Single nucleotide polymorphisms in clinics: Fantasy or reality for cancer?

Single nucleotide polymorphisms (SNPs) have been classically used for dissecting various human complex disorders using candidate gene studies. During the last decade, large scale SNP analysis i.e. genome-wide association studies (GWAS) have provided an agnostic approach to identify possible genetic loci associated with heterogeneous disease such as cancer susceptibility, prognosis of survival or drug response. Further, the advent of new technologies, including microarray based genotyping as well as high throughput next generation sequencing has opened new avenues for SNPs to be used in clinical practice. It is speculated that the utility of SNPs to understand the mechanisms, biology of variable drug response and ultimately treatment individualization based on the individual’s genome composition will be indispensable in the near future. In the current review, we discuss the advantages and disadvantages of the clinical utility of genetic variants in disease risk-prediction, prognosis, clinical outcome and pharmacogenomics. The lessons and challenges for the utility of SNP based biomarkers are also discussed, including the need for additional functional validation studies.

Visual analytics for large-scale bioinformatic data sets

Rapid advances in sequencing technologies (Next Generation Sequencing or NGS) have led to a vast increase in the quantity of bioinformatics data available, with this increasing scale presenting enormous challenges to researchers seeking to identify complex interactions. This paper is concerned with the domain of transcriptional regulation, and the use of visualisation to identify relationships between specific regulatory proteins (the transcription factors or TFs) and their associated target genes (TGs). We present preliminary work from an ongoing study which aims to determine the effectiveness of different visual representations and large scale displays in supporting discovery. Following an iterative process of implementation and evaluation, representations were tested by potential users in the bioinformatics domain to determine their efficacy, and to understand better the range of ad hoc practices among bioinformatics literate users. Results from two rounds of small scale user studies are considered with initial findings suggesting that bioinformaticians require richly detailed views of TF data, features to compare TF layouts between organisms quickly, and ways to keep track of interesting data points.

Risedronate in adults with osteogenesis imperfecta type I: Increased bone mineral density and decreased bone turnover, but high fracture rate persists

Summary Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. Introduction Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. Methods Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. Results Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm 2, p=0.007; mean Z-score, -1.93 vs. -1.58, p=0.002), with no significant change at TH. P1NP fell by 37% (p=0.00041), with no significant change in bone ALP (p=0.15). Bone pain did not change significantly (p=0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. Conclusions Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

Palliative care problem severity score: Reliability and acceptability in a national study

Background The Palliative Care Problem Severity Score is a clinician-rated tool to assess problem severity in four palliative care domains (pain, other symptoms, psychological/spiritual, family/carer problems) using a 4-point categorical scale (absent, mild, moderate, severe). Aim To test the reliability and acceptability of the Palliative Care Problem Severity Score. Design: Multi-centre, cross-sectional study involving pairs of clinicians independently rating problem severity using the tool. Setting/participants Clinicians from 10 Australian palliative care services: 9 inpatient units and 1 mixed inpatient/community-based service. Results A total of 102 clinicians participated, with almost 600 paired assessments completed for each domain, involving 420 patients. A total of 91% of paired assessments were undertaken within 2 h. Strength of agreement for three of the four domains was moderate: pain (Kappa = 0.42, 95% confidence interval = 0.36 to 0.49); psychological/spiritual (Kappa = 0.48, 95% confidence interval = 0.42 to 0.54); family/carer (Kappa = 0.45, 95% confidence interval = 0.40 to 0.52). Strength of agreement for the remaining domain (other symptoms) was fair (Kappa = 0.38, 95% confidence interval = 0.32 to 0.45). Conclusion The Palliative Care Problem Severity Score is an acceptable measure, with moderate reliability across three domains. Variability in inter-rater reliability across sites and participant feedback indicate that ongoing education is required to ensure that clinicians understand the purpose of the tool and each of its domains. Raters familiar with the patient they were assessing found it easier to assign problem severity, but this did not improve inter-rater reliability.

