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Introduction: Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy., Methods/design: We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation., Results/discussion: With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S., Trial Registration: NCT04496739., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: All authors have disclosed no conflicts of interest.

Background: Psychiatric patients are susceptible to adverse mental health outcome during COVID-19 pandemic, but its associated factors are understudied. This observational cross-sectional study aimed to comprehensively examine prevalence and correlates of psychological distress, in terms of depression, anxiety and post-traumatic-stress-disorder (PTSD)-like symptoms, among Chinese adult psychiatric outpatients amidst the peak of fifth COVID-19 wave in Hong-Kong., Methods: A total of 415 patients (comprising 246 patients with common-mental-disorders [CMD] and 169 with severe-mental-disorders [SMD]) and 399 demographically-matched controls without mental disorders were assessed with self-rated questionnaires between 28-March and 8-April-2022, encompassing illness profile, mental health symptoms, psychosocial measures (loneliness, resilience, coping styles) and COVID-19 related factors. Univariate and multivariable logistic regression analyses were conducted to determine variables associated with moderate-to-severe depressive, anxiety and PTSD-like symptoms among psychiatric patients., Results: Our results showed that CMD patients had the greatest psychological distress relative to SMD patients and controls. Approximately 40-55% CMD patients and 25% SMD patients exhibited moderate-to-severe depression, anxiety and PTSD-like symptoms. Multivariable regression analyses revealed that female gender, lower educational attainment, single marital status, being housewife, more severe insomnia, psychotic-like symptoms and cognitive complaints, self-harm behavior, lower resilience, avoidance coping, never contracting COVID-19 infection, greater fear of contagion, and longer exposure to pandemic-related information were independently associated with depression, anxiety and/or PTSD-like symptoms in psychiatric patients., Conclusions: Our results affirm increased vulnerability of psychiatric patients toward psychological distress during pandemic. An array of identified correlates facilitates early detection of high-risk psychiatric patients for targeted strategies to minimize pandemic-related negative psychological impact., (© 2024. The Author(s).)

Background: Psychiatric patients are susceptible to adverse mental health impacts during COVID-19, but complex interplays between psychopathology and pandemic-related variables remain elusive. This study aimed to investigate concomitant associations between psychopathological symptoms, psychological measures and COVID-19 related variables in Chinese psychiatric patients during the peak of fifth pandemic wave in Hong Kong., Methods: We employed network analysis to investigate inter-relationships among psychopathological symptoms (including depression, anxiety, post-traumatic stress disorder-like [PTSD-like] symptoms, insomnia, psychotic symptoms), cognitive complaints, health-related quality of life, loneliness, resilience and selected pandemic-related factors in 415 psychiatric outpatients between 28 March and 8 April, 2022. Network comparisons between genders, diagnosis (common mental disorders [CMD] vs. severe mental disorders [SMD]), and history of contracting COVID-19 at fifth wave were performed as exploratory analyses., Results: Our results showed that anxiety represented the most central node in the network, as indicated by its highest node strength and expected influence, followed by depression and quality of life. Three comparatively strong connections between COVID-19 and psychopathological variables were observed including: fear of contagion and PTSD-like symptoms, COVID-19 stressor burden and PTSD-like symptoms, and COVID-19 stressor burden and insomnia. Network comparison tests revealed significant network structural difference between participants with history of contracting COVID-19 and those without, but showed no significant difference between genders as well as between CMD and SMD patients., Conclusions: Our findings suggest the pivotal role of anxiety in psychopathology network of psychiatric patients amidst COVID-19. Pandemic-related variables are critically associated with trauma/stress and insomnia symptoms. Future research is required to elucidate potential network structural changes between pandemic and post-COVID periods., (© 2024. The Author(s).)

People with mental disorders have increased risk of psychological distress during COVID-19. However, there is limited research comprehensively examining factors associated with suicidal ideation, the strongest predictor of suicidal behavior, among psychiatric patients amidst pandemic. We investigated prevalence and correlates of suicidal ideation in 407 Chinese psychiatric outpatients (diagnosed with mood, anxiety or schizophrenia-spectrum disorders) aged 18-64 years during the peak of fifth COVID-19 wave in Hong Kong between 28 March and 8 April, 2022, based on a comprehensive array of variables encompassing socio-demographics, illness profile, psychopathological symptoms, psychological measures and pandemic-related factors. Univariate and multivariate logistic regression analyses were conducted to determine correlates of suicidal ideation. Results showed that 128 (31.4%) participants exhibited suicidal ideation. Univariate analyses revealed that being unemployed or full-time student, more severe depressive, anxiety, PTSD-like, insomnia and psychotic symptoms, higher levels of loneliness, avoidant-coping, greater pandemic-related stress burden and distress by social-distancing measures were related to suicidal ideation. Conversely, participants with higher monthly household-income, better quality-of-life, and greater resilience were less likely to have suicidal ideation. Notably, only depressive symptom severity was retained in final multivariate model as a factor significantly associated with suicidal ideation. Hence, we observed that approximately one-third of Chinese psychiatric patients experienced suicidal ideation during fifth pandemic wave. Our findings underscore the influence of depressive symptoms being above and beyond that of other psychopathological symptoms, psychological and pandemic-related variables on suicidal ideation. Longitudinal research is required to clarify suicidal ideation trajectories and predictors of persistent suicidal ideation across pandemic and post-pandemic periods., Competing Interests: Conflict of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

