Biclustering models for structured microarray data

©2005 IEEE. Personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution to servers or lists, or to reuse any copyrighted component of this work in other works must be obtained from the IEEE.Microarrays have become a standard tool for investigating gene function and more complex microarray experiments are increasingly being conducted. For example, an experiment may involve samples from several groups or may investigate changes in gene expression over time for several subjects, leading to large three-way data sets. In response to this increase in data complexity, we propose some extensions to the plaid model, a biclustering method developed for the analysis of gene expression data. This model-based method lends itself to the incorporation of any additional structure such as external grouping or repeated measures. We describe how the extended models may be fitted and illustrate their use on real data

Xenoestrogen-Induced ERK-1 and ERK-2 Activation via Multiple Membrane-Initiated Signaling Pathways

Xenoestrogens can mimic or antagonize the activity of physiological estrogens, and the suggested mechanism of xenoestrogen action involves binding to estrogen receptors (ERs). However, the failure of various in vitro or in vivo assays to show strong genomic activity of xenoestrogens compared with estradiol (E(2)) makes it difficult to explain their ability to cause abnormalities in animal (and perhaps human) reproductive functions via this pathway of steroid action. E(2) has also been shown to initiate rapid intracellular signaling, such as changes in levels of intracellular calcium, cAMP, and nitric oxide, and activations of a variety of kinases, via action at the membrane. In this study, we demonstrate that several xenoestrogens can rapidly activate extracellular-regulated kinases (ERKs) in the pituitary tumor cell line GH(3)/B6/F10, which expresses high levels of the membrane receptor for ER-α(mER). We tested a phytoestrogen (coumestrol), organochlorine pesticides or their metabolites (endosulfan, dieldrin, and DDE), and detergent by-products of plastics manufacturing (p-nonylphenol and bisphenol A). These xenoestrogens (except bisphenol A) produced rapid (3–30 min after application), concentration (10(−14)–10(−8) M)-dependent ERK-1/2 phosphorylation but with distinctly different activation patterns. To identify signaling pathways involved in ERK activation, we used specific inhibitors of ERs, epidermal growth factor receptors, Ca(2+) signaling, Src and phosphoinositide-3 kinases, and a membrane structure disruption agent. Multiple inhibitors blocked ERK activation, suggesting simultaneous use of multiple pathways and complex signaling web interactions. However, inhibitors differentially affected each xenoestrogen response examined. These actions may help to explain the distinct abilities of xenoestrogens to disrupt reproductive functions at low concentrations

Repetitive Behavior in Rubinstein–Taybi Syndrome:Parallels with Autism Spectrum Phenomenology

Syndrome specific repetitive behavior profiles have been described previously. A detailed profile is absent for Rubinstein–Taybi syndrome (RTS). The Repetitive Behaviour Questionnaire and Social Communication Questionnaire were completed for children and adults with RTS (N = 87), Fragile-X (N = 196) and Down (N = 132) syndromes, and individuals reaching cut-off for autism spectrum disorder (N = 228). Total and matched group analyses were conducted. A phenotypic profile of repetitive behavior was found in RTS. The majority of behaviors in RTS were not associated with social-communication deficits or degree of disability. Repetitive behavior should be studied at a fine-grained level. A dissociation of the triad of impairments might be evident in RTS

