A New Way of Identifying Biomarkers in Biomedical Basic-Research Studies

A simple, nonparametric and distribution free method was developed for quick identification of the most meaningful biomarkers among a number of candidates in complex biological phenomena, especially in relatively small samples. This method is independent of rigid model forms or other link functions. It may be applied both to metric and non-metric data as well as to independent or matched parallel samples. With this method identification of the most relevant biomarkers is not based on inferential methods; therefore, its application does not require corrections of the level of significance, even in cases of thousands of variables. Hence, the introduced method is appropriate to analyze and evaluate data of complex investigations in clinical and pre-clinical basic research, such as gene or protein expressions, phenotype-genotype associations in case-control studies on the basis of thousands of genes and SNPs (single nucleotide polymorphism), search of prevalence in sleep EEG-Data, functional magnetic resonance imaging (fMRI) or others

Stress from Uncertainty from Graduation to Retirement—A Population-Based Study of Swiss Physicians

BACKGROUND: Uncertainty shapes many decisions made by physicians everyday. Uncertainty and physicians’ inability to handle it may result in substandard care and unexplained variations in patterns of care. OBJECTIVE: To describe socio-demographic and professional characteristics of reactions to uncertainty among physicians from all specialties, including physicians in training. DESIGN: Cross-sectional postal survey. PARTICIPANT: All physicians practicing in Geneva, Switzerland (n = 1,994). MEASUREMENT: Reaction to medical care uncertainty was measured with the Anxiety Due to Uncertainty and Concern About Bad Outcomes scales. The questionnaire also included items about professional characteristics and work-related satisfaction scales. RESULTS: After the first mailing and two reminders, 1,184 physicians responded to the survey. In univariate analysis, women, junior physicians, surgical specialists, generalist physicians, and physicians with lower workloads had higher scores in both scales. In multivariate models, sex, medical specialty, and workload remained significantly associated with both scales, whereas clinical experience remained associated only with concern about bad outcomes. Higher levels of anxiety due to uncertainty were associated with lower scores of work-related satisfaction, while higher levels of concern about bad outcomes were associated with lower satisfaction scores for patient care, personal rewards, professional relations, and general satisfaction, but not for work-related burden or satisfaction with income-prestige. The negative effect of anxiety due to uncertainty on work-related satisfaction was more important for physicians in training. CONCLUSION: Physicians’ reactions to uncertainty in medical care were associated with several dimensions of work-related satisfaction. Physicians in training experienced the greatest impact of anxiety due to uncertainty on their work-related satisfaction. Incorporating strategies to deal with uncertainty into residency training may be useful

Interference of functional dual-tasks on gait in untrained people with Parkinson's disease and healthy controls: a cross-sectional study