The lack of benchmark data sets with inbuilt ground-truth makes it challenging to compare the performance of existing long-read isoform detection and differential expression analysis workflows. Here, we present a benchmark experiment using two human lung adenocarcinoma cell lines that were each profiled in triplicate together with synthetic, spliced, spike-in RNAs (sequins). Samples were deeply sequenced on both Illumina short-read and Oxford Nanopore Technologies long-read platforms. Alongside the ground-truth available via the sequins, we created in silico mixture samples to allow performance assessment in the absence of true positives or true negatives. Our results show that StringTie2 and bambu outperformed other tools from the six isoform detection tools tested, DESeq2, edgeR and limma-voom were best among the five differential transcript expression tools tested and there was no clear front-runner for performing differential transcript usage analysis between the five tools compared, which suggests further methods development is needed for this application., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: The extent of cognitive impairment and its association with psychological distress among people with pre-existing mental illness during COVID-19 is understudied. This study aimed to investigate prevalence and correlates of subjective cognitive impairment (SCI) in Chinese psychiatric patients during fifth-wave of COVID-19 in Hong Kong (HK)., Methods: Four-hundred-eight psychiatric outpatients aged 18-64 years were assessed with questionnaires between 28 March and 8 April 2022, encompassing illness profile, psychopathological symptoms, coping-styles, resilience, and COVID-19 related factors. Participants were categorized into moderate-to-severe and intact/mild cognitive impairment (CI+ vs. CI-) groups based on severity of self-reported cognitive complaints. Univariate and multivariate regression analyses were conducted to determine variables associated with CI+ status., Results: One-hundred-ninety-nine participants (48.8%) experienced CI+. A multivariate model on psychopathological symptoms found that depressive and post-traumatic-stress-disorder (PTSD)-like symptoms were related to CI+, while a multivariate model on coping, resilience and COVID-19 related factors revealed that avoidant coping, low resilience and more stressors were associated with CI+. Final combined model demonstrated the best model performance and showed that more severe depressive and PTSD-like symptoms, and adoption of avoidant coping were significantly associated with CI+., Conclusion: Almost half of the sample of psychiatric patients reported cognitive complaints during fifth-wave of COVID-19 in HK. Greater depressive and PTSD-like symptom severity, and maladaptive (avoidant) coping were found as correlates of SCI. COVID-19 related factors were not independently associated with SCI in psychiatric patients. Early detection with targeted psychological interventions may therefore reduce psychological distress, and hence self-perceived cognitive difficulties in this vulnerable population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fung, Chan, Chui, Wong, Chan, Chu, So, Chung, Lee, Cheng, Law, Chan and Chang.)

Group heteroscedasticity is commonly observed in pseudo-bulk single-cell RNA-seq datasets and its presence can hamper the detection of differentially expressed genes. Since most bulk RNA-seq methods assume equal group variances, we introduce two new approaches that account for heteroscedastic groups, namely voomByGroup and voomWithQualityWeights using a blocked design (voomQWB). Compared to current gold-standard methods that do not account for group heteroscedasticity, we show results from simulations and various experiments that demonstrate the superior performance of voomByGroup and voomQWB in terms of error control and power when group variances in pseudo-bulk single-cell RNA-seq data are unequal., (© 2023. The Author(s).)

Background: Contrasting the well-described effects of early intervention (EI) services for youth-onset psychosis, the potential benefits of the intervention for adult-onset psychosis are uncertain. This paper aims to examine the effectiveness of EI on functioning and symptomatic improvement in adult-onset psychosis, and the optimal duration of the intervention., Methods: 360 psychosis patients aged 26-55 years were randomized to receive either standard care (SC, n = 120), or case management for two (2-year EI, n = 120) or 4 years (4-year EI, n = 120) in a 4-year rater-masked, parallel-group, superiority, randomized controlled trial of treatment effectiveness (Clinicaltrials.gov: NCT00919620). Primary (i.e. social and occupational functioning) and secondary outcomes (i.e. positive and negative symptoms, and quality of life) were assessed at baseline, 6-month, and yearly for 4 years., Results: Compared with SC, patients with 4-year EI had better Role Functioning Scale (RFS) immediate [interaction estimate = 0.008, 95% confidence interval (CI) = 0.001-0.014, p = 0.02] and extended social network (interaction estimate = 0.011, 95% CI = 0.004-0.018, p = 0.003) scores. Specifically, these improvements were observed in the first 2 years. Compared with the 2-year EI group, the 4-year EI group had better RFS total ( p = 0.01), immediate ( p = 0.01), and extended social network ( p = 0.05) scores at the fourth year. Meanwhile, the 4-year ( p = 0.02) and 2-year EI ( p = 0.004) group had less severe symptoms than the SC group at the first year., Conclusions: Specialized EI treatment for psychosis patients aged 26-55 should be provided for at least the initial 2 years of illness. Further treatment up to 4 years confers little benefits in this age range over the course of the study.