Malnutrition in children with chronic liver disease accepted for liver transplantation : clinical profile and effect on outcome

The nutritional profiles of 37 children (aged 0.5-14.0 years) with chronic liver disease at the time of acceptance for orthotopic liver transplantation (OLTP) have been evaluated using clinical, biochemical and body composition methods. Nutritional progress while waiting for a donor has been related to outcome, whether transplanted or not. At the time of acceptance, most children were underweight (mean standard deviation (s.d.) weight = -1.4 ± 0.2) and stunted (mean s.d. height = - 2.2 ± 0.4), had low serum albumin (27/35) and had reduced body fat and depleted body cell mass (measured by total body potassium - mean % expected for age = 58 ± 5%, n = 15). Mean ad libitum nutrient intake was 63 ± 5% of recommended daily intake (RDI). Those who died while waiting (n = 8) had significantly lower mean initial s.d. weight compared with those transplanted. The overall actuarial 1 year survival of those who were transplanted (mean waiting time = 75 days) was 81% but those who were initially well nourished (s.d. weight >-1.0) had an actuarial 1 year survival of 100%. There were no significant differences in actuarial survival in relationship to age, type of transplant (whole liver or segmental), liver biochemistry or the presence or absence of ascites. Of the total group accepted for OLTP, whether transplanted or not, the overall 1 year survival for those who were relatively well nourished was 88% and for those undernourished (initial s.d. weight <-1.0) was 38% (P<0.003). Declining nutritional status during the waiting period also adversely affected outcome. We conclude that malnutrition and/or declining nutritional status is a major factor adversely affecting survival in children awaiting OLTP. In transplant units where waiting time is greater than 40 days, earlier referral, prioritization of cases and the use of adult donor livers may reduce this risk and efforts to maintain or improve nutritional status deserve further study.

A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer

Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P<2.3×10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. SIGNIFICANCE Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk.

A study of the use of the Edinburgh postnatal depression scale with parent groups outside the postpartum period

The Edinburgh Postnatal Depression Scale (EPDS) was sent by post to 206 mothers and 201 fathers of toddlers (aged between 19 and 22 months). At the same time these parents also completed subscales of the Crown—Crisp Experiential Index (CCEI). The responses were used to assess the feasibility of postal completion of the EPDS and its acceptability to parents outside the postpartum year, particularly fathers for whom there have been no previous reports of its use. On a small sub-group, the sensitivity, specificity and predictive values of the measures were assessed using the Present. State Examination. Answers to the depression subscale of the CCEI to the EPDS and to the Present State Examination were compared to assess validity. Completion of the postally-administered EPDS was satisfactory, though some difficulties were experienced in a second postal administration to a subsample. The scale was completed without obvious error or omission and this, combined with positive comments from parents, suggests the acceptability of the scale to both mothers and fathers. The mean scores were higher for mothers than for fathers, but the pattern of distribution was similar with a marked positive skew and a distinct decline in scores above 10. Because the subsample of parents interviewed was small the calculation of sensitivity and specificity has to be treated with caution. However, the results for mothers suggest that the EPDS has satisfactory validity for this group and one superior to the depression subscale of the CCEI. Among the fathers interviewed there were insufficient cases to enable calculation of sensitivity and specificity. Other results were encouraging, however, and suggest the merit of further studies of the application and validity of the EPDS with fathers.

Exercise and psychosocial interventions in breast cancer survivors: Preliminary results of a randomized controlled trial

Physical and psychological decline is common in the post-treatment breast cancer population, yet the efficacy of concurrent interventions to meet both physical- psychosocial needs in this population has not been extensively examined. PURPOSE: This study explores the effects of a combined exercise and psychosocial intervention model on selected physiological-psychological parameters in post-treated breast cancer. METHODS: Forty-one breast cancer survivors were randomly assigned to one of four groups for an 8-week intervention: exercise only [EX, n=13] (aerobic and resistance training), psychosocial therapy only [PS, n=11] (biofeedback), combined EX and PS [EX+PS, n=11], or to control conditions [CO, n=6]. Mean delta score (post-intervention - baseline) were calculated for each of the following: body weight, % body fat (skin folds), predicted VO2max (Modified Bruce Protocol), overall dynamic muscular endurance [OME] (RMCRI protocol), static balance (Single leg stance test), dynamic balance (360° turn and 4-square step test), fatigue (Revised Piper Scale), and quality of life (FACT-B). A one-way ANOVA was used to analyze the preliminary results of this on-going randomized trial. RESULTS: Overall, there were significant differences in the delta scores for predicted VO2max, OME, and dynamic balance among the 4 groups (p<0.05). The EX+PS group showed a significant improvement in VO2max compared with the PS group (4.2 ± 3.8 vs. -0.9 ± 4.2 mL/kg/min; p<0.05). Both the EX+PS and EX groups showed significant improvements in OME compared with the PS and CO groups (44.5 ± 23.5 and 43.4 ± 22.1 vs. -3.9 ± 15.2 and 2.7 ± 13.7 repetitions; p<0.05). All 3 intervention groups showed significant improvements in dynamic balance compared with the CO group (-0.8 ± 0.6, -0.6 ± 0.8, and -0.6 ±1.0 vs. 0.6 ± 0.6 seconds; p<0.05). Overall, changes in fatigue tended towards significance among the 4 groups (p = 0.08), with decreased fatigue in the intervention groups and increased fatigue in the CO group. CONCLUSIONS: Our preliminary findings suggest that EX and PS seem to produce greater positive changes in the outcome measures than CO. However, at this point no definite conclusions can be made on the additive effects of combining the EX and PS interventions.

