Interactions within the MHC contribute to the genetic architecture of celiac disease.

Interaction analysis of GWAS can detect signal that would be ignored by single variant analysis, yet few robust interactions in humans have been detected. Recent work has highlighted interactions in the MHC region between known HLA risk haplotypes for various autoimmune diseases. To better understand the genetic interactions underlying celiac disease (CD), we have conducted exhaustive genome-wide scans for pairwise interactions in five independent CD case-control studies, using a rapid model-free approach to examine over 500 billion SNP pairs in total. We found 14 independent interaction signals within the MHC region that achieved stringent replication criteria across multiple studies and were independent of known CD risk HLA haplotypes. The strongest independent CD interaction signal corresponded to genes in the HLA class III region, in particular PRRC2A and GPANK1/C6orf47, which are known to contain variants for non-Hodgkin's lymphoma and early menopause, co-morbidities of celiac disease. Replicable evidence for statistical interaction outside the MHC was not observed. Both within and between European populations, we observed striking consistency of two-locus models and model distribution. Within the UK population, models of CD based on both interactions and additive single-SNP effects increased explained CD variance by approximately 1% over those of single SNPs. The interactions signal detected across the five cohorts indicates the presence of novel associations in the MHC region that cannot be detected using additive models. Our findings have implications for the determination of genetic architecture and, by extension, the use of human genetics for validation of therapeutic targets.

Comparison of oral surgery task performance in a virtual reality surgical simulator and an animal model using objective measures.

The use of virtual reality (VR) simulation for surgical training has gathered much interest in recent years. Despite increasing popularity and usage, limited work has been carried out in the use of automated objective measures to quantify the extent to which performance in a simulator resembles performance in the operating theatre, and the effects of simulator training on real world performance. To this end, we present a study exploring the effects of VR training on the performance of dentistry students learning a novel oral surgery task. We compare the performance of trainees in a VR simulator and in a physical setting involving ovine jaws, using a range of automated metrics derived by motion analysis. Our results suggest that simulator training improved the motion economy of trainees without adverse effects on task outcome. Comparison of surgical technique on the simulator with the ovine setting indicates that simulator technique is similar, but not identical to real world technique.

GWIS--model-free, fast and exhaustive search for epistatic interactions in case-control GWAS.

BACKGROUND: It has been hypothesized that multivariate analysis and systematic detection of epistatic interactions between explanatory genotyping variables may help resolve the problem of "missing heritability" currently observed in genome-wide association studies (GWAS). However, even the simplest bivariate analysis is still held back by significant statistical and computational challenges that are often addressed by reducing the set of analysed markers. Theoretically, it has been shown that combinations of loci may exist that show weak or no effects individually, but show significant (even complete) explanatory power over phenotype when combined. Reducing the set of analysed SNPs before bivariate analysis could easily omit such critical loci. RESULTS: We have developed an exhaustive bivariate GWAS analysis methodology that yields a manageable subset of candidate marker pairs for subsequent analysis using other, often more computationally expensive techniques. Our model-free filtering approach is based on classification using ROC curve analysis, an alternative to much slower regression-based modelling techniques. Exhaustive analysis of studies containing approximately 450,000 SNPs and 5,000 samples requires only 2 hours using a desktop CPU or 13 minutes using a GPU (Graphics Processing Unit). We validate our methodology with analysis of simulated datasets as well as the seven Wellcome Trust Case-Control Consortium datasets that represent a wide range of real life GWAS challenges. We have identified SNP pairs that have considerably stronger association with disease than their individual component SNPs that often show negligible effect univariately. When compared against previously reported results in the literature, our methods re-detect most significant SNP-pairs and additionally detect many pairs absent from the literature that show strong association with disease. The high overlap suggests that our fast analysis could substitute for some slower alternatives. CONCLUSIONS: We demonstrate that the proposed methodology is robust, fast and capable of exhaustive search for epistatic interactions using a standard desktop computer. First, our implementation is significantly faster than timings for comparable algorithms reported in the literature, especially as our method allows simultaneous use of multiple statistical filters with low computing time overhead. Second, for some diseases, we have identified hundreds of SNP pairs that pass formal multiple test (Bonferroni) correction and could form a rich source of hypotheses for follow-up analysis. AVAILABILITY: A web-based version of the software used for this analysis is available at http://bioinformatics.research.nicta.com.au/gwis.