Introduction: With the start of the COVID-19 pandemic, the various social distancing policies imposed have mandated psychiatrists to consider the option of using telepsychiatry as an alternative to face-to-face interview in Hong Kong. Limitations over sample size, methodology and information technology were found in previous studies and the reliability of symptoms assessment remained a concern., Aim: To evaluate the reliability of assessment of psychiatric symptoms by telepsychiatry comparing with face-to-face psychiatric interview., Method: This study recruited a sample of adult psychiatric patients in psychiatric wards in Queen Mary Hospital. Semi-structural interviews with the use of standardized psychiatric assessment scales were carried out in telepsychiatry and face-to-face interview respectively by two clinicians and the reliability of psychiatric symptoms elicited were assessed., Results: 90 patients completed the assessments The inter-method reliability in Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Columbia Suicide Severity Rating Scale and Brief Psychiatric Rating Scale showed good agreement when compared with face-to-face interview., Conclusion: Symptoms assessment by telepsychiatry is comparable to assessment conducted by face-to-face interview., Competing Interests: Declaration of Competing Interest I declare that the study and manuscript represent my own work. It is part of my dissertation for completing the HKCPsych Part III Examination. Dr. Chi Wing Law is my supervisor. Dr. Yeung Wai Tat and I conducted all the clinical interviews and collected the clinical data from the assessment scales, questionnaires and the Hospital Authority Clinical Management System for all subjects. Diagnosis of the diseases were confirmed by team meetings with consultants in individual teams and documented in clinical records. Statistical analysis was conducted by me with the assistance by Mr. Edward Choi and I held several meetings with him in between to confirm on the relevant statistical methods used. Tables and figures related to statistical analysis were done by me. As the investigator of this study, I take direct responsibility for the study design, subject recruitment, data collection, results interpretation and write up of the dissertation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Glimma 1.0 introduced intuitive, point-and-click interactive graphics for differential gene expression analysis. Here, we present a major update to Glimma that brings improved interactivity and reproducibility using high-level visualization frameworks for R and JavaScript. Glimma 2.0 plots are now readily embeddable in R Markdown, thus allowing users to create reproducible reports containing interactive graphics. The revamped multidimensional scaling plot features dashboard-style controls allowing the user to dynamically change the colour, shape and size of sample points according to different experimental conditions. Interactivity was enhanced in the MA-style plot for comparing differences to average expression, which now supports selecting multiple genes, export options to PNG, SVG or CSV formats and includes a new volcano plot function. Feature-rich and user-friendly, Glimma makes exploring data for gene expression analysis more accessible and intuitive and is available on Bioconductor and GitHub., (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

A modified Chromium 10x droplet-based protocol that subsamples cells for both short-read and long-read (nanopore) sequencing together with a new computational pipeline (FLAMES) is developed to enable isoform discovery, splicing analysis, and mutation detection in single cells. We identify thousands of unannotated isoforms and find conserved functional modules that are enriched for alternative transcript usage in different cell types and species, including ribosome biogenesis and mRNA splicing. Analysis at the transcript level allows data integration with scATAC-seq on individual promoters, improved correlation with protein expression data, and linked mutations known to confer drug resistance to transcriptome heterogeneity., (© 2021. The Author(s).)

While the intrinsic apoptosis pathway is thought to play a central role in shaping the B cell lineage, its precise role in mature B cell homeostasis remains elusive. Using mice in which mature B cells are unable to undergo apoptotic cell death, we show that apoptosis constrains follicular B (FoB) cell lifespan but plays no role in marginal zone B (MZB) cell homeostasis. In these mice, FoB cells accumulate abnormally. This intensifies intercellular competition for BAFF, resulting in a contraction of the MZB cell compartment, and reducing the growth, trafficking, and fitness of FoB cells. Diminished BAFF signaling dampens the non-canonical NF-κB pathway, undermining FoB cell growth despite the concurrent triggering of a protective p53 response. Thus, MZB and FoB cells exhibit a differential requirement for the intrinsic apoptosis pathway. Homeostatic apoptosis constrains the size of the FoB cell compartment, thereby preventing competition-induced FoB cell atrophy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Development of a branching tree in the embryonic lung is crucial for the formation of a fully mature functional lung at birth. Sox9+ cells present at the tip of the primary embryonic lung endoderm are multipotent cells responsible for branch formation and elongation. We performed a genetic screen in murine primary cells and identified aurora kinase b (Aurkb) as an essential regulator of Sox9+ cells ex vivo. In vivo conditional knockout studies confirmed that Aurkb was required for lung development but was not necessary for postnatal growth and the repair of the adult lung after injury. Deletion of Aurkb in embryonic Sox9+ cells led to the formation of a stunted lung that retained the expression of Sox2 in the proximal airways, as well as Sox9 in the distal tips. Although we found no change in cell polarity, we showed that loss of Aurkb or chemical inhibition of Aurkb caused Sox9+ cells to arrest at G2/M, likely responsible for the lack of branch bifurcation. This work demonstrates the power of genetic screens in identifying novel regulators of Sox9+ progenitor cells and lung branching morphogenesis., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Application of Oxford Nanopore Technologies' long-read sequencing platform to transcriptomic analysis is increasing in popularity. However, such analysis can be challenging due to the high sequence error and small library sizes, which decreases quantification accuracy and reduces power for statistical testing. Here, we report the analysis of two nanopore RNA-seq datasets with the goal of obtaining gene- and isoform-level differential expression information. A dataset of synthetic, spliced, spike-in RNAs ('sequins') as well as a mouse neural stem cell dataset from samples with a null mutation of the epigenetic regulator Smchd1  was analysed using a mix of long-read specific tools for preprocessing together with established short-read RNA-seq methods for downstream analysis. We used limma-voom to perform differential gene expression analysis, and the novel FLAMES pipeline to perform isoform identification and quantification, followed by DRIMSeq and limma-diffSplice (with stageR ) to perform differential transcript usage analysis. We compared results from the sequins dataset to the ground truth, and results of the mouse dataset to a previous short-read study on equivalent samples. Overall, our work shows that transcriptomic analysis of long-read nanopore data using long-read specific preprocessing methods together with short-read differential expression methods and software that are already in wide use can yield meaningful results., (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Influenza A virus (IAV) is rapidly detected in the airways by the immune system, with resident parenchymal cells and leukocytes orchestrating viral sensing and the induction of antiviral inflammatory responses. The airways are innervated by heterogeneous populations of vagal sensory neurons which also play an important role in pulmonary defense. How these neurons respond to IAV respiratory infection remains unclear. Here, we use a murine model to provide the first evidence that vagal sensory neurons undergo significant transcriptional changes following a respiratory IAV infection. RNA sequencing on vagal sensory ganglia showed that IAV infection induced the expression of many genes associated with an antiviral and pro-inflammatory response and this was accompanied by a significant increase in inflammatory cell recruitment into the vagal ganglia. Assessment of gene expression in single-vagal sensory neurons confirmed that IAV infection induced a neuronal inflammatory phenotype, which was most prominent in bronchopulmonary neurons, and also evident in some neurons innervating other organs. The altered transcriptome could be mimicked by intranasal treatment with cytokines and the lung homogenates of infected mice, in the absence of infectious virus. These data argue that IAV pulmonary infection and subsequent inflammation induces vagal sensory ganglia neuroinflammation and this may have important implications for IAV-induced morbidity., (© 2021 Federation of American Societies for Experimental Biology.)

