The flashfm approach for fine-mapping multiple quantitative traits.

Joint fine-mapping that leverages information between quantitative traits could improve accuracy and resolution over single-trait fine-mapping. Using summary statistics, flashfm (flexible and shared information fine-mapping) fine-maps signals for multiple traits, allowing for missing trait measurements and use of related individuals. In a Bayesian framework, prior model probabilities are formulated to favour model combinations that share causal variants to capitalise on information between traits. Simulation studies demonstrate that both approaches produce broadly equivalent results when traits have no shared causal variants. When traits share at least one causal variant, flashfm reduces the number of potential causal variants by 30% compared with single-trait fine-mapping. In a Ugandan cohort with 33 cardiometabolic traits, flashfm gave a 20% reduction in the total number of potential causal variants from single-trait fine-mapping. Here we show flashfm is computationally efficient and can easily be deployed across publicly available summary statistics for signals in up to six traits.

Working and caring for a child with chronic illness: A review of current literature.

BACKGROUND: Advances in medical knowledge have contributed to the increase in the number of children living with some form of long-term chronic illness or condition. As a consequence of these advancements, treatments that are more accessible and easier to administer, usually within a child's home, have been developed. However, this may mean that parents take on greater treatment responsibility and require extra time and energy to meet these tasks, additional to other responsibilities. This review paper aims to summarize and critique existing literature on working parents of children with a chronic condition, by focusing on patterns of parent work, the challenges experienced, and the flow-on consequences to well-being. METHODS: Employing a narrative, meta-synthesis of the current literature, this review identified 3 key themes related to working parents of children with chronic illness. RESULTS: The paper first identifies that although employment is less common, these parents are not necessarily nonworking. Second, these parents experience numerous challenges including balancing work and family, time constraints, stress, and feelings of "doing it all." And third, the above challenges lead to additional impacts on parental quality of life. CONCLUSIONS: This review summarizes what is currently known about work patterns, challenges, and consequences in parents of children with chronic conditions. Employment is clearly impacted for these parents. Although workplace challenges have been extensively researched, other challenges (eg, personal and family) and impacts on their well-being have not. This review discusses the present standing of this research. It outlines the strengths and limitations of the current literature, makes recommendations for future research, and suggests theoretical and practical implications of the further findings.

A two-step method for variable selection in the analysis of a case-cohort study.

Background: Accurate detection and estimation of true exposure-outcome associations is important in aetiological analysis; when there are multiple potential exposure variables of interest, methods for detecting the subset of variables most likely to have true associations with the outcome of interest are required. Case-cohort studies often collect data on a large number of variables which have not been measured in the entire cohort (e.g. panels of biomarkers). There is a lack of guidance on methods for variable selection in case-cohort studies. Methods: We describe and explore the application of three variable selection methods to data from a case-cohort study. These are: (i) selecting variables based on their level of significance in univariable (i.e. one-at-a-time) Prentice-weighted Cox regression models; (ii) stepwise selection applied to Prentice-weighted Cox regression; and (iii) a two-step method which applies a Bayesian variable selection algorithm to obtain posterior probabilities of selection for each variable using multivariable logistic regression followed by effect estimation using Prentice-weighted Cox regression. Results: Across nine different simulation scenarios, the two-step method demonstrated higher sensitivity and lower false discovery rate than the one-at-a-time and stepwise methods. In an application of the methods to data from the EPIC-InterAct case-cohort study, the two-step method identified an additional two fatty acids as being associated with incident type 2 diabetes, compared with the one-at-a-time and stepwise methods. Conclusions: The two-step method enables more powerful and accurate detection of exposure-outcome associations in case-cohort studies. An R package is available to enable researchers to apply this method.

Weibull regression with Bayesian variable selection to identify prognostic tumour markers of breast cancer survival.

