Effects of selection and drift on G matrix evolution in a heterogeneous environment: a multivariate Qst-Fst Test with the freshwater snail Galba truncatula.

Unraveling the effect of selection vs. drift on the evolution of quantitative traits is commonly achieved by one of two methods. Either one contrasts population differentiation estimates for genetic markers and quantitative traits (the Q(st)-F(st) contrast) or multivariate methods are used to study the covariance between sets of traits. In particular, many studies have focused on the genetic variance-covariance matrix (the G matrix). However, both drift and selection can cause changes in G. To understand their joint effects, we recently combined the two methods into a single test (accompanying article by Martin et al.), which we apply here to a network of 16 natural populations of the freshwater snail Galba truncatula. Using this new neutrality test, extended to hierarchical population structures, we studied the multivariate equivalent of the Q(st)-F(st) contrast for several life-history traits of G. truncatula. We found strong evidence of selection acting on multivariate phenotypes. Selection was homogeneous among populations within each habitat and heterogeneous between habitats. We found that the G matrices were relatively stable within each habitat, with proportionality between the among-populations (D) and the within-populations (G) covariance matrices. The effect of habitat heterogeneity is to break this proportionality because of selection for habitat-dependent optima. Individual-based simulations mimicking our empirical system confirmed that these patterns are expected under the selective regime inferred. We show that homogenizing selection can mimic some effect of drift on the G matrix (G and D almost proportional), but that incorporating information from molecular markers (multivariate Q(st)-F(st)) allows disentangling the two effects.

Factors predisposing to dislocation after primary total hip arthroplasty: a multivariate analysis.

We conducted this study to determine the relative influence of various mechanical and patient-related factors on the incidence of dislocation after primary total hip asthroplasty (THA). Of 2,023 THAs, 21 patients who had at least 1 dislocation were compared with a control group of 21 patients without dislocation, matched for age, gender, pathology, and year of surgery. Implant positioning, seniority of the surgeon, American Society of Anesthesiologists (ASA) score, and diminished motor coordination were recorded. Data analysis included univariate and multivariate methods. The dislocation risk was 6.9 times higher if total anteversion was not between 40 degrees and 60 degrees and 10 times higher in patients with high ASA scores. Surgeons should pay attention to total anteversion (cup and stem) of THA. The ASA score should be part of the preoperative assessment of the dislocation risk.

Discovery of a 29-gene panel in peripheral blood mononuclear cells for the detection of colorectal cancer and adenomas using high throughput real-time PCR.

Colorectal cancer (CRC) is the second leading cause of cancer-related death in developed countries. Early detection of CRC leads to decreased CRC mortality. A blood-based CRC screening test is highly desirable due to limited invasiveness and high acceptance rate among patients compared to currently used fecal occult blood testing and colonoscopy. Here we describe the discovery and validation of a 29-gene panel in peripheral blood mononuclear cells (PBMC) for the detection of CRC and adenomatous polyps (AP). Blood samples were prospectively collected from a multicenter, case-control clinical study. First, we profiled 93 samples with 667 candidate and 3 reference genes by high throughput real-time PCR (OpenArray system). After analysis, 160 genes were retained and tested again on 51 additional samples. Low expressed and unstable genes were discarded resulting in a final dataset of 144 samples profiled with 140 genes. To define which genes, alone or in combinations had the highest potential to discriminate AP and/or CRC from controls, data were analyzed by a combination of univariate and multivariate methods. A list of 29 potentially discriminant genes was compiled and evaluated for its predictive accuracy by penalized logistic regression and bootstrap. This method discriminated AP >1cm and CRC from controls with a sensitivity of 59% and 75%, respectively, with 91% specificity. The behavior of the 29-gene panel was validated with a LightCycler 480 real-time PCR platform, commonly adopted by clinical laboratories. In this work we identified a 29-gene panel expressed in PBMC that can be used for developing a novel minimally-invasive test for accurate detection of AP and CRC using a standard real-time PCR platform.

