Genome-wide association study of multiple sclerosis confirms a novel locus at 5p13.1.

Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36 × 10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS.

Validation of a new tool to assess health-related quality of life in psoriasis: the PSO-LIFE questionnaire.

BACKGROUND Several questionnaires have been used to measure health related quality of life (HRQoL) in patients with psoriasis, few have been adapted for use in Spain; none of them was developed specifically for the Spanish population. The purpose of the study was to validate and assess the sensitivity to change of a new questionnaire to measure HRQOL in patients with psoriasis (PSO-LIFE). METHODS Observational, prospective, multicenter study performed in centers around Spain. Patients with active or inactive psoriasis completed the PSO-LIFE together with other Dermatology Quality of Life Index (DLQI) and Psoriasis Disability Index (PDI). A control group of patients with urticaria or atopic dermatitis was also included. Internal consistency and test-retest reliability of the PSO-LIFE were assessed by calculating Cronbach's alpha and Intraclass Correlation Coefficient (ICC). Validity was assessed by examining factorial structure, the capacity to discriminate between groups, and correlations with other measures. Sensitivity to change was measured using effect sizes. RESULTS The final sample included for analysis consisted of 304 patients and 56 controls. Mean (SD) age of psoriasis patients was 45.3 (14.5) years compared to 38.8 (14) years for controls (p < 0.01). Cronbach's alpha for the PSO-LIFE was 0.95 and test-retest reliability using the ICC was 0.98. Factor analysis showed the questionnaire to be unidimensional. Mean (SD) PSO-LIFE scores differed between patients with psoriasis and controls (64.9 [22.5] vs 69.4 [17.3]; p < 0.05), between those with active and inactive disease (57.4 [20.4] vs 76.4 [20.6]; p < 0.01), and between those with visible and non-visible lesions (63.0 [21.9] vs. 74.8 [23.9]; p < 0.01). The correlation between PSO-LIFE and PASI scores was moderate (r = -0.43) while correlations with DLQI and PDI dimensions ranged from moderate to high (between 0.4 and 0.8). Effect size on the PSO-LIFE in patients reporting 'much improved' health status at study completion was 1.01 (large effect size). CONCLUSIONS The present results provide substantial support for the reliability, validity, and responsiveness of the PSO-LIFE questionnaire in the population for which it was designed.

Evaluation of email alerts in practice: Part 2. Validation of the information assessment method.

RATIONALE AND OBJECTIVE:. The information assessment method (IAM) permits health professionals to systematically document the relevance, cognitive impact, use and health outcomes of information objects delivered by or retrieved from electronic knowledge resources. The companion review paper (Part 1) critically examined the literature, and proposed a 'Push-Pull-Acquisition-Cognition-Application' evaluation framework, which is operationalized by IAM. The purpose of the present paper (Part 2) is to examine the content validity of the IAM cognitive checklist when linked to email alerts. METHODS: A qualitative component of a mixed methods study was conducted with 46 doctors reading and rating research-based synopses sent on email. The unit of analysis was a doctor's explanation of a rating of one item regarding one synopsis. Interviews with participants provided 253 units that were analysed to assess concordance with item definitions. RESULTS AND CONCLUSION: The content relevance of seven items was supported. For three items, revisions were needed. Interviews suggested one new item. This study has yielded a 2008 version of IAM.

Validation interne de la version française du NEO-PI-R et influence de l'âge, du sexe et de la profession

We have examined the internal validity of the French translation of the NEO PI-R personality test which measures the « big five » (Rolland, 1993). The impact of age, gender and professional categories on the NEO PI-R scales was assessed. A large sample (n=731) of subjects of different age, gender and profession and a sample of Swiss students (n=261) responding anonymously were used. Factor analyses confirmed the structure of the instrument (5 domains) and the structures of the domains in terms of facets (six facets within each domain). On the other hand, the age has a significant impact on all the domains of the NEO PI-R; the gender has an impact on the scores on N (neuroticism), O (openness) and A (agreeableness), and the profession has an impact on the domains E (extraversion), O (openness) and A (agreeableness). The scores on several facets are also affected by those three variables. Our study gives the researchers and the practitioner a reference score table according to the studied variables.

