SDA)]. Chlamydia-positive cases and two negative controls completed a risk factor questionnaire. Chlamydia-positive cases were invited into a randomised controlled trial of partner notification strategies. Samples of individuals testing negative completed psychological questionnaires before and after screening. In-depth interviews were conducted at all stages of screening. Chlamydia transmission and cost-effectiveness of screening were investigated in a transmission dynamic model. SETTING AND PARTICIPANTS: General population in the Bristol and Birmingham areas of England. In total, 19,773 women and men aged 16-39 years were randomly selected from 27 general practice lists. RESULTS: Screening invitations reached 73% (14,382/19,773). Uptake (4731 participants), weighted for sampling, was 39.5% (95% CI 37.7, 40.8%) in women and 29.5% (95% CI 28.0, 31.0%) in men aged 16-39 years. Chlamydia prevalence (219 positive results) in 16-24 year olds was 6.2% (95% CI 4.9, 7.8%) in women and 5.3% (95% CI 4.4, 6.3%) in men. The case-control study did not identify any additional factors that would help target screening. Screening did not adversely affect anxiety, depression or self-esteem. Participants welcomed the convenience and privacy of home-sampling. The relative sensitivity of PCR on male urine specimens was 100% (95% CI 89.1, 100%). The combined relative sensitivities of PCR and SDA using female urine and vulvovaginal swabs were 91.8% (86.1, 95.7, 134/146) and 97.3% (93.1, 99.2%, 142/146). A total of 140 people (74% of eligible) participated in the randomised trial. Compared with referral to a genitourinary medicine clinic, partner notification by practice nurses resulted in 12.4% (95% CI -3.7, 28.6%) more patients with at least one partner treated and 22.0% (95% CI 6.1, 37.8%) more patients with all partners treated. The health service and patients costs (2005 prices) of home-based postal chlamydia screening were 21.47 pounds (95% CI 19.91 pounds, 25.99) per screening invitation and 28.56 pounds (95% CI 22.10 pounds, 30.43) per accepted offer. Preliminary modelling found an incremental cost-effectiveness ratio (2003 prices) comparing screening men and women annually to no screening in the base case of 27,000 pounds/major outcome averted at 8 years. If estimated screening uptake and pelvic inflammatory disease incidence were increased, the cost-effectiveness ratio fell to 3700 pounds/major outcome averted. CONCLUSIONS: Proactive screening for chlamydia in women and men using home-collected specimens was feasible and acceptable. Chlamydia prevalence rates in men and women in the general population are similar. Nucleic acid amplification tests can be used on first-catch urine specimens and vulvovaginal swabs. The administrative costs of proactive screening were similar to those for opportunistic screening. Using empirical estimates of screening uptake and incidence of complications, screening was not cost-effective.

Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population.

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.