A novel approach to the determination of clinical decision thresholds

Our objective was to determine the test and treatment thresholds for common acute primary care conditions. We presented 200 clinicians with a series of web-based clinical vignettes, describing patients with possible influenza, acute coronary syndrome (ACS), pneumonia, deep vein thrombosis (DVT) and urinary tract infection (UTI). We randomly varied the probability of disease and asked whether the clinician wanted to rule out disease, order tests or rule in disease. By randomly varying the probability, we obtained clinical decisions across a broad range of disease probabilities that we used to create threshold curves. For influenza, the test (4.5% vs 32%, p<0.001) and treatment (55% vs 68%, p=0.11) thresholds were lower for US compared with Swiss physicians. US physicians had somewhat higher test (3.8% vs 0.7%, p=0.107) and treatment (76% vs 58%, p=0.005) thresholds for ACS than Swiss physicians. For both groups, the range between test and treatment thresholds was greater for ACS than for influenza (which is sensible, given the consequences of incorrect diagnosis). For pneumonia, US physicians had a trend towards higher test thresholds and lower treatment thresholds (48% vs 64%, p=0.076) than Swiss physicians. The DVT and UTI scenarios did not provide easily interpretable data, perhaps due to poor wording of the vignettes. We have developed a novel approach for determining decision thresholds. We found important differences in thresholds for US and Swiss physicians that may be a function of differences in healthcare systems. Our results can also guide development of clinical decision rules and guidelines.

MBIS: multivariate Bayesian image segmentation tool.

We present MBIS (Multivariate Bayesian Image Segmentation tool), a clustering tool based on the mixture of multivariate normal distributions model. MBIS supports multichannel bias field correction based on a B-spline model. A second methodological novelty is the inclusion of graph-cuts optimization for the stationary anisotropic hidden Markov random field model. Along with MBIS, we release an evaluation framework that contains three different experiments on multi-site data. We first validate the accuracy of segmentation and the estimated bias field for each channel. MBIS outperforms a widely used segmentation tool in a cross-comparison evaluation. The second experiment demonstrates the robustness of results on atlas-free segmentation of two image sets from scan-rescan protocols on 21 healthy subjects. Multivariate segmentation is more replicable than the monospectral counterpart on T1-weighted images. Finally, we provide a third experiment to illustrate how MBIS can be used in a large-scale study of tissue volume change with increasing age in 584 healthy subjects. This last result is meaningful as multivariate segmentation performs robustly without the need for prior knowledge.

Establishing an association between a peri-operative perfusion score system (PerfSCORE) and post-operative patient morbidity/mortality during CPB cardiac surgery.

BACKGROUND: To date, there is no quality assurance program that correlates patient outcome to perfusion service provided during cardiopulmonary bypass (CPB). A score was devised, incorporating objective parameters that would reflect the likelihood to influence patient outcome. The purpose was to create a new method for evaluating the quality of care the perfusionist provides during CPB procedures and to deduce whether it predicts patient morbidity and mortality. METHODS: We analysed 295 consecutive elective patients. We chose 10 parameters: fluid balance, blood transfused, Hct, ACT, PaO2, PaCO2, pH, BE, potassium and CPB time. Distribution analysis was performed using the Shapiro-Wilcoxon test. This made up the PerfSCORE and we tried to find a correlation to mortality rate, patient stay in the ICU and length of mechanical ventilation. Univariate analysis (UA) using linear regression was established for each parameter. Statistical significance was established when p < 0.05. Multivariate analysis (MA) was performed with the same parameters. RESULTS: The mean age was 63.8 +/- 12.6 years with 70% males. There were 180 CABG, 88 valves, and 27 combined CABG/valve procedures. The PerfSCORE of 6.6 +/- 2.4 (0-20), mortality of 2.7% (8/295), CPB time 100 +/- 41 min (19-313), ICU stay 52 +/- 62 hrs (7-564) and mechanical ventilation of 10.5 +/- 14.8 hrs (0-564) was calculated. CPB time, fluid balance, PaO2, PerfSCORE and blood transfused were significantly correlated to mortality (UA, p < 0.05). Also, CPB time, blood transfused and PaO2 were parameters predicting mortality (MA, p < 0.01). Only pH was significantly correlated for predicting ICU stay (UA). Ultrafiltration (UF) and CPB time were significantly correlated (UA, p < 0.01) while UF (p < 0.05) was the only parameter predicting mechanical ventilation duration (MA). CONCLUSIONS: CPB time, blood transfused and PaO2 are independent risk factors of mortality. Fluid balance, blood transfusion, PaO2, PerfSCORE and CPB time are independent parameters for predicting morbidity. PerfSCORE is a quality of perfusion measure that objectively quantifies perfusion performance.

