Economic and Practical Factors in Diagnosing HNPCC Using Clinical Criteria, Immunohistochemistry and Microsatellite Instability Analysis

Aim: To determine a cost-efficient strategy for HNPCC molecular diagnostic testing. Methods: 138 families referred to a Regional Genetics Service had hMLH1 and hMSH2 mutation analysis. The sensitivity and specificity of clinical selection criteria with or without immunohistochemistry (IHC) and microsatellite instability (MSI) analysis to further refine case selection and the effect of these approaches on the cost of mutation analysis were examined. Results: Clearly deleterious mutations were identified in 49/138 (35.5%) of all families tested. The most sensitive criteria for identifying families with MMR mutations were the full Bethesda guidelines but these have poor specificity. IHC and MSI were useful pre-screening tools. Conclusion: A cost-efficient approach in laboratories where IHC and/or MSI analysis are available, is to use inclusive (non-specific) criteria to select cases, followed by IHC and then MSI. Where one or both results are abnormal, proceed to further mutation analysis. Where MSI or IHC or tumour blocks are not available, more restrictive clinical criteria may be more appropriate for cost-efficient case selection

Identifying performance-based outcome measures of physical function in people with haemophilia (IPOP)

Introduction: Recent recommendations of core outcome sets for haemophilia highlight the need for including measures of performance-based physical health and physical function sustainability. To date, there is no consensus on what outcomes might be of value to clinicians and patients. Aim: To identify instruments of performance-based physical function to monitor musculoskeletal health in people with haemophilia that are practical in the clinical setting. Methods: Utilising components from the Activities and Participation Category of the WHO International Classification of Functioning (WHO-ICF), a consensus-based, decision analysis approach was used to: identify activities people with haemophilia have most difficulty performing; identify quantitative performance-based measures of identified activities via a scoping review; and obtain views on acceptability of the tests utilising a DELPHI approach. Results: Eleven activities were identified: maintaining a standing position, walking long distances, walking up and down stairs, walking on different surfaces, running, hopping, jumping, squatting, kneeling, undertaking a complex lower limb task, undertaking a complex upper limb task. Following a 2-round DELPHI survey of international physiotherapists, the 6-min walk test, timed up and down stairs, 30-s sit to stand, single leg stance, tandem stance, single hop for distance (children only) and timed up and go (adults only) reached consensus. Conclusion: This study is the first step in defining a core set of performance-based instruments to monitor physical health and sustainability of physical function outcomes in people with haemophilia. Establishing the psychometric properties of the instruments and whether they are meaningful to people with haemophilia is essential

Identifying performance-based outcome measures of physical function in people with haemophilia (IPOP)

Introduction: Recent recommendations of core outcome sets for haemophilia highlight the need for including measures of performance-based physical health and physical function sustainability. To date, there is no consensus on what outcomes might be of value to clinicians and patients. Aim: To identify instruments of performance-based physical function to monitor musculoskeletal health in people with haemophilia that are practical in the clinical setting. Methods: Utilising components from the Activities and Participation Category of the WHO International Classification of Functioning (WHO-ICF), a consensus-based, decision analysis approach was used to: identify activities people with haemophilia have most difficulty performing; identify quantitative performance-based measures of identified activities via a scoping review; and obtain views on acceptability of the tests utilising a DELPHI approach. Results: Eleven activities were identified: maintaining a standing position, walking long distances, walking up and down stairs, walking on different surfaces, running, hopping, jumping, squatting, kneeling, undertaking a complex lower limb task, undertaking a complex upper limb task. Following a 2-round DELPHI survey of international physiotherapists, the 6-min walk test, timed up and down stairs, 30-s sit to stand, single leg stance, tandem stance, single hop for distance (children only) and timed up and go (adults only) reached consensus. Conclusion: This study is the first step in defining a core set of performance-based instruments to monitor physical health and sustainability of physical function outcomes in people with haemophilia. Establishing the psychometric properties of the instruments and whether they are meaningful to people with haemophilia is essential

Identifying performance-based outcome measures of physical function in people with haemophilia (IPOP)