Differential expression analysis of genomic data types, such as RNA-sequencing experiments, use linear models to determine the size and direction of the changes in gene expression. For RNA-sequencing, there are several established software packages for this purpose accompanied with analysis pipelines that are well described. However, there are two crucial steps in the analysis process that can be a stumbling block for many -- the set up an appropriate model via design matrices and the set up of comparisons of interest via contrast matrices. These steps are particularly troublesome because an extensive catalogue for design and contrast matrices does not currently exist. One would usually search for example case studies across different platforms and mix and match the advice from those sources to suit the dataset they have at hand. This article guides the reader through the basics of how to set up design and contrast matrices. We take a practical approach by providing code and graphical representation of each case study, starting with simpler examples (e.g. models with a single explanatory variable) and move onto more complex ones (e.g. interaction models, mixed effects models, higher order time series and cyclical models). Although our work has been written specifically with a limma -style pipeline in mind, most of it is also applicable to other software packages for differential expression analysis, and the ideas covered can be adapted to data analysis of other high-throughput technologies. Where appropriate, we explain the interpretation and differences between models to aid readers in their own model choices. Unnecessary jargon and theory is omitted where possible so that our work is accessible to a wide audience of readers, from beginners to those with experience in genomics data analysis., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Law CW et al.)

RNA-seq datasets can contain millions of intron reads per library that are typically removed from downstream analysis. Only reads overlapping annotated exons are considered to be informative since mature mRNA is assumed to be the major component sequenced, especially for poly(A) RNA libraries. In this study, we show that intron reads are informative, and through exploratory data analysis of read coverage that intron signal is representative of both pre-mRNAs and intron retention. We demonstrate how intron reads can be utilized in differential expression analysis using our index method where a unique set of differentially expressed genes can be detected using intron counts. In exploring read coverage, we also developed the superintronic software that quickly and robustly calculates user-defined summary statistics for exonic and intronic regions. Across multiple datasets, superintronic enabled us to identify several genes with distinctly retained introns that had similar coverage levels to that of neighbouring exons. The work and ideas presented in this paper is the first of its kind to consider multiple biological sources for intron reads through exploratory data analysis, minimizing bias in discovery and interpretation of results. Our findings open up possibilities for further methods development for intron reads and RNA-seq data in general., (© The Author(s) 2019. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

In eukaryotic cells, messenger RNA (mRNA) molecules are exported from the nucleus to the cytoplasm, where they are translated. The highly conserved protein nuclear RNA export factor1 (Nxf1) is an important mediator of this process. Although studies in yeast and in human cell lines have shed light on the biochemical mechanisms of Nxf1 function, its contribution to mammalian physiology is less clear. Several groups have identified recurrent NXF1 mutations in chronic lymphocytic leukemia (CLL), placing it alongside several RNA-metabolism factors (including SF3B1, XPO, RPS15) whose dysregulation is thought to contribute to CLL pathogenesis. We report here an allelic series of germline point mutations in murine Nxf1. Mice heterozygous for these loss-of-function Nxf1 mutations exhibit thrombocytopenia and lymphopenia, together with milder hematological defects. This is primarily caused by cell-intrinsic defects in the survival of platelets and peripheral lymphocytes, which are sensitized to intrinsic apoptosis. In contrast, Nxf1 mutations have almost no effect on red blood cell homeostasis. Comparative transcriptome analysis of platelets, lymphocytes, and erythrocytes from Nxf1-mutant mice shows that, in response to impaired Nxf1 function, the cytoplasmic representation of transcripts encoding regulators of RNA metabolism is altered in a unique, lineage-specific way. Thus, blood cell lineages exhibit differential requirements for Nxf1-mediated global mRNA export., (© 2020 by The American Society of Hematology.)