As data-rich medical datasets are becoming routinely collected, there is a growing demand for regression methodology that facilitates variable selection over a large number of predictors. Bayesian variable selection algorithms offer an attractive solution, whereby a sparsity inducing prior allows inclusion of sets of predictors simultaneously, leading to adjusted effect estimates and inference of which covariates are most important. We present a new implementation of Bayesian variable selection, based on a Reversible Jump MCMC algorithm, for survival analysis under the Weibull regression model. A realistic simulation study is presented comparing against an alternative LASSO-based variable selection strategy in datasets of up to 20,000 covariates. Across half the scenarios, our new method achieved identical sensitivity and specificity to the LASSO strategy, and a marginal improvement otherwise. Runtimes were comparable for both approaches, taking approximately a day for 20,000 covariates. Subsequently, we present a real data application in which 119 protein-based markers are explored for association with breast cancer survival in a case cohort of 2287 patients with oestrogen receptor-positive disease. Evidence was found for three independent prognostic tumour markers of survival, one of which is novel. Our new approach demonstrated the best specificity.

Effects of Emotional Experience in Lexical Decision.

Previous research has examined the effects of emotional experience (i.e., the ease with which words evoke emotion information) in semantic categorization (SCT), word naming, and Stroop tasks (Newcombe et al., 2012; Siakaluk et al., 2014; Moffat et al., 2015). However, to date there are no published reports on whether emotional experience influences performance in the lexical decision task (LDT). In the present study, we examined the influence of emotional experience in LDT using three different stimulus sets. In Experiment 1 we used a stimulus set used by both Kousta et al. (2009; Experiment 1) and Yap and Seow (2014) that is comprised of 40 negative, 40 positive, and 40 neutral words; in Experiment 2 we used a stimulus set comprised of 150 abstract nouns; and in Experiment 3 we used a stimulus set comprised of 373 verbs. We observed facilitatory effects of emotional experience in each of the three experiments, such that words with higher emotional experience ratings were associated with faster response latencies. These results are important because the influence of emotional experience: (a) is observed in stimulus sets comprised of different types of words, demonstrating the generalizability of the effect in LDT; (b) accounts for LDT response latency variability above and beyond the influences of valence and arousal, and is thus a robust dimension of conceptual knowledge;

Femoral intercondylar notch width size: a comparison between siblings with and without anterior cruciate ligament injuries.

PURPOSE: Anterior cruciate ligament (ACL) injuries in siblings are commonly observed in the clinic. One, possibly genetic, factor contributing to the pathogenesis of sibling injuries may be narrow intercondylar notches, which are well recognized as predisposing to ACL injury. This study aimed primarily to: (1) assess the incidence of ACL injuries in siblings within an existing study cohort, (2) compare intercondylar notch width size in injured compared to matched uninjured control siblings and (3) compare the number of injured versus control sibling pairs sharing a narrow notch. METHODS: Twenty-four ACL-injured siblings from 10 families were matched for age, gender, family composition and sports activity, with 24 uninjured siblings from another 10 families. Intercondylar radiographs were taken to calculate anterior and posterior notch width indices (NWI). Notch size and the number of narrow notches in sibling pairs were compared between groups. RESULTS: Thirteen of 72 ACL-study participants had siblings with torn ACLs. Mean anterior NWI was 0.18 and 0.24 (p < 0.001), and mean posterior NWI was 0.26 and 0.3 (p = 0.006) for injured and uninjured siblings, respectively. Sixty percent of injured sibling pairs shared a narrow notch, while no uninjured sibling pairs did so (p = 0.003). CONCLUSION: This study showed that siblings (and often sibling pairs) with injuries do have significantly narrower notches than those without. This could partly explain the prevalence of ACL injuries in siblings. To reduce ACL-injury rates, we advise that siblings of ACL-injured athletes with narrow notches, be radiologically screened, and if necessary, cautioned and counselled regarding preventative training. LEVEL OF EVIDENCE: Case-control study, Level III.

Comprehensive genome-wide evaluation of lapatinib-induced liver injury yields a single genetic signal centered on known risk allele HLA-DRB1*07:01.