Validation de la version française de l'échelle de contrôle de Levenson (IPC), influence de variables démographiques et de la personnalité

We have examined the internal validity of the Levenson's locus of control scales (IPC, Internal, Powerful others and Chances), translated by Loas et al. (1994). The impact of different demographic variables on the Levenson's locus of control scales was assessed. After, we studied the relation between the IPC scales and the NEO PI R, personality inventory that measures the big five. A large sample (n=200) of subjects of different age, gender and profession and a sample of Swiss students (n=161) responding anonymously were used. The reliability of the IPC scale is acceptable. The analyses of the impact of the demographic variables show that gender and level of education have an influence on the I (intern) scale. Age, gender, level of education and profession have an impact on the P (powerful others) scale. The analyses of the relationship between locus of control and personality showed that there was a negative correlation between I (intern) and Neuroticism and a positive correlation between I and Extraversion and Consciousness. The P (powerful others) scale correlate positively with Neuroticism and negatively with Openness and Agreability. The C scale (chance) correlate positively with Neuroticism. Our study also gives the researchers and the practitioner a reference score table according to the gender, the age, the level of education and the profession.

Validation d'une version abrégée du TCI (TCI-56) sur un échantillon de jeunes fumeurs et non-fumeurs

Introduction: The psychobiological seven-factor model proposed by Cloninger et al. (1993) takes into account temperament and character dimensions to describe personality. Four of the dimensions are linked with biological, genetic and neuroanatomic structures, whereas the three other dimensions are related to the degree of individual, social and spiritual development. A study conducted by Wills et al. (1994) with adolescents showed that substance abuse was associated with high scores on Novelty Seeking and low scores on Harm Avoidance and Reward Dependence. The aim of the present study was, firstly, to create a short form of Cloninger's (1993) Temperament and Character Inventory (TCI) and, secondly, to study the impact of nicotine dependence as well as demographic variables on a sample of young adults. Method: We created a short form of the TCI containing 56 items (TCI-56), 8 for each scale. Responses are made on a five-point Likert type scale. A Swiss sample (n=211), of 116 women and 95 men, aged from 15 to 30 years, participated in this study. Our population was divided into a group of 81 smokers and another of 130 non-smokers, according to their scores on the Fagerstörm test for nicotine dependence (1999). Results: The structural validation consisted of two separate factor analysis with varimax rotations, one for the temperamental items, and the other, for the character ones. The first factor analysis conducted on the items of the temperament scales allowed to extract 4 factors explaining 40.7% of the variance. The correlations between factors and scales are the following: r=.71 for Novelty Seeking, r=.69 for Persistence, r=.95 for Harm Avoidance, r=.94 for Reward Dependence. The second factor analysis conducted on the items of the character scales allowed to extract 3 factors explaining 41.5% of the variance. The correlations between factors and scales are the following: r=.94 for Self-Directedness, r=.91 for Cooperativeness and r=.99 for Self-Transcendence. The internal consistencies range from α=.65 to α=.75 for the temperament scales, and from α=.71 to α=.83 for the three character scales. Concerning, the impact of the nicotine dependence, we observed that smokers have significantly higher scores for Novelty seeking, than non-smokers (p=.01). We found no difference for Harm Avoidance and Reward Dependence. Nevertheless, smokers seem to have the tendency to score higher on Transcendence (p=.06). Moreover, people having smoked more than 100 cigarettes in their life have significantly higher scores on this scale (p.04) and the correlation between Transcendence and the Fagerstörm test is significant (r=.19). We also found gender differences: the women (N=116) obtain significantly higher scores for Harm Avoidance (p<.001), for Reward Dependence (p<.001) and for Cooperation (p=.01). We further found a significant correlation between age and Self-Directedness, r=.34. We observed no interaction between gender and smoking or age and smoking on the dimensions of the TCI-56. Discussion: The TCI short form (TCI-56) seems to be a valid and useful inventory to assess personality differences. Confirming the results of others about the relation between addiction and personality, we found that smokers have significantly higher scores for Novelty seeking, than non-smokers. But we were not able to find any significant differences for Harm Avoidance and Reward Dependence. This might be due to our sample that was made of young adults. This study also shows that Transcendence could be an interesting dimension for studies on Tobacco smoking to consider. Concerning the impact of demographic variables, we observed that age and gender have specific and coherent influence on personality.