Examination of a scale assessing attitudes towards individuals with intellectual disability in China

This study examined the applicability of the four-factor structure of the short form of the Community Living Attitudes Scale-Intellectual disability1 (CLAS-ID) in China, using a sample of 325 Chinese community members. Confirmatory factor analysis revealed that the original structure of the short form of the CLAS-ID did not adequately fit the data from the current sample. Most items of the Exclusion and Similarity subscales were retained while items on the Empowerment and Sheltering subscales were removed. Chinese community members held generally positive attitudes towards people with intellectual disability. However, a measurement tool originating from the Chinese context is needed to provide a better understanding of attitudes towards individuals with intellectual disability in mainland China.

The Connor-Davidson Resilience Scale (CD-RISC): Dimensionality and age-related measurement invariance with Australian cricketers

Objective This study explored the dimensionality and measurement invariance of the 25-item Connor-Davidson Resilience Scale (CD-RISC; Connor & Davidson, 2003) across samples of adult (n = 321; aged 20–36) and adolescent (n = 199; aged 12–18) Australian cricketers. Design Cross-sectional, self-report survey Methods An online, multi-section questionnaire. Results Confirmatory factor and item level analyses supported the psychometric superiority of a revised 10-item, unidimensional model of resilience over the original 25-item, five-factor measurement model. Positive and moderate correlations with hardiness as well as negative and moderate correlations with burnout components were evidenced thereby providing support for the convergent validity of the unidimensional model. Measurement invariance analyses of the unidimensional model across the two age-group samples supported configural (i.e., same factor structure across groups), metric (i.e., same pattern of factor loadings across the groups), and partial scalar invariance (i.e., mostly the same intercepts across the groups). Conclusion Evidence for a psychometrically sound measure of resilient qualities of the individual provides an important foundation upon which researchers can identify the antecedents to and outcomes of resilience in sport contexts.

Direct measurement of inner prosthesis loading during activities of daily living: Proposal for classification of functional outcome

Background The purpose of this presentation is to outline the relevance of the categorization of the load regime data to assess the functional output and usage of the prosthesis of lower limb amputees. The objectives are • To highlight the need for categorisation of activities of daily living • To present a categorization of load regime applied on residuum, • To present some descriptors of the four types of activity that could be detected, • To provide an example the results for a case. Methods The load applied on the osseointegrated fixation of one transfemoral amputee was recorded using a portable kinetic system for 5 hours. The load applied on the residuum was divided in four types of activities corresponding to inactivity, stationary loading, localized locomotion and directional locomotion as detailed in previously publications. Results The periods of directional locomotion, localized locomotion, and stationary loading occurred 44%, 34%, and 22% of recording time and each accounted for 51%, 38%, and 12% of the duration of the periods of activity, respectively. The absolute maximum force during directional locomotion, localized locomotion, and stationary loading was 19%, 15%, and 8% of the body weight on the anteroposterior axis, 20%, 19%, and 12% on the mediolateral axis, and 121%, 106%, and 99% on the long axis. A total of 2,783 gait cycles were recorded. Discussion Approximately 10% more gait cycles and 50% more of the total impulse than conventional analyses were identified. The proposed categorization and apparatus have the potential to complement conventional instruments, particularly for difficult cases.

