Efficient inference for genetic association studies with multiple outcomes

Combined inference for heterogeneous high-dimensional data is critical in modern biology, where clinical and various kinds of molecular data may be available from a single study. Classical genetic association studies regress a single clinical outcome on many genetic variants one by one, but there is an increasing demand for joint analysis of many molecular outcomes and genetic variants in order to unravel functional interactions. Unfortunately, most existing approaches to joint modelling are either too simplistic to be powerful or are impracticable for computational reasons. Inspired by Richardson et al. (2010, Bayesian Statistics 9), we consider a sparse multivariate regression model that allows simultaneous selection of predictors and associated responses. As Markov chain Monte Carlo (MCMC) inference on such models can be prohibitively slow when the number of genetic variants exceeds a few thousand, we propose a variational inference approach which produces posterior information very close to that of MCMC inference, at a much reduced computational cost. Extensive numerical experiments show that our approach outperforms popular variable selection methods and tailored Bayesian procedures, dealing within hours with problems involving hundreds of thousands of genetic variants and tens to hundreds of clinical or molecular outcomes

Sickness certification in primary care - the physician's role.

Sickness certification is a routine task of primary care (PC) physicians which has an impact on patients' health, the health care system and the economy. As sickness certification is poorly studied, we quantified sickness certification and explored qualitatively the sickness certification process by Swiss PC physicians. PC physicians participating in the Swiss Sentinel Surveillance Network (SSSN) recorded the frequency and duration of absence from work of each related consultation and certificate during 2005. Patients' age and gender, reason for sick leave, psychosocial cofactors, problems at the workplace, type of employment, type of occupation, duration of absence (weeks) and type of certificate were registered. Physicians' views on the procedure and their suggestions for change were gathered before and after the study by means of a questionnaire containing four open-ended questions. Of the 223 SSSN physicians 73% participated. A total of 24,676 forms issued by 150 physicians were analysed. An average of four certificates was issued per 100 consultations; somewhat fewer by internists than by general practitioners and less in rural areas than urban areas. Psychosocial or work-related factors were mentioned in 20% of the certificates and were more often associated with longer absences from work. These factors were seen as inseparable from the somatic factors. Recommendations for change included the prolongation of self declaration time, a uniform declaration form, availability of an authority to which complex cases can be referred and the use of case management models. Sickness certificates were issued in 4% of GP consultations. This task has been assessed by physicians as part of their function. The certification process should be improved through better coordination and communication between all parties involved: patients, employers, insurers, physicians and politicians

Coupled spin states in armchair graphene nanoribbons with asymmetric zigzag edge extensions

Carbon-based magnetic structures promise significantly longer coherence times than traditional magnetic materials, which is of fundamental importance for spintronic applications. An elegant way of achieving carbon-based magnetic moments is the design of graphene nanostructures with an imbalanced occupation of the two sublattices forming the carbon honeycomb lattice. According to Lieb's theorem, this induces local magnetic moments that are proportional to the sublattice imbalance. Exact positioning of sublattice imbalanced nanostructures in graphene nanomaterials hence offers a route to control interactions between induced local magnetic moments and to obtain graphene nanomaterials with magnetically non-trivial ground states. Here, we show that such sublattice imbalanced nanostructures can be incorporated along a large band gap armchair graphene nanoribbon on the basis of asymmetric zigzag edge extensions, which is achieved by incorporating specifically designed precursor monomers during the bottom-up fabrication of the graphene nanoribbons. Scanning tunneling spectroscopy of an isolated and electronically decoupled zigzag edge extension reveals Hubbard-split states in accordance with theoretical predictions. Investigation of pairs of such zigzag edge extensions reveals ferromagnetic, antiferromagnetic or quenching of the magnetic interactions depending on the relative alignment of the asymmetric edge extensions. Moreover, a ferromagnetic spin chain is demonstrated for a periodic pattern of zigzag edge extensions along the nanoribbon axis. This work opens a route towards the design and fabrication of graphene nanoribbon-based spin chains with complex magnetic ground states

Combining clinical factors and quantitative ultrasound improves the detection of women both at low and high risk for hip fracture