Plasma lipidomic analysis of stable and unstable coronary artery disease.

OBJECTIVE: Traditional risk factors for coronary artery disease (CAD) fail to adequately distinguish patients who have atherosclerotic plaques susceptible to instability from those who have more benign forms. Using plasma lipid profiling, this study aimed to provide insight into disease pathogenesis and evaluate the potential of lipid profiles to assess risk of future plaque instability. METHODS AND RESULTS: Plasma lipid profiles containing 305 lipids were measured on 220 individuals (matched healthy controls, n=80; stable angina, n=60; unstable coronary syndrome, n=80) using electrospray-ionisation tandem mass spectrometry. ReliefF feature selection coupled with an L2-regularized logistic regression based classifier was used to create multivariate classification models which were verified via 3-fold cross-validation (1000 repeats). Models incorporating both lipids and traditional risk factors provided improved classification of unstable CAD from stable CAD (C-statistic=0.875, 95% CI 0.874-0.877) compared with models containing only traditional risk factors (C-statistic=0.796, 95% CI 0.795-0.798). Many of the lipids identified as discriminatory for unstable CAD displayed an association with disease acuity (severity), suggesting that they are antecedents to the onset of acute coronary syndrome. CONCLUSION: Plasma lipid profiling may contribute to a new approach to risk stratification for unstable CAD.

Towards defining dental drilling competence, part 1: a study of bone drilling technique.

Technical skills are critical for dentists. Computer-based simulation offers a range of potential benefits for surgical training, but to date the development of simulators has not been characterized by a structured investigation of specific mechanisms by which trainees attain competence. This two-part study contributes to the understanding of the manner in which surgical psychomotor skills are acquired so that this knowledge can be incorporated into the design of training simulations. We studied participant groups of varying skill levels as they performed a drilling task in oral surgery. In this first part of our study, we investigated the elements of surgical technique and differences in the drilling performance of novice, competent, and expert dentists. Our results indicate that novice dentists employ a technique that differs considerably in drilling stroke length and duration from that employed by experts. Expert dentists perform faster, apply more force, lift the bur off the bone less, and produce superior results compared with novices.

Towards defining dental drilling competence, part 2: a study of cues and factors in bone drilling.

The study of expertise in surgery aims to facilitate the development of improved training methods by understanding the characteristics of expert practitioners. In this article and its companion, we present our study of the characteristics of competence and expertise in the field of oral surgery. We observed participants of different skill levels as they performed an ex vivo drilling task designed to test the psychomotor skill of distinguishing the material boundaries between tooth and bone. Part 1 of this study examined the physical characteristics of drilling performance, while this article examines the cognitive aspects of performance. In this article we investigate the psychomotor cues used for decision making during drilling and explore other factors that affect a participant's ability to distinguish tooth from bone. Our results suggest that visual and tactile cues were the most important cues guiding drilling performance in all participant groups. Our results also suggest that when compared to experts, novices relied more on visual cues rather than tactile cues and lacked the psychomotor skills required to utilize the broader range of cues used by experts.

Impact of patient adherence and test performance on the cost-effectiveness of cervical cancer screening in developing countries: the case of Honduras.

OBJECTIVE: We examined the impact of patient adherence and screening test performance on the cost-effectiveness of visual inspection with acetic acid (VIA) and Pap smears when used with colposcopy for diagnosis. MATERIALS AND METHODS: Cost-effectiveness analysis was performed using computer modeling. The primary outcome was cancer prevalence in the 10 years after screening. Three hypothetical populations of 35-year-old women were compared: never-screened women, women screened with VIA, and women screened with Pap smears. We used community-based data from our screening program in Honduras to estimate screening test sensitivity and specificity, adherence to follow-up, and costs of screening and colposcopy services. Published data were used to model disease outcomes. RESULTS: VIA was more sensitive than Pap smears (70% vs. 4%), less expensive (U.S. 0.23 dollars vs. 3.17 dollars), and the 2-vist VIA system had a higher rate of adherence to follow-up than the 3-visit Pap smear system (84% vs. 38%). VIA had a higher false-positive rate than Pap smears resulting in higher colposcopy referral rates, but more dysplasia was detected and treated. Cost-effectiveness analysis revealed that screening with VIA would cost U.S. 3,198 dollars per cancer case avoided and reduce cancer cases by 42%, versus U.S. 36,802 dollars and 2% for Pap screening. Although Pap smear quality was low in Honduras, sensitivity analysis showed that VIA was more cost-effective than Pap smears, even when test accuracy was equivalent. CONCLUSION: In developing countries, systems barriers can limit the cost-effectiveness of Pap smears. VIA may be a cost-effective alternative for some resource-poor settings, although systems barriers, quality control, and feasibility issues must be considered.