Prevalence and factors associated with difficulty and intention to quit smoking in Switzerland.

ABSTRACT: BACKGROUND: Recent data indicate a slight decrease in the prevalence of smoking in Switzerland, but little is known regarding the intention and difficulty to quit smoking among current smokers. Hence, we aimed to quantify the difficulty and intention to quit smoking among current smokers in Switzerland. METHODS: Cross-sectional study including 607 female and 658 male smokers. Difficulty, intention and motivation to quit smoking were assessed by questionnaire. RESULTS: 90% of women and 85% of men reported being "very difficult" or "difficult" to quit smoking. Almost three quarters of smokers (73% of women and 71% of men) intended to quit; however, less than 20% of them were in the preparation stage and 40% were in the precontemplation stage. On multivariate analysis, difficulty to quit was lower among men (Odds ratio and 95% [confidence interval]: 0.51 [0.35-0.74]) and increased with nicotine dependence and number of previous quitting attempts (OR=3.14 [1.75-5.63] for 6+ attempts compared to none). Intention to quit decreased with increasing age (OR=0.48 [0.30-0.75] for [greater than or equal to]65 years compared to <45 years) and increased with nicotine dependence, the number of previous quitting attempts (OR=4.35 [2.76-6.83] for 6+ attempts compared to none) and among non-cigarette smokers (OR=0.51 [0.28-0.92]). Motivation to quit was inversely associated with nicotine dependence and positively associated with the number of previous quitting attempts and personal history of lung disease. CONCLUSION: Over two thirds of Swiss smokers want to quit. However, only a small fraction wishes to do so in the short term. Nicotine dependence, previous attempts to quit or previous history of lung disease are independently associated with difficulty and intention to quit.

Ecologic correlations of selected food groups with disease incidence and mortality in Switzerland.

Background: There is little information regarding the impact of diet on disease incidence and mortality in Switzerland. We assessed ecologic correlations between food availability and disease.Methods: In this ecologic study for the period 1970-2009, food availability was measured using the food balance sheets of the Food and Agriculture Organization of the United Nations. Standardized mortality rates (SMRs) were obtained from the Swiss Federal Office of Statistics. Cancer incidence data were obtained from the World Health Organization Health For All database and the Vaud Cancer Registry. Associations between food availability and mortality/incidence were assessed at lags 0, 5, 10, and 15 years by multivariate regression adjusted for total caloric intake.Results: Alcoholic beverages and fruit availability were positively associated, and fish availability was inversely associated, with SMRs for cardiovascular diseases. Animal products, meat, and animal fats were positively associated with the SMR for ischemic heart disease only. For cancer, the results of analysis using SMRs and incidence rates were contradictory. Alcoholic beverages and fruits were positively associated with SMRs for all cancer but inversely associated with all-cancer incidence rates. Similar findings were obtained for all other foods except vegetables, which were weakly inversely associated with SMRs and incidence rates. Use of a 15-year lag reversed the associations with animal and vegetal products, weakened the association with alcohol and fruits, and strengthened the association with fish.Conclusions: Ecologic associations between food availability and disease vary considerably on the basis of whether mortality or incidence rates are used in the analysis. Great care is thus necessary when interpreting our results.

Fusion of Multi-Atlas Segmentations with Spatial Distribution Modeling

In recent years, multi-atlas fusion methods have gainedsignificant attention in medical image segmentation. Inthis paper, we propose a general Markov Random Field(MRF) based framework that can perform edge-preservingsmoothing of the labels at the time of fusing the labelsitself. More specifically, we formulate the label fusionproblem with MRF-based neighborhood priors, as an energyminimization problem containing a unary data term and apairwise smoothness term. We present how the existingfusion methods like majority voting, global weightedvoting and local weighted voting methods can be reframedto profit from the proposed framework, for generatingmore accurate segmentations as well as more contiguoussegmentations by getting rid of holes and islands. Theproposed framework is evaluated for segmenting lymphnodes in 3D head and neck CT images. A comparison ofvarious fusion algorithms is also presented.