Objective: Stigma has a deleterious effect on functioning in individuals with bipolar disorder (BD). However, there has been no research investigating how stigma coping predicts self-stigma and functioning in BD. Furthermore, how different stages of self-stigma might affect functioning is unclear. The following hypotheses were examined: (1) Stigma coping by withdrawal and secrecy was associated with more self-stigma; (2) Stigma coping by withdrawal and secrecy was associated with worse social functioning; and (3) Later stages of self-stigma were associated with worse social functioning., Methods: A random sample of remitted BD in a regional psychiatric clinic was examined using a cross-sectional design (n = 115). Self-stigma was measured using the Chinese versions of Self-Stigma of Mental Illness Scale (C-SSMIS). Social functioning was assessed using the Functional Assessment Short Test (FAST). Stigma coping was evaluated using the Stigma Coping Orientation Scale (SCOS)., Results: Multiple regression analysis revealed that coping by secrecy was associated with the stereotype agreement subscale of C-SSMIS, while coping by withdrawal was associated with the C-SSMIS self-concurrence and self-esteem decrement subscales. Another regression analysis showed that FAST total score was associated with the self-esteem decrement subscale of C-SSMIS and the severity of depressive and manic symptoms., Conclusion: We showed that self-esteem decrement, the final stage of self-stigma, was the most crucial stage in determining psychosocial functioning. Our findings suggested that stigma-reduction intervention should be arranged during the early stage of BD and targeted at various dysfunctional stigma coping., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Multidisciplinary care (MDC) encourages multiple specialists to formulate a unified treatment plan. We sought to determine the frequency and predictors of MDC and assess the association between MDC and nationally-recognized quality metrics in patients with breast cancer. Methods: We used the surveillance, epidemiology, and end results-medicare dataset to evaluate patients diagnosed with stages I-III breast cancer who underwent breast-conserving surgery between 2002 and 2011 with follow-up to 2012. We defined MDC as a visit claim from a surgeon, radiation oncologist and medical oncologist within 12 months of diagnosis. We used multivariable regression analysis to determine the association between demographic and clinical variables and MDC, and to assess the association between MDC and three nationally-recognized quality indicators (adjuvant hormone therapy for hormone receptor-positive tumors, chemotherapy for hormone receptor-negative cancer, and radiation after lumpectomy). Results: Of the 61,039 patients in our initial cohort, 53,849 (88.2%) saw a medical oncologist, 46,521 (76.2%) saw a radiation oncologist, and 43,280 (70.9%) were evaluated by all three providers the first year after diagnosis. MDC use was higher in patients with the highest socioeconomic status compared with the lowest [odds ratio (OR) 1.74, 95% CI 1.63-1.86], in patients diagnosed in later years, and those with stage III disease compared to stage I [OR 1.29, 95% CI 1.19-1.41]. Patients older in age (≥80 vs. 65-69 years, OR 0.33, 95% CI 0.31-0.34), patients with more comorbidities, those who lived in a rural setting compared to urban (OR 0.61, 95% CI 0.57-0.64), and unmarried patients (OR 0.79, 95% CI 0.76-0.82) were less likely to see all three providers. In a multivariable analysis, MDC use was associated with increased likelihood of meeting each quality metric. Conclusion: Early stage breast cancer patients were evaluated by a surgeon, radiation oncologist and medical oncologist less than 75% of the time. Enhanced coordination of care and navigation programs may improve the quality of care delivered.

Purpose: Follow-up guidelines vary widely among national organizations for patients with early-stage breast cancer treated with curative intent. We sought to evaluate the patterns and predictors of provider follow-up care within the first 5 years after diagnosis., Methods: Using the SEER-Medicare linked data set, we evaluated patients who were diagnosed with stage I and II breast cancer who underwent breast-conserving surgery from 2002 to 2007 with follow-up until 2012. We defined discontinuation of follow-up as > 12 months from the previous physician visit without a visit claim from either a surgeon, medical oncologist, or radiation oncologist. We performed a multivariable logistic regression and Cox proportional hazards regression analysis to determine factors associated with the discontinuation of follow-up care., Results: Of the 30,053 patients enrolled in our initial cohort, 25,781 (85.8%) saw a medical oncologist and 21,612 (71.9%) saw a radiation oncologist in the first year in addition to a surgeon. Over the 5 years, 6,302 patients (21.0%) discontinued follow-up visits. Discontinuation of physician visits increased with increasing age. Women with stage II cancer ( v stage I) were less likely to discontinue follow-up visits (odds ratio, 0.78; 95% CI, 0.73 to 0.83). Time to early discontinuation was greater for patients with hormone receptor-negative tumors (hazard ratio, 1.14; 95% CI, 1.05 to 1.24). Women who were diagnosed more recently were less likely to discontinue seeing any physician., Conclusion: Twenty-one percent of patients with early-stage breast cancer discontinued seeing any oncology provider over the 5 years after diagnosis. Coordination of follow-up care between oncology specialists may reduce discontinuation rates and increase clinical efficiency.