[EN] Background In Parkinson's disease (PD) population, performing secondary tasks while walking further deteriorates gait and restrict mobility in functional contexts of daily life. This study (1) analyzed the interference of functional cognitive and motor secondary task on untrained people with PD and (2) compared their walking with healthy subjects. Methods Forty people with PD (aged 66.72 [7.5] years, Hoehn and Yahr stage I-II-III, on-medication) composed the PD group (PDG) and 43 participants (aged 66.60 [8.75] years) formed the group of healthy counterparts (HG). Gait was evaluated through spatiotemporal, kinematic and kinetic outcomes in five conditions: single task (ST) and visual, verbal, auditory and motor dual-task (DT). Results The velocity, stride length, and braking force performance of both groups was statistically higher in the ST condition than in verbal, auditory and motor DT (p.05). Conclusions: In untrained participants with PD, verbal and motor secondary tasks affect gait significantly, while auditory and visual tasks interfere to a lesser extent. Untrained people with PD have a poorer gait performance than their healthy counterparts, but in different grades according to the analyzed variables. Trial registration The data in this paper are part of a single-blind, randomized, controlled trial and correspond to the evaluations performed before a physical rehabilitation program, retrospectively registered with the number at clinicaltrial.govNCT04038866.San Martín Valenzuela, C.; Dueñas Moscardó, L.; Lopez Pascual, J.; Serra-Añó, P.; Tomás, JM. (2020). Interference of functional dual-tasks on gait in untrained people with Parkinson's disease and healthy controls: a cross-sectional study. BMC Musculoskeletal Disorders. 21(1):1-11. https://doi.org/10.1186/s12891-020-03431-xS111211Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79:368–76.Soh S-E, McGinley JL, Watts JJ, Iansek R, Murphy AT, Menz HB, et al. Determinants of health-related quality of life in people with Parkinson’s disease: a path analysis. Qual Life Res. 2013;22:1543–53.Tan D, Danoudis M, McGinley J, Morris ME. Relationships between motor aspects of gait impairments and activity limitations in people with Parkinson’s disease: a systematic review. Parkinsonism Relat Disord. 2012;18:117–24.Kelly VE, Eusterbrock AJ, Shumway-Cook A. A review of dual-task walking deficits in people with Parkinson’s disease: motor and cognitive contributions, mechanisms, and clinical implications. Parkinson’s Disease. 2012;918719.Sofuwa O, Nieuwboer A, Desloovere K, Willems A-M, Chavret F, Jonkers I. Quantitative gait analysis in Parkinson’s disease: comparison with a healthy control group. Arch Phys Med Rehabil. 2005;86:1007–13.Beauchet O, Berrut G. Gait and dual-task: definition, interest, and perspectives in the elderly. Psychologie et NeuroPsychiatrie du Vieillissement. 2006;4:215–25.Raffegeau TE, Krehbiel LM, Kang N, Thijs FJ, Altmann LJP, Cauraugh JH, et al. A meta-analysis: Parkinson’s disease and dual-task walking. Parkinsonism Relat Disord. 2019 May;62:28–35.Eric R. Kandel, James H. Schwartz, Thomas M. Jessell, Steven a. Siegelbaum, A. J. Hudspeth. Principles of neural science. Fifth edition. McGraw-Hill Medical: United States of America; 2013.Eisinger RS, Cernera S, Gittis A, Gunduz A, Okun MS. A review of basal ganglia circuits and physiology: application to deep brain stimulation. Parkinsonism Relat Disord. 2019 Feb;59:9–20.Isella V, Mapelli C, Morielli N, De Gaspari D, Siri C, Pezzoli G, et al. Validity and metric of MiniMental Parkinson and MiniMental state examination in Parkinson’s disease. Neurol Sci. 2013;34:1751–8.Morris ME, McGinley J, Huxham F, Collier J, Iansek R. Constraints on the kinetic, kinematic and spatiotemporal parameters of gait in Parkinson’s disease. Hum Mov Sci. 1999;18:461–83.Brauer SG, Morris ME. Can people with Parkinson’s disease improve dual tasking when walking? Gait & Posture. 2010;31:229–33.Baron EI, Miller Koop M, Streicher MC, Rosenfeldt AB, Alberts JL. Altered kinematics of arm swing in Parkinson’s disease patients indicates declines in gait under dual-task conditions. Parkinsonism Relat Disord. 2018;48:61–7.Rochester L, Galna B, Lord S, Burn D. The nature of dual-task interference during gait in incident Parkinson’s disease. Neuroscience. 2014;265:83–94.Logan D, Kiemel T, Dominici N, Cappellini G, Ivanenko Y, Lacquaniti F, et al. The many roles of vision during walking. Exp Brain Res. 2010;206:337–50.de Luna RA, Mihailovic A, Nguyen AM, Friedman DS, Gitlin LN, Ramulu PY. The Association of Glaucomatous Visual Field Loss and Balance. Transl Vis Sci Technol. 2017 May 22;6(3):8.Suarez H, Geisinger D, Ferreira ED, Nogueira S, Arocena S, Roman CS, et al. Balance in Parkinson’s disease patients changing the visual input. Brazilian Journal of Otorhinolaryngology. 2011;77:651–5.Wu T, Hallett M. Neural correlates of dual task performance in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2008;79:760–6.Canning CG. The effect of directing attention during walking under dual-task conditions in Parkinson’s disease. Parkinsonism Relat Disord. 2005;11:95–9.Wu T, Liu J, Zhang H, Hallett M, Zheng Z, Chan P. Attention to automatic movements in Parkinson’s disease: modified automatic mode in the striatum. Cereb Cortex. 2015;25:3330–42.de Roiz R. M, Cacho EWA, Pazinatto MM, Reis JG, Cliquet a. Barasnevicius-Quagliato EMA Gait analysis comparing Parkinson’s disease with healthy elderly subjects Arq Neuropsiquiatr. 2010;68:81–6.Grabli D, Karachi C, Welter M-L, Lau B, Hirsch EC, Vidailhet M, et al. Normal and pathological gait: what we learn from Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2012 Oct;83(10):979–85.Anna C, Serena F, Maurizio F. Del Sorbo Francesca, Romito Luigi M., Elia Antonio E., et al. quantitative gait analysis in parkin disease: possible role of dystonia. Mov Disord. 2016;31:1720–8.Morris M, Iansek R, McGinley J, Matyas T, Huxham F. Three-dimensional gait biomechanics in Parkinson’s disease: evidence for a centrally mediated amplitude regulation disorder. Mov Disord. 2005;20:40–50.Peterson CL, Kautz SA, Neptune RR. Braking and propulsive impulses increase with speed during accelerated and decelerated walking. Gait Posture. 2011;33:562–7.Chiu M-C, Wang M-J. The effect of gait speed and gender on perceived exertion, muscle activity, joint motion of lower extremity, ground reaction force and heart rate during normal walking. Gait & Posture. 2007;25:385–92.Muniz AMS, Liu H, Lyons KE, Pahwa R, Liu W, Nobre FF, et al. Comparison among probabilistic neural network, support vector machine and logistic regression for evaluating the effect of subthalamic stimulation in Parkinson disease on ground reaction force during gait. J Biomech. 2010;43:720–6.Chastan N, Do MC, Bonneville F, Torny F, Bloch F, Westby GWM, et al. Gait and balance disorders in Parkinson’s disease: impaired active braking of the fall of Centre of gravity. Mov Disord. 2009;24:188–95.Perneger T. What's wrong with Bonferroni adjustments. BMJ. 1998 Apr 18;316(7139):1236–8