Health Care for Mitochondrial Disorders in Canada: A Survey of Physicians

Background: An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care. Methods: We conducted a cross-sectional survey of Canadian physicians involved in the diagnosis and/or ongoing care of patients with mitochondrial diseases. We used snowball sampling to identify potentially eligible participants, who were contacted by mail up to five times and invited to complete a questionnaire by mail or internet. The questionnaire addressed: personal experience in providing care for mitochondrial disorders; diagnostic and treatment practices; challenges in accessing tests or treatments; and views regarding research priorities. Results: We received 58 survey responses (52% response rate). Most respondents (83%) reported spending 20% or less of their clinical practice time caring for patients with mitochondrial disorders. We identified important variation in diagnostic care, although assessments frequently reported as diagnostically helpful (e.g., brain magnetic resonance imaging, MRI/MR spectroscopy) were also recommended in published guidelines. Approximately half (49%) of participants would recommend mitochondrial cocktails for all or most patients, but we identified variation in responses regarding specific vitamins and cofactors. A majority of physicians recommended studies on the development of effective therapies as the top research priority. Conclusions: While Canadian physicians\u27 views about diagnostic care and disease management are aligned with published recommendations, important variations in care reflect persistent areas of uncertainty and a need for empirical evidence to support and update standard protocols

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Evaluation of a multi-disciplinary back pain rehabilitation programme—individual and group perspectives

To evaluate the impact of a multi-disciplinary back pain rehabilitation programme using a combination of individual and group change data. A total of 261 consecutive patients attending an assessment session for the back pain rehabilitation programme completed the SF-36 health survey questionnaire. The patients were requested to complete the questionnaires again at programme completion and at the 6-month follow-up. The Reliable Change Index was used to define 'clinical significance' in terms of the assessment of individual change. Half of those patients considered to be suitable for the programme subsequently completed it. In group terms, non-completers scored lower than completers on all SF-36 scales. Statistically significant improvements were evident for those completing the programme (all scales at P < 0.000), with improvement maintained at follow-up. In individual terms, 'clinical significance' was exceeded most frequently in the Physical Functioning and Role Physical scales. Whilst some participants lost previous improvements between completion and follow-up, others improved over this same time period. The majority of those completing the programme showed improvement in at least one scale. Adding assessment of individual change to traditional group change measures provides greater insight into the impact a rehabilitation programme has upon participants' quality of life. Whilst the programme is clearly effective for those who complete it, work is required to limit post-programme deterioration and improve uptak

Overestimation of Postpartum Depression Prevalence Based on a 5-item Version of the EPDS:Systematic Review and Individual Participant Data Meta-analysis

Objective:The Maternal Mental Health in Canada, 2018/2019, survey reported that 18% of 7,085 mothers who recently gave birth reported "feelings consistent with postpartum depression" based on scores >= 7 on a 5-item version of the Edinburgh Postpartum Depression Scale (EPDS-5). The EPDS-5 was designed as a screening questionnaire, not to classify disorders or estimate prevalence; the extent to which EPDS-5 results reflect depression prevalence is unknown. We investigated EPDS-5 >= 7 performance relative to major depression prevalence based on a validated diagnostic interview, the Structured Clinical Interview for DSM (SCID).Methods:We searched Medline, Medline In-Process & Other Non-Indexed Citations, PsycINFO, and the Web of Science Core Collection through June 2016 for studies with data sets with item response data to calculate EPDS-5 scores and that used the SCID to ascertain depression status. We conducted an individual participant data meta-analysis to estimate pooled percentage of EPDS-5 >= 7, pooled SCID major depression prevalence, and the pooled difference in prevalence.Results:A total of 3,958 participants from 19 primary studies were included. Pooled prevalence of SCID major depression was 9.2% (95% confidence interval [CI] 6.0% to 13.7%), pooled percentage of participants with EPDS-5 >= 7 was 16.2% (95% CI 10.7% to 23.8%), and pooled difference was 8.0% (95% CI 2.9% to 13.2%). In the 19 included studies, mean and median ratios of EPDS-5 to SCID prevalence were 2.1 and 1.4 times.Conclusions:Prevalence estimated based on EPDS-5 >= 7 appears to be substantially higher than the prevalence of major depression. Validated diagnostic interviews should be used to establish prevalence

Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukemia

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2DBCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital; by a Stand Up to Cancer Innovative Research Grant and St. Baldrick’s Foundation Scholar Award (to C.G.M.); by a St. Baldrick’s Consortium Award (S.P.H.), by a Leukemia and Lymphoma Society Specialized Center of Research grant (S.P.H. and C.G.M.), by a Lady Tata Memorial Trust Award (I.I.), by a Leukemia and Lymphoma Society Special Fellow Award and Alex’s Lemonade Stand Foundation Young Investigator Awards (K.R.), by an Alex’s Lemonade Stand Foundation Award (M.L.) and by National Cancer Institute Grants CA21765 (St Jude Cancer Center Support Grant), U01 CA157937 (C.L.W. and S.P.H.), U24 CA114737 (to Dr Gastier-Foster), NCI Contract HHSN261200800001E (to Dr Gastier-Foster), U10 CA180820 (ECOG-ACRIN Operations) and CA180827 (E.P.); U10 CA180861 (C.D.B. and G.M.); U24 CA196171 (The Alliance NCTN Biorepository and Biospecimen Resource); CA145707 (C.L.W. and C.G.M.); and grants to the COG: U10 CA98543 (Chair’s grant and supplement to support the COG ALL TARGET project), U10 CA98413 (Statistical Center) and U24 CA114766 (Specimen Banking). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E

Vegetarian eating

The philosophical literature may seem to be replete with arguments for vegetarianism based on harm to animals. However, these arguments turn out to be arguments for veganism, not vegetarianism. This chapter explores whether anything can be said for vegetarianism. Some reasons motivating vegetarianism seem to be very personal, and so not the sorts of things that could be the foundation of a moral argument. Meanwhile, though they may hold some weight, arguments about vegetarianism as a “middle way” between veganism and omnivorism are highly contingent. Both of these routes, then, may seem unsatisfying to the vegetarian. Could there be a principled case for vegetarianism? Tzachi Zamir is the one philosopher who has argued at length for vegetarianism over veganism, but a close examination of his arguments show that they are not as compelling as they first seem. A final option remains open: there may be potential for arguments critiquing the eating of animals’ flesh and/or their bodies that are independent of concerns about harms to animals in food production. Such arguments, which have been hinted at in animal ethics, offer a critique of meat consumption, but not, necessarily, of egg and dairy consumption. Perhaps, then, they could form the basis of a principled case for vegetarianism that does not immediately become a case for veganism. The consequences of such an argument, if one can be made, are not simple

Elevated plasma levels of cardiac troponin-I predict left ventricular systolic dysfunction in patients with myotonic dystrophy type 1:A multicentre cohort follow-up study

Objective: High sensitivity plasma cardiac troponin-I (cTnI) is emerging as a strong predictor of cardiac events in a variety of settings. We have explored its utility in patients with myotonic dystrophy type 1 (DM1). Methods: 117 patients with DM1 were recruited from routine outpatient clinics across three health boards. A single measurement of cTnI was made using the ARCHITECT STAT Troponin I assay. Demographic, ECG, echocardiographic and other clinical data were obtained from electronic medical records. Follow up was for a mean of 23 months. Results: Fifty five females and 62 males (mean age 47.7 years) were included. Complete data were available for ECG in 107, echocardiography in 53. Muscle Impairment Rating Scale score was recorded for all patients. A highly significant excess (p = 0.0007) of DM1 patients presented with cTnI levels greater than the 99th centile of the range usually observed in the general population (9 patients; 7.6%). Three patients with elevated troponin were found to have left ventricular systolic dysfunction (LVSD), compared with four of those with normal range cTnI (33.3% versus 3.7%; p = 0.001). Sixty two patients had a cTnI level &#60; 5ng/L, of whom only one had documented evidence of LVSD. Elevated cTnI was not predictive of severe conduction abnormalities on ECG, or presence of a cardiac device, nor did cTnI level correlate with muscle strength expressed by Muscle Impairment Rating Scale score. Conclusions: Plasma cTnI is highly elevated in some ambulatory patients with DM1 and shows promise as a tool to aid cardiac risk stratification, possibly by detecting myocardial involvement. Further studies with larger patient numbers are warranted to assess its utility in this setting