Development and validation of PCR-based assays for diagnosis of American cutaneous leishmaniasis and identificatio nof the parasite species

In this study, PCR assays targeting different Leishmania heat-shock protein 70 gene (hsp70) regions, producing fragments ranging in size from 230-390 bp were developed and evaluated to determine their potential as a tool for the specific molecular diagnosis of cutaneous leishmaniasis (CL). A total of 70 Leishmania strains were analysed, including seven reference strains (RS) and 63 previously typed strains. Analysis of the RS indicated a specific region of 234 bp in the hsp70 gene as a valid target that was highly sensitive for detection of Leishmania species DNA with capacity of distinguishing all analyzed species, after polymerase chain reaction-restriction fragment length polymorfism (PCR-RFLP). This PCR assay was compared with other PCR targets used for the molecular diagnosis of leishmaniasis: hsp70 (1400-bp region), internal transcribed spacer (ITS)1 and glucose-6-phosphate dehydrogenase (G6pd). A good agreement among the methods was observed concerning the Leishmania species identification. Moreover, to evaluate the potential for molecular diagnosis, we compared the PCR targets hsp70-234 bp, ITS1, G6pd and mkDNA using a panel of 99 DNA samples from tissue fragments collected from patients with confirmed CL. Both PCR-hsp70-234 bp and PCR-ITS1 detected Leishmania DNA in more than 70% of the samples. However, using hsp70-234 bp PCR-RFLP, identification of all of the Leishmania species associated with CL in Brazil can be achieved employing a simpler and cheaper electrophoresis protocol.

Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism.

BACKGROUND: The Outpatient Bleeding Risk Index (OBRI) and the Kuijer, RIETE and Kearon scores are clinical prognostic scores for bleeding in patients receiving oral anticoagulants for venous thromboembolism (VTE). We prospectively compared the performance of these scores in elderly patients with VTE. METHODS: In a prospective multicenter Swiss cohort study, we studied 663 patients aged ≥ 65 years with acute VTE. The outcome was a first major bleeding at 90 days. We classified patients into three categories of bleeding risk (low, intermediate and high) according to each score and dichotomized patients as high vs. low or intermediate risk. We calculated the area under the receiver-operating characteristic (ROC) curve, positive predictive values and likelihood ratios for each score. RESULTS: Overall, 28 out of 663 patients (4.2%, 95% confidence interval [CI] 2.8-6.0%) had a first major bleeding within 90 days. According to different scores, the rate of major bleeding varied from 1.9% to 2.1% in low-risk, from 4.2% to 5.0% in intermediate-risk and from 3.1% to 6.6% in high-risk patients. The discriminative power of the scores was poor to moderate, with areas under the ROC curve ranging from 0.49 to 0.60 (P = 0.21). The positive predictive values and positive likelihood ratios were low and varied from 3.1% to 6.6% and from 0.72 to 1.59, respectively. CONCLUSION: In elderly patients with VTE, existing bleeding risk scores do not have sufficient accuracy and power to discriminate between patients with VTE who are at a high risk of short-term major bleeding and those who are not.

Immunologic evaluation and validation of methods using synthetic peptides derived from Mycobacterium tuberculosis for the diagnosis of tuberculosis infection

The goal of this study was to demonstrate the usefulness of an enzyme-linked immunosorbent assay (ELISA) for the serodiagnosis of pulmonary tuberculosis (PTB) and extrapulmonary TB (EPTB). This assay used 20 amino acid-long, non-overlapped synthetic peptides that spanned the complete Mycobacterium tuberculosis ESAT-6 and Ag85A sequences. The validation cohort consisted of 1,102 individuals who were grouped into the following five diagnostic groups: 455 patients with PTB, 60 patients with EPTB, 40 individuals with non-EPTB, 33 individuals with leprosy and 514 healthy controls. For the PTB group, two ESAT-6 peptides (12033 and 12034) had the highest sensitivity levels of 96.9% and 96.2%, respectively, and an Ag85A-peptide (29878) was the most specific (97.4%) in the PTB groups. For the EPTB group, two Ag85A peptides (11005 and 11006) were observed to have a sensitivity of 98.3% and an Ag85A-peptide (29878) was also the most specific (96.4%). When combinations of peptides were used, such as 12033 and 12034 or 11005 and 11006, 99.5% and 100% sensitivities in the PTB and EPTB groups were observed, respectively. In conclusion, for a cohort that consists entirely of individuals from Venezuela, a multi-antigen immunoassay using highly sensitive ESAT-6 and Ag85A peptides alone and in combination could be used to more rapidly diagnose PTB and EPTB infection.

Development and validation of a risk score predicting substantial weight gain over 5 years in middle-aged European men and women.