Objectives: To facilitate early diagnosis of infants with hearing loss, a universal newborn hearing screening program (UNHS) has been implemented in Hong Kong's public hospitals for over a decade. However, there have been no known studies investigating parent attitudes to, and satisfaction with, UNHS since its launch in Hong Kong. The present study aimed to investigate knowledge of UNHS as well as infant hearing development, and attitudes and satisfaction with UNHS, in Hong Kong mothers with newborns. The study was designed to help evaluate and improve an established UNHS public hospital program, based on the perspectives of service users., Methods: A researcher-developed questionnaire was administered to 102 mothers whose newborn had received UNHS in the postnatal wards of a large public hospital in Hong Kong. The questionnaire considered parental knowledge of UNHS and infant hearing development, attitudes and satisfaction toward public hospital UNHS. In the knowledge dimension, parents' preferred time and location for pre-test information delivery, interpretation of screening results, and knowledge of hearing developmental milestones were surveyed. In addition, maternal attitudes to and satisfaction with UNHS screening services, the potential impact of UNHS on parent emotions and parent-baby bonding, attitudes toward informed consent, and willingness to comply with diagnostic assessment referral were also be surveyed., Results: Mean participant scores on knowledge of infant hearing development were relatively low (M = 2.59/6.0, SD = 0.90). Many mothers also underestimated the potential ongoing risks of hearing impairment in babies. Around 80% of mothers thought an infant could not have hearing impairment after passing the screening. In addition, one-third of mothers thought a baby could not later develop hearing impairment in infancy or childhood. In terms of attitudes and satisfaction, participants gave somewhat negative ratings for questions regarding receiving sufficient information about the screening (M = 2.90/5.0, SD = 1.27), screening procedure (M = 2.20/5.0, SD = 1.08), and sufficiency of information about results (M = 2.87/5.0, SD = 1.14). Nonetheless, participants gave positive ratings concerning whether screening could lead to early diagnosis (M = 4.61/5.0, SD = 0.57) and over 95% of mothers supported UNHS despite potential for false positive results. Mothers reported a high willingness to bring their baby to follow-up assessments if required (M = 4.53/5.0, SD = 0.56). Participants gave positive ratings for their level of satisfaction with the time and location of first UNHS information provision (M = 4.34/5.0, SD = 0.80) and the way permission was asked for screening the baby (M = 4.04/5.0, SD = 0.97) but alternative procedures were also recommended. Most recommendations focused on providing more information about the test and a more detailed explanation of screening results., Conclusions: The survey results highlighted the need to provide more information to parents about infant hearing development to support home monitoring for signs of hearing loss after UNHS, as well as more detailed explanation and information regarding hearing screening and the implications of results to parents. Regardless of location, surveys of this type may provide valuable support for UNHS program quality assurance., (Copyright © 2017. Published by Elsevier B.V.)

Gene set enrichment analysis is a popular approach for prioritising the biological processes perturbed in genomic datasets. The Bioconductor project hosts over 80 software packages capable of gene set analysis. Most of these packages search for enriched signatures amongst differentially regulated genes to reveal higher level biological themes that may be missed when focusing only on evidence from individual genes. With so many different methods on offer, choosing the best algorithm and visualization approach can be challenging. The EGSEA package solves this problem by combining results from up to 12 prominent gene set testing algorithms to obtain a consensus ranking of biologically relevant results.This workflow demonstrates how EGSEA can extend limma-based differential expression analyses for RNA-seq and microarray data using experiments that profile 3 distinct cell populations important for studying the origins of breast cancer. Following data normalization and set-up of an appropriate linear model for differential expression analysis, EGSEA builds gene signature specific indexes that link a wide range of mouse or human gene set collections obtained from MSigDB, GeneSetDB and KEGG to the gene expression data being investigated. EGSEA is then configured and the ensemble enrichment analysis run, returning an object that can be queried using several S4 methods for ranking gene sets and visualizing results via heatmaps, KEGG pathway views, GO graphs, scatter plots and bar plots. Finally, an HTML report that combines these displays can fast-track the sharing of results with collaborators, and thus expedite downstream biological validation. EGSEA is simple to use and can be easily integrated with existing gene expression analysis pipelines for both human and mouse data., Competing Interests: Competing interests: MA and MN are employees of CSL Limited.

Motivation: graphics for RNA-sequencing and microarray gene expression analyses may contain upwards of tens of thousands of points. Details about certain genes or samples of interest are easily obscured in such dense summary displays. Incorporating interactivity into summary plots would enable additional information to be displayed on demand and facilitate intuitive data exploration., Results: The open-source Glimma package creates interactive graphics for exploring gene expression analysis with a few simple R commands. It extends popular plots found in the limma package, such as multi-dimensional scaling plots and mean-difference plots, to allow individual data points to be queried and additional annotation information to be displayed upon hovering or selecting particular points. It also offers links between plots so that more information can be revealed on demand. Glimma is widely applicable, supporting data analyses from a number of well-established Bioconductor workflows ( limma , edgeR and DESeq2 ) and uses D3/JavaScript to produce HTML pages with interactive displays that enable more effective data exploration by end-users. Results from Glimma can be easily shared between bioinformaticians and biologists, enhancing reporting capabilities while maintaining reproducibility., Availability and Implementation: The Glimma R package is available from http://bioconductor.org/packages/Glimma/ ., Contact: su.s@wehi.edu.au , law@wehi.edu.au or mritchie@wehi.edu.au., (© The Author 2017. Published by Oxford University Press.)