Lapatinib is associated with a low incidence of serious liver injury. Previous investigations have identified and confirmed the Class II allele HLA-DRB1*07:01 to be strongly associated with lapatinib-induced liver injury; however, the moderate positive predictive value limits its clinical utility. To assess whether additional genetic variants located within the major histocompatibility complex locus or elsewhere in the genome may influence lapatinib-induced liver injury risk, and potentially lead to a genetic association with improved predictive qualities, we have taken two approaches: a genome-wide association study and a whole-genome sequencing study. This evaluation did not reveal additional associations other than the previously identified association for HLA-DRB1*07:01. The present study represents the most comprehensive genetic evaluation of drug-induced liver injury (DILI) or hypersensitivity, and suggests that investigation of possible human leukocyte antigen associations with DILI and other hypersensitivities represents an important first step in understanding the mechanism of these events.

Effects of emotional and sensorimotor knowledge in semantic processing of concrete and abstract nouns.

There is much empirical evidence that words' relative imageability and body-object interaction (BOI) facilitate lexical processing for concrete nouns (e.g., Bennett et al., 2011). These findings are consistent with a grounded cognition framework (e.g., Barsalou, 2008), in which sensorimotor knowledge is integral to lexical processing. In the present study, we examined whether lexical processing is also sensitive to the dimension of emotional experience (i.e., the ease with which words evoke emotional experience), which is also derived from a grounded cognition framework. We examined the effects of emotional experience, imageability, and BOI in semantic categorization for concrete and abstract nouns. Our results indicate that for concrete nouns, emotional experience was associated with less accurate categorization, whereas imageability and BOI were associated with faster and more accurate categorization. For abstract nouns, emotional experience was associated with faster and more accurate categorization, whereas BOI was associated with slower and less accurate categorization. This pattern of results was observed even with many other lexical and semantic dimensions statistically controlled. These findings are consistent with Vigliocco et al.'s (2009) theory of semantic representation, which states that emotional knowledge underlies meanings for abstract concepts, whereas sensorimotor knowledge underlies meanings for concrete concepts.

Early infection with Trichuris trichiura and allergen skin test reactivity in later childhood.

BACKGROUND: Allergic diseases cause a large and increasing burden in developed countries and in urban centres in middle-income countries. The causes of this increase are unknown and, currently, there are no interventions to prevent the development of allergic diseases. The 'hygiene hypothesis' has tried to explain the increase through a reduction in the frequency of childhood infections causing a failure to program the immune system for adequate immune regulation. Intestinal helminth parasites are prevalent in childhood in developing countries and are associated with a lower prevalence of allergen skin test reactivity and asthma. OBJECTIVES: To investigate whether children who had intestinal helminth infections during early childhood have a lower prevalence of allergen skin test reactivity later in childhood. METHODS: We re-visited a population of 1055 children from whom stool samples had been collected for detection of intestinal helminth infections for another study, and collected new stool samples and performed allergen skin prick testing. Information on potential confounding variables was collected. RESULTS: Children with heavy infections with Trichuris trichiura in early childhood had a significantly reduced prevalence of allergen skin test reactivity in later childhood, even in the absence of T. trichiura infection at the time of skin testing in later childhood. CONCLUSION: Early heavy infections with T. trichiura may protect against the development of allergen skin test reactivity in later childhood. Novel treatments to program immune-regulation in early childhood in a way that mimics the effects of early infections with T. trichiura may offer new strategies for the prevention of allergic disease.

The effectiveness of a pre-operative home-based physiotherapy programme for chronic anterior cruciate ligament deficiency.