A community-based education program about cervical cancer improves knowledge and screening behavior in Honduran women.

OBJECTIVES: This study examined changes in knowledge and behavior after a community-based cervical cancer education program in Honduras. METHODS: The program consisted of radio broadcasts targeting rural women and presentations to community nurses. The effectiveness of the radio broadcasts was assessed using a cross-sectional design (control groups n = 124, n = 243; intervention group n = 233). A pre-/post-test design was used to evaluate the nurses' training program (n = 32). A subset of nurses (n = 16) was retested two years later. Evaluation included t tests, chi-square and Fisher exact analyses. RESULTS: The radio broadcast increased the proportion of women who were familiar with the term "cervical cancer," who could identify means of preventing cervical cancer, and who understood the purpose of the Pap smear. In addition, older and under-screened women were successfully recruited for screening via radio. The nurses' program improved understanding of the correct use of the Pap smear, the age-related risk of dysplasia, and the proper triage of abnormal results. The nurses retained a significant amount of knowledge two years after this training. CONCLUSIONS: In developing countries, inexpensive, community-based educational programs using radio broadcasts and lecture presentations can increase cervical cancer knowledge and improve screening behavior.

A community-based education program about cervical cancer improves knowledge and screening behavior in Honduran women

OBJECTIVES: This study examined changes in knowledge and behavior after a community-based cervical cancer education program in Honduras. METHODS: The program consisted of radio broadcasts targeting rural women and presentations to community nurses. The effectiveness of the radio broadcasts was assessed using a cross-sectional design (control groups n = 124, n = 243; intervention group n = 233). A pre-/ post-test design was used to evaluate the nurses’ training program (n = 32). A subset of nurses (n = 16) was retested two years later. Evaluation included t tests, chi-square and Fisher exact analyses. RESULTS: The radio broadcast increased the proportion of women who were familiar with the term "cervical cancer," who could identify means of preventing cervical cancer, and who understood the purpose of the Pap smear. In addition, older and under-screened women were successfully recruited for screening via radio. The nurses’ program improved understanding of the correct use of the Pap smear, the age-related risk of dysplasia, and the proper triage of abnormal results. The nurses retained a significant amount of knowledge two years after this training. CONCLUSIONS: In developing countries, inexpensive, community-based educational programs using radio broadcasts and lecture presentations can increase cervical cancer knowledge and improve screening behavior.

OBJETIVOS: Examinar los cambios ocurridos en el conocimiento sobre el cáncer cervicouterino y el comportamiento ante el tamizaje después de un programa educacional basado en la comunidad en Honduras. MÉTODOS: El programa consistió en transmisiones radiales dirigidas a mujeres de zonas rurales y conferencias a enfermeros de la comunidad. La eficacia de las transmisiones radiales se evaluó mediante un diseño transversal (grupos de control: n = 124 y n = 243; grupo de intervención: n = 233). Se utilizó una prueba previa y otra posterior para evaluar el programa de entrenamiento de enfermeros (n = 32). Después de dos años se repitió la prueba a un subgrupo de enfermeros (n = 16). Se emplearon las pruebas exacta de Fisher, de la t de Student y de la ji al cuadrado. RESULTADOS: Las transmisiones radiales elevaron la proporción de mujeres familiarizadas con el término "cáncer cervicouterino", que podían identificar las vías para prevenir el cáncer cervicouterino y que comprendían los objetivos de la prueba de Papanicolau. Además, mediante el radio se reclutaron exitosamente para tamizar más mujeres de los grupos de mayor edad y menos tamizadas. Con el programa para enfermeros se mejoró la comprensión del uso correcto de la prueba de Papanicolau, del riego relativo de displasia según la edad y de la conducta apropiada a seguir ante resultados alterados. Los enfermeros retenían una cantidad importante de conocimientos dos años después del entrenamiento. CONCLUSIONES: En los países en desarrollo, el empleo de programas educacionales poco costosos basados en la comunidad mediante transmisiones radiales y conferencias puede elevar el conocimiento sobre el cáncer cervicouterino y mejorar el comportamiento ante el tamizaje.