Cancer screening in a middle-aged general population: factors associated with practices and attitudes

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to identify factors associated with cancer screening practices and with general attitudes toward cancer screening in a general population.</p> <p>Methods</p> <p>Mailed survey of 30–60 year old residents of Geneva, Switzerland, that included questions about screening for five cancers (breast, cervix uteri, prostate, colon, skin) in the past 3 years, attitudes toward screening, health care use, preventive behaviours and socio-demographic characteristics. Cancer screening practice was dichotomised as having done at least one screening test in the past 3 years versus none.</p> <p>Results</p> <p>The survey response rate was 49.3% (2301/4670). More women than men had had at least one cancer screening test in the past 3 years (83.2% vs 34.5%, p < 0.001). A majority of women had had a cervical smear (76.6%) and a mammography (age 30–49: 35.0%; age 50 and older: 90.3%); and 55.1% of men 50–60 years old had been screened for prostate cancer. Other factors associated with screening included older age, higher income, a doctor visit in the past 6 months, reporting a greater number of preventive behaviours and a positive attitude toward screening. Factors linked with positive attitudes included female gender, higher level of education, gainful employment, higher income, a doctor visit in the past 6 months and a personal history of cancer.</p> <p>Conclusion</p> <p>Attitudes play an important role in cancer screening practices among middle-aged adults in the general population, independent of demographic variables (age and sex) that determine in part screening recommendations. Negative attitudes were the most frequent among men and the most socio-economically disadvantaged. The moderate participation rate raises the possibility of selection bias.</p

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers

"Test and treat" or presumptive treatment for malaria in high transmission situations? A reflection on the latest WHO guidelines

Recent WHO guidelines recommend a universal "test and treat" strategy for malaria, mainly by use of rapid diagnostic test (RDT) in all areas. The evidence for this approach is questioned here as there is a risk of over-reliance on parasitological diagnosis in high transmission situations, which still exist. In such areas, when a patient has fever or other malaria symptoms, the presence of Plasmodium spp neither reliably confirms malaria as the cause of the fever, nor excludes the possibility of other diseases. This is because the patient may be an asymptomatic carrier of malaria parasites and suffer from another disease

Assessment of heterogeneity between European Populations: a Baltic and Danish replication case-control study of SNPs from a recent European ulcerative colitis genome wide association study

<p>Abstract</p> <p>Background</p> <p>Differences in the genetic architecture of inflammatory bowel disease between different European countries and ethnicities have previously been reported. In the present study, we wanted to assess the role of 11 newly identified UC risk variants, derived from a recent European UC genome wide association study (GWAS) (Franke <it>et al</it>., 2010), for 1) association with UC in the Nordic countries, 2) for population heterogeneity between the Nordic countries and the rest of Europe, and, 3) eventually, to drive some of the previous findings towards overall genome-wide significance.</p> <p>Methods</p> <p>Eleven SNPs were replicated in a Danish sample consisting of 560 UC patients and 796 controls and nine missing SNPs of the German GWAS study were successfully genotyped in the Baltic sample comprising 441 UC cases and 1156 controls. The independent replication data was then jointly analysed with the original data and systematic comparisons of the findings between ethnicities were made. Pearson's χ², Breslow-Day (BD) and Cochran-Mantel-Haenszel (CMH) tests were used for association analyses and heterogeneity testing.</p> <p>Results</p> <p>The rs5771069 (<it>IL17REL</it>) SNP was not associated with UC in the Danish panel. The rs5771069 (<it>IL17REL</it>) SNP was significantly associated with UC in the combined Baltic, Danish and Norwegian UC study sample driven by the Norwegian panel (OR = 0.89, 95% CI: 0.79-0.98, P = 0.02). No association was found between rs7809799 <it>(SMURF1/KPNA7) </it>and UC (OR = 1.20, 95% CI: 0.95-1.52, P = 0.10) or between UC and all other remaining SNPs. We had 94% chance of detecting an association for rs7809799 <it>(SMURF1/KPNA7) </it>in the combined replication sample, whereas the power were 55% or lower for the remaining SNPs.</p> <p>Statistically significant P_BDwas found for OR heterogeneity between the combined Baltic, Danish, and Norwegian panel versus the combined German, British, Belgian, and Greek panel (rs7520292 (P = 0.001), rs12518307 (P = 0.007), and rs2395609 (TCP11) (P = 0.01), respectively).</p> <p>No SNP reached genome-wide significance in the combined analyses of all the panels.</p> <p>Conclusions</p> <p>This replication study supports an important role for the studied rs5771069 (<it>IL17REL</it>) SNP, but not for rs7809799 (<it>SMURF1</it>/<it>KPNA7</it>), in UC etiology in the Danish, Baltic, and Norwegian populations. Significant genetic heterogeneity was suggested for rs7520292, rs12518307, and rs2395609 (<it>TCP11</it>) in UC etiology between the Nordic and the other European populations.</p