BACKGROUND Identifying individuals at high risk of excess weight gain may help targeting prevention efforts at those at risk of various metabolic diseases associated with weight gain. Our aim was to develop a risk score to identify these individuals and validate it in an external population. METHODS We used lifestyle and nutritional data from 53°758 individuals followed for a median of 5.4 years from six centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) to develop a risk score to predict substantial weight gain (SWG) for the next 5 years (derivation sample). Assuming linear weight gain, SWG was defined as gaining ≥ 10% of baseline weight during follow-up. Proportional hazards models were used to identify significant predictors of SWG separately by EPIC center. Regression coefficients of predictors were pooled using random-effects meta-analysis. Pooled coefficients were used to assign weights to each predictor. The risk score was calculated as a linear combination of the predictors. External validity of the score was evaluated in nine other centers of the EPIC study (validation sample). RESULTS Our final model included age, sex, baseline weight, level of education, baseline smoking, sports activity, alcohol use, and intake of six food groups. The model's discriminatory ability measured by the area under a receiver operating characteristic curve was 0.64 (95% CI = 0.63-0.65) in the derivation sample and 0.57 (95% CI = 0.56-0.58) in the validation sample, with variation between centers. Positive and negative predictive values for the optimal cut-off value of ≥ 200 points were 9% and 96%, respectively. CONCLUSION The present risk score confidently excluded a large proportion of individuals from being at any appreciable risk to develop SWG within the next 5 years. Future studies, however, may attempt to further refine the positive prediction of the score.

Responsiveness of the Multiple Sclerosis International Quality of Life questionnaire to disability change: a longitudinal study.

BACKGROUND Responsiveness, defined as the ability to detect a meaningful change, is a core psychometric property of an instrument measuring quality of life (QoL) rarely reported in multiple sclerosis (MS) studies. OBJECTIVE To assess the responsiveness of the Multiple Sclerosis International Quality of Life (MusiQoL) questionnaire to change in disability over 24 months, defined by change in the Expanded Disability Status Scale (EDSS) score. METHODS Patients with MS were enrolled into a multicenter, longitudinal observational study. QoL was assessed using both the MusiQoL and the 36-Item Short-Form (SF-36) instruments at baseline and every 6 months thereafter up to month 24; neurological assessments, including EDSS score, were performed at each evaluation. RESULTS The 24-month EDSS was available for 524 patients. In the 107 worsened patients, two specific dimensions of MusiQoL, the sentimental and sexual life and the relationships with health care system dimensions, and 'physical' scores of SF-36 showed responsiveness. CONCLUSIONS Whereas specific dimensions of MusiQoL identified EDSS changes, the MusiQoL index did not detect disability changes in worsened MS patients in a 24-month observational study. Future responsiveness validation studies should include longer follow-up and more representative samples.

Estimating Gross Value Added (GVA) across multiple scales: theoretical approach and empirical validation

This paper presents an application of the Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism (MuSIASEM) approach to the estimation of quantities of Gross Value Added (GVA) referring to economic entities defined at different scales of study. The method first estimates benchmark values of the pace of GVA generation per hour of labour across economic sectors. These values are estimated as intensive variables –e.g. €/hour– by dividing the various sectorial GVA of the country (expressed in € per year) by the hours of paid work in that same sector per year. This assessment is obtained using data referring to national statistics (top down information referring to the national level). Then, the approach uses bottom-up information (the number of hours of paid work in the various economic sectors of an economic entity –e.g. a city or a province– operating within the country) to estimate the amount of GVA produced by that entity. This estimate is obtained by multiplying the number of hours of work in each sector in the economic entity by the benchmark value of GVA generation per hour of work of that particular sector (national average). This method is applied and tested on two different socio-economic systems: (i) Catalonia (considered level n) and Barcelona (considered level n-1); and (ii) the region of Lima (considered level n) and Lima Metropolitan Area (considered level n-1). In both cases, the GVA per year of the local economic entity –Barcelona and Lima Metropolitan Area – is estimated and the resulting value is compared with GVA data provided by statistical offices. The empirical analysis seems to validate the approach, even though the case of Lima Metropolitan Area indicates a need for additional care when dealing with the estimate of GVA in primary sectors (agriculture and mining).

Nutrient patterns and their food sources in an International Study Setting: report from the EPIC study.