Length of hospital stay and postdischarge mortality in patients with pulmonary embolism: a statewide perspective

BACKGROUND: The optimal length of stay (LOS) for patients with pulmonary embolism (PE) is unknown. Although reducing LOS is likely to save costs, the effects on patient safety are unclear. We sought to identify patient and hospital factors associated with LOS and assess whether LOS was associated with postdischarge mortality. METHODS: We evaluated patients discharged with a primary diagnosis of PE from 186 acute care hospitals in Pennsylvania (January 2000 through November 2002). We used discrete survival models to examine the association between (1) patient and hospital factors and the time to discharge and (2) LOS and postdischarge mortality within 30 days of presentation, adjusting for patient and hospital factors. RESULTS: Among 15 531 patient discharges with PE, the median LOS was 6 days, and postdischarge mortality rate was 3.3%. In multivariate analysis, patients from Philadelphia were less likely to be discharged on a given day (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.73-0.93), as were black patients (OR, 0.88; 95% CI, 0.82-0.94).The odds of discharge decreased notably with greater patient severity of illness and in patients without private health insurance. Adjusted postdischarge mortality was significantly higher for patients with an LOS of 4 days or less (OR, 1.55; 95% CI, 1.21-2.00) relative to those with an LOS of 5 to 6 days. CONCLUSIONS: Several hospital and patient factors were independently associated with LOS. Patients with a very short LOS had greater postdischarge mortality relative to patients with a typical LOS, suggesting that physicians may inappropriately select patients with PE for early discharge who are at increased risk of complications

Patient-ventilator asynchrony during non-invasive ventilation for acute respiratory failure: a multicenter study.

OBJECTIVE : To determine the prevalence of patient-ventilator asynchrony in patients receiving non-invasive ventilation (NIV) for acute respiratory failure. DESIGN : Prospective multicenter observation study. SETTING : Intensive care units in three university hospitals. METHODS: Patients consecutively admitted to ICU were included. NIV, performed with an ICU ventilator, was set by the clinician. Airway pressure, flow, and surface diaphragmatic electromyography were recorded continuously for 30 min. Asynchrony events and the asynchrony index (AI) were determined from visual inspection of the recordings and clinical observation. RESULTS: A total of 60 patients were included, 55% of whom were hypercapnic. Auto-triggering was present in 8 (13%) patients, double triggering in 9 (15%), ineffective breaths in 8 (13%), premature cycling 7 (12%) and late cycling in 14 (23%). An AI > 10%, indicating severe asynchrony, was present in 26 patients (43%), whose median (25-75 IQR) AI was 26 (15-54%). A significant correlation was found between the magnitude of leaks and the number of ineffective breaths and severity of delayed cycling. Multivariate analysis indicated that the level of pressure support and the magnitude of leaks were weakly, albeit significantly, associated with an AI > 10%. Patient comfort scale was higher in pts with an AI < 10%. CONCLUSION: Patient-ventilator asynchrony is common in patients receiving NIV for acute respiratory failure. Our results suggest that leaks play a major role in generating patient-ventilator asynchrony and discomfort, and point the way to further research to determine if ventilator functions designed to cope with leaks can reduce asynchrony in the clinical setting.

Determinants of generic drug substitution in Switzerland.

Background: Since generic drugs have the same therapeutic effect as the original formulation but at generally lower costs, their use should be more heavily promoted. However, a considerable number of barriers to their wider use have been observed in many countries. The present study examines the influence of patients, physicians and certain characteristics of the generics' market on generic substitution in Switzerland.Methods: We used reimbursement claims' data submitted to a large health insurer by insured individuals living in one of Switzerland's three linguistic regions during 2003. All dispensed drugs studied here were substitutable. The outcome (use of a generic or not) was modelled by logistic regression, adjusted for patients' characteristics (gender, age, treatment complexity, substitution groups) and with several variables describing reimbursement incentives (deductible, co-payments) and the generics' market (prices, packaging, co-branded original, number of available generics, etc.).Results: The overall generics' substitution rate for 173,212 dispensed prescriptions was 31%, though this varied considerably across cantons. Poor health status (older patients, complex treatments) was associated with lower generic use. Higher rates were associated with higher out-of-pocket costs, greater price differences between the original and the generic, and with the number of generics on the market, while reformulation and repackaging were associated with lower rates. The substitution rate was 13% lower among hospital physicians. The adoption of the prescribing practices of the canton with the highest substitution rate would increase substitution in other cantons to as much as 26%.Conclusions: Patient health status explained a part of the reluctance to substitute an original formulation by a generic. Economic incentives were efficient, but with a moderate global effect. The huge interregional differences indicated that prescribing behaviours and beliefs are probably the main determinant of generic substitution.