Comparative analysis of long DNA sequences by per element information content using different contexts.

BACKGROUND: Features of a DNA sequence can be found by compressing the sequence under a suitable model; good compression implies low information content. Good DNA compression models consider repetition, differences between repeats, and base distributions. From a linear DNA sequence, a compression model can produce a linear information sequence. Linear space complexity is important when exploring long DNA sequences of the order of millions of bases. Compressing a sequence in isolation will include information on self-repetition. Whereas compressing a sequence Y in the context of another X can find what new information X gives about Y. This paper presents a methodology for performing comparative analysis to find features exposed by such models. RESULTS: We apply such a model to find features across chromosomes of Cyanidioschyzon merolae. We present a tool that provides useful linear transformations to investigate and save new sequences. Various examples illustrate the methodology, finding features for sequences alone and in different contexts. We also show how to highlight all sets of self-repetition features, in this case within Plasmodium falciparum chromosome 2. CONCLUSION: The methodology finds features that are significant and that biologists confirm. The exploration of long information sequences in linear time and space is fast and the saved results are self documenting.

Cost-effectiveness of a low-carbohydrate diet and a standard diet in severe obesity.

OBJECTIVE: Low-carbohydrate diets have become a popular alternative to standard diets for weight loss. Our aim was to compare the cost-effectiveness of these two diets. RESEARCH METHODS AND PROCEDURES: The patient population included 129 severely obese subjects (BMI = 42.9) from a randomized trial; participants had a high prevalence of diabetes or metabolic syndrome. We compared within-trial costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (CER) for the two study groups. We imputed missing values for QALYs. The CER was bootstrapped to derive 95% confidence intervals and to define acceptability cut-offs. We took a societal perspective for our analysis. RESULTS: Total costs during the one year of the trial were 6742 dollars +/- 6675 and 6249 dollars +/- 5100 for the low-carbohydrate and standard groups, respectively (p = 0.78). Participants experienced 0.64 +/- 0.02 and 0.61 +/- 0.02 QALYs during the one year of the study, respectively (p = 0.17 for difference). The point estimate of the incremental CER was -1225 dollars/QALY (i.e., the low-carbohydrate diet dominated the standard diet). However, in the bootstrap analysis, the wide spread of CERs caused the 95% confidence interval to be undefined. The probabilities that the low-carbohydrate diet was acceptable, using cut-offs of 50,000 dollars/QALY, 100,000 dollars/QALY, and 150,000 dollars/QALY, were 72.4% 78.6%, and 79.8%, respectively. DISCUSSION: The low-carbohydrate diet was not more cost-effective for weight loss than the standard diet in the patient population studied. Larger studies are needed to better assess the cost-effectiveness of dietary therapies for weight loss.

Free fatty acids, insulin resistance, and corrected qt intervals in morbid obesity: effect of weight loss during 6 months with differing dietary interventions.

OBJECTIVE: To assess whether shortening of the corrected QT (QTc) interval is most closely associated with changes in weight, insulin resistance, or free fatty acids (FFAs) (or some combination of these factors). METHODS: We randomized 75 severely obese subjects without diabetes to either a low-carbohydrate or a conventional low-fat weight-loss diet for 6 months. We measured QTc, insulin sensitivity, body mass index, and FFAs at baseline and at 6 months. Analysis was performed to determine whether improvement in weight, in insulin resistance, or in FFAs has the greatest effect on reducing the QTc interval. RESULTS: "Completers" of both the low-carbohydrate diet (N = 25) and the low-fat diet (N = 22) had a decrease in weight, but the weight loss was greater in the low-carbohydrate group. A statistically significant decrease in QTc from baseline was observed only in the low-carbohydrate group. QTc in the low-carbohydrate group correlated with improvement in insulin resistance, but this finding was not significant after correction for the greater weight loss. FFAs or weight loss was not correlated with QTc in either dietary group. CONCLUSION: Low-carbohydrate dieting is associated with a greater decrease in the QTc interval in comparison with low-fat dieting. Improvements in insulin resistance seem to have a relatively weak mechanistic role, and a decrease in FFAs has no apparent role in the reduction of the QTc interval.

Adipocytokine changes caused by low-carbohydrate compared to conventional diets in obesity.