Assessment of the severity of Ebola virus disease in Sierra Leone in 2014–2015

The current Ebola virus disease (EVD) epidemic in West Africa is unprecedented in scale, and Sierra Leone is the most severely affected country. The case fatality risk (CFR) and hospitalization fatality risk (HFR) were used to characterize the severity of infections in confirmed and probable EVD cases in Sierra Leone. Proportional hazards regression models were used to investigate factors associated with the risk of death in EVD cases. In total, there were 17 318 EVD cases reported in Sierra Leone from 23 May 2014 to 31 January 2015. Of the probable and confirmed EVD cases with a reported final outcome, a total of 2536 deaths and 886 recoveries were reported. CFR and HFR estimates were 74·2% [95% credibility interval (CrI) 72·6–75·5] and 68·9% (95% CrI 66·2–71·6), respectively. Risks of death were higher in the youngest (0–4 years) and oldest (≥60 years) age groups, and in the calendar month of October 2014. Sex and occupational status did not significantly affect the mortality of EVD. The CFR and HFR estimates of EVD were very high in Sierra Leone.

Openness to experience as a predictor and outcome of upward job changes into managerial and professional positions

In industrial and organizational psychology, there is a long tradition of studying personality as an antecedent of work outcomes. Recently, however, scholars have suggested that personality characteristics may not only predict, but also change due to certain work experiences, a notion that is depicted in the dynamic developmental model (DDM) of personality and work. Upward job changes are an important part of employees’ careers and career success in particular, and we argue that these career transitions can shape personality over time. In this study, we investigate the Big Five personality characteristics as both predictors and outcomes of upward job changes into managerial and professional positions. We tested our hypotheses by applying event history analyses and propensity score matching to a longitudinal dataset collected over five years from employees in Australia. Results indicated that participants’ openness to experience not only predicted, but that changes in openness to experience also followed from upward job changes into managerial and professional positions. Our findings thus provide support for a dynamic perspective on personality characteristics in the context of work and careers.

Validity of the OMNI rating of perceived exertion scale for children and adolescents with cerebral palsy

Aim This study evaluated the validity of the OMNI Walk/Run Rating of Perceived Exertion (OMNI-RPE) scores with heart rate and oxygen consumption (VO2) for children and adolescents with cerebral palsy (CP). Method Children and adolescents with CP, aged 6 to 18 years and Gross Motor Function Classification System (GMFCS) levels I to III completed a physical activity protocol with seven trials ranging in intensity from sedentary to moderate-to-vigorous. VO2 and heart rate were recorded during the physical activity trials using a portable indirect calorimeter and heart rate monitor. Participants reported OMNI-RPE scores for each trial. Concurrent validity was assessed by calculating the average within-subject correlation between OMNI-RPE ratings and the two physiological indices. Results For the correlational analyses, 48 participants (22 males, 26 females; age 12y 6mo, SD 3y 4mo) had valid bivariate data for VO2 and OMNI-RPE, while 40 participants (21 males, 19 females; age 12y 5mo, SD 2y 9mo) had valid bivariate data for heart rate and OMNI-RPE. VO2 (r=0.80; 95% CI 0.66–0.88) and heart rate (r=0.83; 95% CI 0.70–0.91) were moderately to highly correlated to OMNI-RPE scores. No difference was found for the correlation of physiological data and OMNI-RPE scores across the three GMFCS levels. The OMNI-RPE scores increased significantly in a dose-response manner (F6,258=116.1, p<0.001) as exercise intensity increased from sedentary to moderate-to-vigorous. Interpretation OMNI-RPE is a clinically feasible option to monitor exercise intensity in ambulatory children and adolescents with CP.

Location and scale mixtures of Gaussians with flexible tail behaviour: Properties, inference and application to multivariate clustering

The family of location and scale mixtures of Gaussians has the ability to generate a number of flexible distributional forms. The family nests as particular cases several important asymmetric distributions like the Generalized Hyperbolic distribution. The Generalized Hyperbolic distribution in turn nests many other well known distributions such as the Normal Inverse Gaussian. In a multivariate setting, an extension of the standard location and scale mixture concept is proposed into a so called multiple scaled framework which has the advantage of allowing different tail and skewness behaviours in each dimension with arbitrary correlation between dimensions. Estimation of the parameters is provided via an EM algorithm and extended to cover the case of mixtures of such multiple scaled distributions for application to clustering. Assessments on simulated and real data confirm the gain in degrees of freedom and flexibility in modelling data of varying tail behaviour and directional shape.