BACKGROUND AND PURPOSE: Little evidence supports the prescription of pre-operative rehabilitation in the treatment of chronic anterior cruciate ligament-deficient (ACLD) subjects. The aim of the present study was to assess the effectiveness of a specific six-week pre-operative exercise programme on ACLD knees. METHOD: A single, masked, controlled study was designed. This comprised two matched groups of 12 chronically ACLD patients awaiting reconstruction and a group of 12 matched uninjured control subjects. Only one ACLD group received a home-based exercise and educational programme. Assessment before and after the exercise intervention included: knee joint stability (clinical and KT1000 evaluation); muscle strength (Cybex II); standing balance and functional performance (agility, [corrected] and subjective tests). RESULTS: At the time of initial assessment there were no statistically significant differences in any measures for the two ACLD groups but both ACLD groups were significantly different from the uninjured control group as regards quadriceps strength and function. Measures taken after six weeks showed no significant improvement in the untreated ACLD group or in the uninjured control group. The treated ACLD group showed significant improvement in the following measures: quadriceps strength measured at 60 degrees and 120 degrees per second (p < 0.001); single leg standing balance with eyes closed (p < 0.001); instrumented passive stability at 20 lb (89 N) force (p = 0.003); agility and subjective performance (p < 0.001). The incidence of unstable episodes had decreased in the treated ACLD group, reducing further damage to the joint. CONCLUSION: This study leaves little doubt that pre-operative physiotherapy had a positive effect on motor function in ACLD subjects and should be prescribed routinely to maximize muscle stabilizing potential prior to reconstruction. Patients report improved stability and, in certain cases, may avoid surgery. The finding that exercise increased the passive stability of the joint was unexpected and requires further investigation.

The effect of anticoagulation on the restoration of range of motion after total knee arthroplasty: enoxaparin versus aspirin.

Anticoagulation used for thromboembolic prophylaxis following total knee arthroplasty (TKA) could interfere with movement. This study compares the effect of 2 anticoagulants, enoxaparin and aspirin, on restoration of range of motion (ROM) after TKA. Two groups of 75 consecutive patients, matched for age, arthritic severity, and preoperative ROM, underwent TKA. Flexion and extension milestone measures were recorded daily. Results show a highly statistically significant difference (P<.001) between the 2 groups when comparing the days on which these milestones were achieved. Group 1 (enoxaparin) reached 90 degrees, 100 degrees and 110 degrees of flexion in 8.4, 10.4, and 12.4 days, respectively. Group 2 (aspirin) reached the same goals in 6.8, 8.5, and 10.6 days, respectively. At 15 months after surgery, no statistically significant difference in flexion was seen between the groups (122 degrees vs 121 degrees ). Enoxaparin delayed the return of early but not long-term flexion after TKA.

The relationship between knee strength and functional stability before and after anterior cruciate ligament reconstruction.

Functional stability of the knee is dependent on an intact ligamentous system and the timely and efficient contraction of supporting musculature. The aim of this study was to assess the relationship between muscle strength and functional stability in 31 patients pre- and post-operatively, following a unilateral anterior cruciate ligament rupture. All subjects underwent reconstructive surgery using semitendonosis and gracilis tendons. Isokinetic strength assessment of quadriceps and hamstring muscles was performed at a rate of movement of 60 degrees /s and 120 degrees /s. Functional stability was determined by performance during five functional stability tests that included the shuttle run, side step, carioca, single and triple hop tests. Pearson's correlation coefficient statistics were applied to pre-operative and post-operative data respectively. These analyses demonstrated a significant positive correlation between quadriceps strength indices at both testing speeds and the two hop tests pre-operatively (p's<0.007) and between quadriceps strength indices at both speeds and all five functional tests post-operatively (p's<0.01). Assessed using Steiger's formula, there was a significant increase in the correlation between quadriceps strength indices and three functional tests post-operatively compared to pre-operatively (p<0.05). No significant correlation between hamstring strength indices and functional scores existed pre- or post-operatively. This study has shown a significant correlation exists between quadriceps strength indices and functional stability both before and after surgery, this relationship does not reach significance between hamstring strength indices and functional stability.

Muscle strength and function before and after anterior cruciate ligament reconstruction using semitendonosus and gracilis.