BACKGROUND Compared to food patterns, nutrient patterns have been rarely used particularly at international level. We studied, in the context of a multi-center study with heterogeneous data, the methodological challenges regarding pattern analyses. METHODOLOGY/PRINCIPAL FINDINGS We identified nutrient patterns from food frequency questionnaires (FFQ) in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study and used 24-hour dietary recall (24-HDR) data to validate and describe the nutrient patterns and their related food sources. Associations between lifestyle factors and the nutrient patterns were also examined. Principal component analysis (PCA) was applied on 23 nutrients derived from country-specific FFQ combining data from all EPIC centers (N = 477,312). Harmonized 24-HDRs available for a representative sample of the EPIC populations (N = 34,436) provided accurate mean group estimates of nutrients and foods by quintiles of pattern scores, presented graphically. An overall PCA combining all data captured a good proportion of the variance explained in each EPIC center. Four nutrient patterns were identified explaining 67% of the total variance: Principle component (PC) 1 was characterized by a high contribution of nutrients from plant food sources and a low contribution of nutrients from animal food sources; PC2 by a high contribution of micro-nutrients and proteins; PC3 was characterized by polyunsaturated fatty acids and vitamin D; PC4 was characterized by calcium, proteins, riboflavin, and phosphorus. The nutrients with high loadings on a particular pattern as derived from country-specific FFQ also showed high deviations in their mean EPIC intakes by quintiles of pattern scores when estimated from 24-HDR. Center and energy intake explained most of the variability in pattern scores. CONCLUSION/SIGNIFICANCE The use of 24-HDR enabled internal validation and facilitated the interpretation of the nutrient patterns derived from FFQs in term of food sources. These outcomes open research opportunities and perspectives of using nutrient patterns in future studies particularly at international level.

Transcultural adaptation and validation of the "Hip and Knee" questionnaire into Spanish.

BACKGROUND The purpose of the present study is to translate and validate the "Hip and Knee Outcomes Questionnaire", developed in English, into Spanish. The 'Hip and Knee Outcomes Questionnaire is a questionnaire planned to evaluate the impact in quality of life of any problem related to the human musculoskeletal system. 10 scientific associations developed it. METHODS The questionnaire underwent a validated translation/retro-translation process. Patients undergoing primary knee arthroplasty, before and six months postoperative, tested the final version in Spanish. Psychometric properties of feasibility, reliability, validity and sensitivity to change were assessed. Convergent validity with SF-36 and WOMAC questionnaires was evaluated. RESULTS 316 patients were included. Feasibility: a high number of missing items in questions 3, 4 and 5 were observed. The number of patients with a missing item was 171 (51.35%) in the preoperative visit and 139 (44.0%) at the postoperative. Internal validity: revision of coefficients in the item-rest correlation recommended removing question 6 during the preoperative visit (coefficient <0.20). Convergent validity: coefficients of correlation with WOMAC and SF-36 scales confirm the questionnaire's validity. Sensitivity to change: statistically significant differences were found between the mean scores of the first visit compared to the postoperative. CONCLUSION The proposed translation to Spanish of the 'Hip and Knee Questionnaire' is found to be reliable, valid and sensible to changes produced at the clinical practice of patients undergoing primary knee arthroplasty. However, some changes at the completion instructions are recommended. LEVEL OF EVIDENCE Level I. Prognostic study.

Validation transculturelle de l'Oswestry disability index en français [Cross-cultural validation of the Oswestry disability index in French]

AIM: The aim of this study was to interpret and validate a French version of the Oswestry disability index (ODI), using a cross-cultural validation method. The validity and reliability of the questionnaire was assessed in order to ensure the psychometric characteristics. METHOD: The cross-cultural validation was carried out according to Beaton's methodology. The study was conducted with 41 patients suffering from low back pain. The correlation between the ODI and the Roland-Morris disability questionnaire (RMDQ), the medical outcome survey short form-36 (MOS SF-36) and a pain visual analogical scale (VAS) was assessed. RESULTS: The validity of the Oswestry questionnaire was studied using the Cronbach Alpha coefficient calculation: 0.87 (n=36). The significant correlation between the ODI and RMDQ was 0.8 (P<0.001, n=41) and 0.71 (P<0.001, n=36) for the pain VAS. The correlation between the ODI and certain subscales (physical functioning 0.7 (P<0.001, n=41), physical role 0.49 et bodily pain 0.73 (P<0.001, n=41)) of the MOS SF-36 were equally significant. The reproducibility of the ODI was calculated using the Wilcoxon matched pairs test: there was no significant difference for eight out of ten sections or for the final score. CONCLUSION: This French translation of the ODI should be considered as valid and reliable. It should be used for any future clinical studies carried out using French language patients. Complimentary studies must be completed in order to assess its sensitivity to change in the event of any modifications in the patients functional capacity.