Background: Colorectal cancer is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related death globally. It is the second most common cancer among both males and females in Malaysia. The economic burden of colorectal cancer is likely to increase over time owing to its current trend and aging population. Cancer survival analysis is an essential indicator for early detection and improvement in cancer treatment. However, there was a scarcity of studies concerning survival of colorectal cancer patients as well as its predictors. Therefore, we aimed to determine the 1-, 3- and 5-year survival rates, compare survival rates among ethnic groups and determine the predictors of survival among colorectal cancer patients., Methods: This was an ambidirectional cohort study conducted at the University Malaya Medical Centre (UMMC) in Kuala Lumpur, Malaysia. All Malaysian citizens or permanent residents with histologically confirmed diagnosis of colorectal cancer seen at UMMC from 1 January 2001 to 31 December 2010 were included in the study. Demographic and clinical characteristics were extracted from the medical records. Patients were followed-up until death or censored at the end of the study (31st December 2010). Censored patients' vital status (whether alive or dead) were cross checked with the National Registration Department. Survival analyses at 1-, 3- and 5-year intervals were performed using the Kaplan-Meier method. Log-rank test was used to compare the survival rates, while Cox proportional hazard regression analysis was carried out to determine the predictors of 5-year colorectal cancer survival., Results: Among 1212 patients, the median survival for colorectal, colon and rectal cancers were 42.0, 42.0 and 41.0 months respectively; while the 1-, 3-, and 5-year relative survival rates ranged from 73.8 to 76.0%, 52.1 to 53.7% and 40.4 to 45.4% respectively. The Chinese patients had the lowest 5-year survival compared to Malay and Indian patients. Based on the 814 patients with data on their Duke's staging, independent predictors of poor colorectal cancer (5-year) survival were male sex (Hazard Ratio [HR]: 1.41; 95% CI: 1.12, 1.76), Chinese ethnicity (HR: 1.41; 95% CI: 1.07,1.85), elevated (≥ 5.1 ng/ml) pre-operative carcino-embryonic antigen (CEA) level (HR: 2.13; 95% CI: 1.60, 2.83), Duke's stage C (HR: 1.68; 95% CI: 1.28, 2.21), Duke's stage D (HR: 4.61; 95% CI: 3.39, 6.28) and emergency surgery (HR: 1.52; 95% CI: 1.07, 2.15)., Conclusions: The survival rates of colorectal cancer among our patients were comparable with those of some Asian countries but lower than those found in more developed countries. Males and patients from the Chinese ethnic group had lower survival rates compared to their counterparts. More advanced staging and late presentation were important predictors of colorectal cancer survival. Health education programs targeting high risk groups and emphasizing the importance of screening and early diagnosis, as well as the recognition of symptoms and risk factors should be implemented. A nationwide colorectal cancer screening program should be designed and implemented to increase early detection and improve survival outcomes.

Carefully designed control experiments provide a gold standard for benchmarking different genomics research tools. A shortcoming of many gene expression control studies is that replication involves profiling the same reference RNA sample multiple times. This leads to low, pure technical noise that is atypical of regular studies. To achieve a more realistic noise structure, we generated a RNA-sequencing mixture experiment using two cell lines of the same cancer type. Variability was added by extracting RNA from independent cell cultures and degrading particular samples. The systematic gene expression changes induced by this design allowed benchmarking of different library preparation kits (standard poly-A versus total RNA with Ribozero depletion) and analysis pipelines. Data generated using the total RNA kit had more signal for introns and various RNA classes (ncRNA, snRNA, snoRNA) and less variability after degradation. For differential expression analysis, voom with quality weights marginally outperformed other popular methods, while for differential splicing, DEXSeq was simultaneously the most sensitive and the most inconsistent method. For sample deconvolution analysis, DeMix outperformed IsoPure convincingly. Our RNA-sequencing data set provides a valuable resource for benchmarking different protocols and data pre-processing workflows. The extra noise mimics routine lab experiments more closely, ensuring any conclusions are widely applicable., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Despite accumulating evidence for a mammary differentiation hierarchy, the basal compartment comprising stem cells remains poorly characterized. Through gene expression profiling of Lgr5 + basal epithelial cells, we identify a new marker, Tetraspanin8 (Tspan8). Fractionation based on Tspan8 and Lgr5 expression uncovered three distinct mammary stem cell (MaSC) subsets in the adult mammary gland. These exist in a largely quiescent state but differ in their reconstituting ability, spatial localization, and their molecular and epigenetic signatures. Interestingly, the deeply quiescent MaSC subset (Lgr5 + Tspan8 hi ) resides within the proximal region throughout life, and has a transcriptome strikingly similar to that of claudin-low tumours. Lgr5 + Tspan8 hi cells appear to originate from the embryonic mammary primordia before switching to a quiescent state postnatally but can be activated by ovarian hormones. Our findings reveal an unexpected degree of complexity within the adult MaSC compartment and identify a dormant subset poised for activation in response to physiological stimuli.

The ability to easily and efficiently analyse RNA-sequencing data is a key strength of the Bioconductor project. Starting with counts summarised at the gene-level, a typical analysis involves pre-processing, exploratory data analysis, differential expression testing and pathway analysis with the results obtained informing future experiments and validation studies. In this workflow article, we analyse RNA-sequencing data from the mouse mammary gland, demonstrating use of the popular edgeR package to import, organise, filter and normalise the data, followed by the limma package with its voom method, linear modelling and empirical Bayes moderation to assess differential expression and perform gene set testing. This pipeline is further enhanced by the Glimma package which enables interactive exploration of the results so that individual samples and genes can be examined by the user. The complete analysis offered by these three packages highlights the ease with which researchers can turn the raw counts from an RNA-sequencing experiment into biological insights using Bioconductor.