This study assessed the quadriceps and hamstring strength before and 6 months after anterior cruciate ligament (ACL) reconstructive surgery using the hamstrings and related the findings to functional performance. Six months after surgery is a critical time for assessment as this is when players are returning to sport. Maximum isokinetic strength of 31 patients with complete unilateral ACL ruptures was measured at speeds of 60 degrees and 120 degrees per second. Functional assessment included the single hop, the triple hop, the shuttle run, side-step and carioca tests. All patients underwent a controlled quadriceps emphasized home-based physiotherapy program both before and after surgery. Results show that before surgery there was a 7.3% quadriceps strength deficit at 60 degrees per second compared to the uninjured leg but no hamstring strength deficit. After surgery there was a statistically significant but relatively small loss of muscle strength. The quadriceps strength deficit had increased to 12% and there was a 10% hamstring deficit. Post-operatively there was an 11% and 6.3% improvement in the hop tests, a 9% (P < 0.01) improvement in the shuttle run, a 15% (P < 0.001) improvement in the side step and a 24% (P < 0.001) improvement in the carioca tests (P < 0.001) despite the loss of muscle strength.

Explicitly questioning the nature of suggestibility in preschoolers' memory and retention.

In research designed to investigate children's suggestible responses on memory tests, 190 preschoolers were read a short story. The same day or six days later, they were exposed to information that was either consistent with the original story details or inconsistent and misleading. One and seven weeks after hearing the story, the children were tested on two types of recognition tasks that involved a choice either between the original and misleading information or between the original and new information with questions that were either explicit or nonexplicit as to the time of the information to be reported. At the 1-week test, children who were exposed to misleading information were significantly less accurate under nonexplicit questioning in recognizing the original from the misleading information than were children presented with consistent information. With explicit questioning, this difference was not significant. When the choice for the children was between original and new items following exposure to delayed misleading postevent information, explicit questioning resulted in significantly more accurate responses at the 7-week test than did nonexplicit questioning. Children questioned explicitly rather than nonexplicitly were more likely to maintain correct responses on both tests. The results are discussed in terms of conversational processes and competing forms of representation in memory retention.

Where to look first for suggestibility in young children.

Preschoolers' suggestibility following exposure to biased information has often been interpreted as indicating that memory traces have been genuinely altered. However, young children may not recognize that the purpose and relevance of questions in experiments on suggestibility is to determine whether they can ignore misinformation in remembering the original details of stories. Instead, children may be prompted to regard the original story details as trivial by experimenters who are perceived as having portrayed these details as unimportant or irrelevant in that they themselves did not bother to get these right. Under such conditions, children may interpret the biased information to mean that a biased alternative was an acceptable, or even a preferred, test choice when compared to the original details. We report the results of an investigation with 3- to 5-year-olds in which children heard a story followed the next day by either biased, unbiased, or no information. The children were able to identify the original story details 6 days later when the questions were phrased in an explicit manner that referred to the time of the information to be recalled.

High-dose caffeine and cardiac rate and rhythm in normal subjects.

In a previous 24-hour study of the electrophysiologic effects of moderate dose caffeine (1 mg/kg body weight/half-life), we found a significant (p less than 0.01) increase in ventricular ectopic beat (VEB) frequency among 18 patients with preexisting primary ventricular dysrhythm (mean 207 +/- 350 VEBs/hour, no caffeine, versus 307 +/- 414 VEBs/hour, caffeine). We also found a statistically insignificant (NS) increase in the incidence of infrequent VEBs in 18 normal control subjects (four of 18, no caffeine vs nine of 18 caffeine). Because of the high risk of beta-error among the previously-studied normal control subjects, we tested another group of 34 normal subjects, 15 males and 19 females with a mean age of 31 years (range 21 to 49 years), using a higher dose of caffeine. All subjects abstained from caffeine for 72 hours and had a control 24-hour Holter ECG recorded between hours 48 and 72. Caffeine half-life was calculated for each subject and caffeine was then ingested at 1 mg/kg every 0.5 half-life during all waking hours. A 24-hour Holter test was recorded, beginning just prior to the second caffeine dose. It was concluded that in normal adults, even high-dose caffeine does not affect prevailing cardiac rhythm and rate, and moreover, does not cause clinically significant ventricular or supraventricular dysrhythm.