Modest weight loss causing a decrease in insulin resistance has been linked to favorable changes in the adipocyte cytokines leptin, adiponectin, and tumor necrosis factor-alpha (TNF-alpha), three emerging risk factors of cardiovascular disease. We previously observed a significant reduction in insulin resistance with weight loss in obese subjects on a low-carbohydrate diet. Based on these previous findings, we hypothesize that a low-carbohydrate diet would be more beneficial in changing leptin, TNF-alpha, and adiponectin than a conventional diet. A total of 75 severely obese (body mass index >/=35 kg/m(2)) subjects were randomized to instruction of 6 months of a low-carbohydrate diet or a conventional calorie-restricted diet. Serum levels of leptin, TNF-alpha, TNF-alpha-soluble receptor 1 (TNF-alpha SR1), and adiponectin were measured at baseline and after 6 months of dietary intervention. Subjects on low-carbohydrate diets experienced a greater decrease in leptin when compared to conventional dieters (p < 0.001). TNF-alpha increased significantly in nondiabetic subjects on conventional vs. low-carbohydrate diets (p = 0.003). Adiponectin and TNF-alpha SR1 change were not significantly different between diets. This is the first study to report the effects of dietary macronutrient alterations on serum adipocytokines in a randomized controlled trial. The greater reduction in insulin resistance and weight on a low-carbohydrate diet, in the short term, translates into greater improvement in leptin but with no significant improvements in TNF-alpha or adiponectin in patients with moderate to severe obesity after 6 months of dietary intervention.

Use of volunteer medical brigades to assess growth in Honduras.

We endeavored to determine whether a visiting volunteer medical group could effectively measure growth status among children in a developing country, identify predictors of poor growth, and thus participate in nutritional surveillance. Cross-sectional measurements of growth and diagnosis of current clinical conditions were made. A sample of 3284 Honduran children aged 2-11 years who sought care from volunteer medical brigades between January 2000 and May 2001 were included in the study. Main outcome measures were height-, weight- and body mass index-for-age z scores. Compared with standard reference data, 10 per cent of children were moderately underweight and 3.3 per cent severely underweight, while 13.7 per cent were moderately stunted and 6.4 per cent were severely stunted. After simultaneous adjustment for demographics, clinical conditions, and village characteristics, nutritional complaints were associated with lower body mass index- and weight-for-age, while children seen in villages with clean water and higher levels of development had higher body mass index- and weight-for-age. Older children had poorer growth for all parameters. It was concluded that Honduran children seeking care from a volunteer medical brigade were underweight and stunted compared with a reference population. This study demonstrates that a visiting volunteer group can collect quality growth data that may assist in nutritional surveillance, identify predictors of poor growth, and provide information useful for local public health initiatives.

A randomized study comparing the effects of a low-carbohydrate diet and a conventional diet on lipoprotein subfractions and C-reactive protein levels in patients with severe obesity.

PURPOSE: To compare the effects of a low-carbohydrate diet and a conventional (fat- and calorie-restricted) diet on lipoprotein subfractions and inflammation in severely obese subjects. METHODS: We compared changes in lipoprotein subfractions and C-reactive protein levels in 78 severely obese subjects, including 86% with either diabetes or metabolic syndrome, who were randomly assigned to either a low-carbohydrate or conventional diet for 6 months. RESULTS: Subjects on a low-carbohydrate diet experienced a greater decrease in large very low-density lipoprotein (VLDL) levels (difference = -0.26 mg/dL, P = 0.03) but more frequently developed detectable chylomicrons (44% vs. 22%, P = 0.04). Both diet groups experienced similar decreases in the number of low-density lipoprotein (LDL) particles (difference = -30 nmol/L, P = 0.74) and increases in large high-density lipoprotein (HDL) concentrations (difference = 0.70 mg/dL, P = 0.63). Overall, C-reactive protein levels decreased modestly in both diet groups. However, patients with a high-risk baseline level (>3 mg/dL, n = 48) experienced a greater decrease in C-reactive protein levels on a low-carbohydrate diet (adjusted difference = -2.0 mg/dL, P = 0.005), independent of weight loss. CONCLUSION: In this 6-month study involving severely obese subjects, we found an overall favorable effect of a low-carbohydrate diet on lipoprotein subfractions, and on inflammation in high-risk subjects. Both diets had similar effects on LDL and HDL subfractions.