Summary: We hypothesized that combining clinical risk factors (CRF) with the heel stiffness index (SI) measured via quantitative ultrasound (QUS) would improve the detection of women both at low and high risk for hip fracture. Categorizing women by risk score improved the specificity of detection to 42.4%, versus 33.8% using CRF alone and 38.4% using the SI alone. This combined CRF-SI score could be used wherever and whenever DXA is not readily accessible. Introduction and hypothesis: Several strategies have been proposed to identify women at high risk for osteoporosis-related fractures; we wanted to investigate whether combining clinical risk factors (CRF) and heel QUS parameters could provide a more accurate tool to identify women at both low and high risk for hip fracture than either CRF or QUS alone. Methods: We pooled two Caucasian cohorts, EPIDOS and SEMOF, into a large database named "EPISEM”, in which 12,064 women, 70 to 100years old, were analyzed. Amongst all the CRF available in EPISEM, we used only the ones which were statistically significant in a Cox multivariate model. Then, we constructed a risk score, by combining the QUS-derived heel stiffness index (SI) and the following seven CRF: patient age, body mass index (BMI), fracture history, fall history, diabetes history, chair-test results, and past estrogen treatment. Results: Using the composite SI-CRF score, 42% of the women who did not report a hip fracture were found to be at low risk at baseline, and 57% of those who subsequently sustained a fracture were at high risk. Using the SI alone, corresponding percentages were 38% and 52%; using CRF alone, 34% and 53%. The number of subjects in the intermediate group was reduced from 5,400 (including 112 hip fractures) and 5,032 (including 111 hip fractures) to 4549 (including 100 including fractures) for the CRF and QUS alone versus the combination score. Conclusions: Combining clinical risk factors to heel bone ultrasound appears to correctly identify more women at low risk for hip fracture than either the stiffness index or the CRF alone; it improves the detection of women both at low and high ris

Preserved decision making ability in early multiple sclerosis

Background : The purpose of this study was to assess decision making in patients with multiple sclerosis (MS) at the earliest clinically detectable time point of the disease. Methods : Patients with definite MS (n = 109) or with clinically isolated syndrome (CIS, n = 56), a disease duration of 3 months to 5 years, and no or only minor neurological impairment (Expanded Disability Status Scale [EDSS] score 0-2.5) were compared to 50 healthy controls using the Iowa Gambling Task (IGT). Results : The performance of definite MS, CIS patients, and controls was comparable for the two main outcomes of the IGT (learning index: p = 0.7; total score: p = 0.6). The IGT learning index was influenced by the educational level and the co-occurrence of minor depression. CIS and MS patients developing a relapse during an observation period of 15 months dated from IGT testing demonstrated a lower learning index in the IGT than patients who had no exacerbation (p = 0.02). When controlling for age, gender and education, the difference between relapsing and non-relapsing patients was at the limit of significance (p = 0.06). Conclusion : Decision making in a task mimicking real life decisions is generally preserved in early MS patients as compared to controls. A possible consequence of MS relapsing activity in the impairment of decision making ability is also suspected in the early phase of M

Determinants of smoking and cessation in older women

BACKGROUND: although the benefits of quitting smoking even at an advanced age have been proved, few campaigns target the older population. The goals of this study were to analyse the characteristics of older women smokers help and support those wanting to quit. METHODS: we assessed the determinants of smoking cessation in a prospective cohort study performed in 7,609 older women. A questionnaire about smoking habits was sent to the 486 eligible smokers. Smoking dependence and smokers' readiness to quit was assessed. Participants who had quit smoking during follow-up were asked about their previous reasons for quitting and the methods used to quit. RESULTS: 372 women of the 424 (88%) responded to our questionnaire and were included. The most common reasons for smoking were relaxation, pleasure, and habit. Major obstacles to quitting smoking were 'no benefit to quitting at an advanced age', 'smoking few or "light" cigarettes yields no negative health consequences', and 'smoking does not increase osteoporotic risk'. During the 3-year follow-up period, 57 of the 372 (15%) women successfully quit smoking. Being an occasional smoker (OR=2.4) and reporting 'quitting is not difficult' (OR=3.7) were positively associated with having recently quit smoking. Only 11% of successful cessations were reported to have received physician advice. CONCLUSIONS: these data illustrate the specific smoking behaviour of older women, suggesting that cessation interventions ought to be tailored to these characteristics. Willingness to quit was associated with a low education level. The most frequent obstacles to quitting were all based on incorrect information

Combining bone resorption markers and heel quantitative ultrasound to discriminate between fracture cases and controls