Abstract Introduction Recent recommendations of core outcome sets for haemophilia highlight the need for including measures of performance-based physical health and physical function sustainability. To date, there is no consensus on what outcomes might be of value to clinicians and patients. Aim To identify instruments of performance-based physical function to monitor musculoskeletal health in people with haemophilia that are practical in the clinical setting. Methods Utilising components from the Activities and Participation Category of the WHO International Classification of Functioning (WHO-ICF), a consensus-based, decision analysis approach was used to: identify activities people with haemophilia have most difficulty performing; identify quantitative performance-based measures of identified activities via a scoping review; and obtain views on acceptability of the tests utilising a DELPHI approach. Results Eleven activities were identified: maintaining a standing position, walking long distances, walking up and down stairs, walking on different surfaces, running, hopping, jumping, squatting, kneeling, undertaking a complex lower limb task, undertaking a complex upper limb task. Following a 2-round DELPHI survey of international physiotherapists, the 6-min walk test, timed up and down stairs, 30-s sit to stand, single leg stance, tandem stance, single hop for distance (children only) and timed up and go (adults only) reached consensus. Conclusion This study is the first step in defining a core set of performance-based instruments to monitor physical health and sustainability of physical function outcomes in people with haemophilia. Establishing the psychometric properties of the instruments and whether they are meaningful to people with haemophilia is essential

COTS software selection process.

Today's need for rapid software development has generated a great interest in employing Commercial-Off-The-Shelf (COTS) software products as a way of managing cost, developing time, and effort. With an abundance of COTS software packages to choose from, the problem now is how to systematically evaluate, rank, and select a COTS product that best meets the software project requirements and at the same time can leverage off the current corporate information technology architectural environment. This paper describes a systematic process for decision support in evaluating and ranking COTS software. Performed right after the requirements analysis, this process provides the evaluators with more concise, structural, and step-by-step activities for determining the best COTS software product with manageable risk. In addition, the process is presented in phases that are flexible to allow for customization or tailoring to meet various projects' requirements

Medial longitudinal arch development of school children : The College of Podiatry Annual Conference 2015: meeting abstracts

Background Foot structure is often classified into flat foot, neutral and high arch type based on the variability of the Medial Longitudinal Arch (MLA). To date, the literature provided contrasting evidence on the age when MLA development stabilises in children. The influence of footwear on MLA development is also unknown. Aim This study aims to (i) clarify whether the MLA is still changing in children from age 7 to 9 years old and (ii) explore the relationship between footwear usage and MLA development, using a longitudinal approach. Methods We evaluated the MLA of 111 healthy school children [age = 6.9 (0.3) years] using three parameters [arch index (AI), midfoot peak pressure (PP) and maximum force (MF: % of body weight)] extracted from dynamic foot loading measurements at baseline, 10-month and 22-month follow-up. Information on the type of footwear worn was collected using survey question. Linear mixed modelling was used to test for differences in the MLA over time. Results Insignificant changes in all MLA parameters were observed over time [AI: P = .15; PP: P = .84; MF: P = .91]. When gender was considered, the AI of boys decreased with age [P = .02]. Boys also displayed a flatter MLA than girls at age 6.9 years [AI: mean difference = 0.02 (0.01, 0.04); P = .02]. At baseline, subjects who wore close-toe shoes displayed the lowest MLA overall [AI/PP/MF: P < .05]. Subjects who used slippers when commencing footwear use experienced higher PP than those who wore sandals [mean difference = 31.60 (1.44, 61.75) kPa; post-hoc P = .04]. Discussion and conclusion Our findings suggested that the MLA of children remained stable from 7 to 9 years old, while gender and the type of footwear worn during childhood may influence MLA development. Clinicians may choose to commence therapy when a child presents with painful flexible flat foot at age 7 years, and may discourage younger children from wearing slippers when they commence using footwear

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes:findings from the ENIGMA Epigenetics Working Group

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions

Beyond the Global Brain Differences:Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and globalbrain differences compared with noncarriers. However, interpreting regional differences is challenging if a globaldifference drives the regional brain differences. Intraindividual variability measures can be used to test for regionaldifferences beyond global differences in brain structure.METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n =30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matchednoncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’sregional difference and global difference, were used to test for regional differences that diverge from the globaldifference.RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differedmore than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thicknessin regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal andsomatosensory cortex differed more than the global difference in cortical thickness.CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distaland 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distaland 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanismsinvolved in altered neurodevelopment