Summary: This nested case-control analysis of a Swiss ambulatory cohort of elderly women assessed the discriminatory power of urinary markers of bone resorption and heel quantitative ultrasound for non-vertebral fractures. The tests all discriminated between cases and controls, but combining the two strategies yielded no additional relevant information. Introduction: Data are limited regarding the combination of bone resorption markers and heel quantitative bone ultrasound (QUS) in the detection of women at risk for fracture. Methods: In a nested case-control analysis, we studied 368 women (mean age 76.2 ± 3.2years), 195 with low-trauma non-vertebral fractures and 173 without, matched for age, BMI, medical center, and follow-up duration, from a prospective study designed to predict fractures. Urinary total pyridinolines (PYD) and deoxypyridinolines (DPD) were measured by high performance liquid chromatography. All women underwent bone evaluations using Achilles+ and Sahara heel QUS. Results: Areas under the receiver operating-characteristic curve (AUC) for discriminative models of the fracture group, with 95% confidence intervals, were 0.62 (0.56-0.68) and 0.59 (0.53-0.65) for PYD and DPD, and 0.64 (0.58-0.69) and 0.65 (0.59-0.71) for Achilles+ and Sahara QUS, respectively. The combination of resorption markers and QUS added no significant discriminatory information to either measurement alone with an AUC of 0.66 (0.60-0.71) for Achilles+ with PYD and 0.68 (0.62-0.73) for Sahara with PYD. Conclusions: Urinary bone resorption markers and QUS are equally discriminatory between non-vertebral fracture patients and controls. However, the combination of bone resorption markers and QUS is not better than either test used alon

Management and prognosis of status epilepticus according to hospital setting: a prospective study.

BACKGROUND: The treatment of status epilepticus (SE) is based on relatively little evidence although several guidelines have been published. A recent study reported a worse SE prognosis in a large urban setting as compared to a peripheral hospital, postulating better management in the latter. The aim of this study was to analyse SE episodes occurring in different settings and address possible explanatory variables regarding outcome, including treatment quality. METHODS: Over six months we prospectively recorded consecutive adults with SE (fit lasting five or more minutes) at the Centre Hospitalier Universitaire Vaudois (CHUV) and in six peripheral hospitals (PH) in the same region. Demographical, historical and clinical variables were collected, including SE severity estimation (STESS score) and adherence to Swiss SE treatment guidelines. Outcome at discharge was categorised as "good" (return to baseline), or "poor" (persistent neurological sequelae or death). RESULTS: Of 54 patients (CHUV: 36; PH 18), 33% had a poor outcome. Whilst age, SE severity, percentage of SE episodes lasting less than 30 minutes and total SE duration were similar, fewer patients had a good outcome at the CHUV (61% vs 83%; OR 3.57; 95% CI 0.8-22.1). Mortality was 14% at the CHUV and 5% at the PH. Most treatments were in agreement with national guidelines, although less often in PH (78% vs 97%, P = 0.04). CONCLUSION: Although not statistically significant, we observed a slightly worse SE prognosis in a large academic centre as compared to smaller hospitals. Since SE severity was similar in the two settings but adherence to national treatment guidelines was higher in the academic centre, further investigation on the prognostic role of SE treatment and outcome determinants is required

On‐surface synthesis of porous graphene nanoribbons containing nonplanar [14]annulene pores

The precise introduction of nonplanar pores in the backbone of graphene nanoribbon represents a great challenge. Here, we explore a synthetic strategy toward the preparation of nonplanar porous graphene nanoribbon from a predesigned dibromohexabenzotetracene monomer bearing four cove-edges. Successive thermal annealing steps of the monomers indicate that the dehalogenative aryl-aryl homocoupling yields a twisted polymer precursor on a gold surface and the subsequent cyclodehydrogenation leads to a defective porous graphene nanoribbon containing nonplanar [14]annulene pores and five-membered rings as characterized by scanning tunneling microscopy and noncontact atomic force microscopy. Although the C–C bonds producing [14]annulene pores are not achieved with high yield, our results provide new synthetic perspectives for the on-surface growth of nonplanar porous graphene nanoribbons

Exploiting existing ground-based remote sensing networks to improve high-resolution weather forecasts

A new generation of high-resolution (1 km) forecast models promises to revolutionize the prediction of hazardous weather such as windstorms, flash floods, and poor air quality. To realize this promise, a dense observing network, focusing on the lower few kilometers of the atmosphere, is required to verify these new forecast models with the ultimate goal of assimilating the data. At present there are insufficient systematic observations of the vertical profiles of water vapor, temperature, wind, and aerosols; a major constraint is the absence of funding to install new networks. A recent research program financed by the European Union, tasked with addressing this lack of observations, demonstrated that the assimilation of observations from an existing wind profiler network reduces forecast errors, provided that the individual instruments are strategically located and properly maintained. Additionally, it identified three further existing European networks of instruments that are currently underexploited, but with minimal expense they could deliver quality-controlled data to national weather services in near–real time, so the data could be assimilated into forecast models. Specifically, 1) several hundred automatic lidars and ceilometers can provide backscatter profiles associated with aerosol and cloud properties and structures with 30-m vertical resolution every minute; 2) more than 20 Doppler lidars, a fairly new technology, can measure vertical and horizontal winds in the lower atmosphere with a vertical resolution of 30 m every 5 min; and 3) about 30 microwave profilers can estimate profiles of temperature and humidity in the lower few kilometers every 10 min. Examples of potential benefits from these instruments are presented