Aberrant expression of the oncogenic transcription factor forkhead box protein 1 (FOXP1) is a common feature of diffuse large B-cell lymphoma (DLBCL). We have combined chromatin immunoprecipitation and gene expression profiling after FOXP1 depletion with functional screening to identify targets of FOXP1 contributing to tumor cell survival. We find that the sphingosine-1-phosphate receptor 2 (S1PR2) is repressed by FOXP1 in activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL cell lines with aberrantly high FOXP1 levels; S1PR2 expression is further inversely correlated with FOXP1 expression in 3 patient cohorts. Ectopic expression of wild-type S1PR2, but not a point mutant incapable of activating downstream signaling pathways, induces apoptosis in DLBCL cells and restricts tumor growth in subcutaneous and orthotopic models of the disease. The proapoptotic effects of S1PR2 are phenocopied by ectopic expression of the small G protein Gα13 but are independent of AKT signaling. We further show that low S1PR2 expression is a strong negative prognosticator of patient survival, alone and especially in combination with high FOXP1 expression. The S1PR2 locus has previously been demonstrated to be recurrently mutated in GCB DLBCL; the transcriptional silencing of S1PR2 by FOXP1 represents an alternative mechanism leading to inactivation of this important hematopoietic tumor suppressor., (© 2016 by The American Society of Hematology.)

Background: RNA-seq has been a boon to the quantitative analysis of transcriptomes. A notable application is the detection of changes in transcript usage between experimental conditions. For example, discovery of pathological alternative splicing may allow the development of new treatments or better management of patients. From an analysis perspective, there are several ways to approach RNA-seq data to unravel differential transcript usage, such as annotation-based exon-level counting, differential analysis of the percentage spliced in, or quantitative analysis of assembled transcripts. The goal of this research is to compare and contrast current state-of-the-art methods, and to suggest improvements to commonly used work flows., Results: We assess the performance of representative work flows using synthetic data and explore the effect of using non-standard counting bin definitions as input to DEXSeq, a state-of-the-art inference engine. Although the canonical counting provided the best results overall, several non-canonical approaches were as good or better in specific aspects and most counting approaches outperformed the evaluated event- and assembly-based methods. We show that an incomplete annotation catalog can have a detrimental effect on the ability to detect differential transcript usage in transcriptomes with few isoforms per gene and that isoform-level prefiltering can considerably improve false discovery rate control., Conclusion: Count-based methods generally perform well in the detection of differential transcript usage. Controlling the false discovery rate at the imposed threshold is difficult, particularly in complex organisms, but can be improved by prefiltering the annotation catalog.

Objective: Universal newborn hearing screening is an established practice among Hong Kong public hospitals using a 2-stage automated auditory brainstem response (AABR) screening protocol. To enhance overall efficiency without sacrificing program accuracy, cost reduction in terms of replacing the initial ear coupler-based screening with a more economical ear insert-based screening procedure was considered. This study examined the utility of an insert-based AABR initial screening approach and the projected cost-effectiveness of a combined probe-based plus follow-up ear coupler AABR screening procedure., Methods: Following prenatal maternal consent, newborn hearing screening was conducted with 167 healthy neonates using a cross-sectional, repeated measures study design. The neonates were screened with AABR sequentially; using ear coupler and ear probe (insert) procedures, in both ears, with two different but comparable AABR instruments. Testing took place in the antenatal ward of a department of obstetrics and gynaecology, at a large public hospital., Results: With the specific combination of instruments deployed for this study insert-based AABR screening generated a five-fold higher rescreen rate and took an additional 50% screening time compared to coupler-based AABR screening. Although the cost of consumables used in a 2-stage AABR screening protocol would reduce by 9.87% if the combined procedure was implemented, the findings indicated AABR screening when conducted with an ear probe has reduced utility compared with conventional ear coupler screening., Conclusions: Significant differences may occur in screening outcomes when changes are made to coupler method. Initiating a 2-stage AABR screening protocol with an ear insert technique may be impracticable in newborn nurseries given the greater number of false positive cases generated by this approach in the present study and the increased time required to carry out an insert-based procedure., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Multiple etiological and prognostic factors have been implied in schizophrenia and its outcome. Advanced paternal age has been reported as a risk factor in schizophrenia. Whether this may affect schizophrenia outcome was not previously studied. We hypothesized that advanced paternal age may have a negative effect on the outcome of relapse in schizophrenia., Method: We interviewed 191 patients with first-episode schizophrenia and their relatives for parental ages, sociodemographic factors at birth, birth rank, family history of psychotic disorders, and obstetric complications. The outcome measure was the presence of relapse at the end of the first year of treatment., Results: In the 1-year follow-up period, 42 (22%) patients experienced 1 or more relapses. The mean paternal age was 34.62 years (SD 7.69). Patients who relapsed had significantly higher paternal age, poorer medication adherence, were female, and were hospitalized at onset, compared with patients who did not relapse. A multivariate regression analysis showed that advanced paternal age (OR 1.05, 95% CI 1.01 to 1.10), medication nonadherence (OR 2.37, 95% CI 1.12 to 4.99), and female sex (OR 2.44, 95% CI 1.14 to 5.24) independently contributed to a higher risk of relapse. Analysis between different paternal age groups found a significantly higher relapse rate with paternal age over 40., Conclusions: Advanced paternal age is found to be modestly but significantly related to more relapses, and such an effect is the strongest at a cut-off of paternal age of 40 years or older. The effect is less likely to be mediated through less effective parental supervision or nonadherence to medication. Other possible biological mechanisms need further explorations.

limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: This study examined the psychometric properties of the Bahasa Malaysia (BM) version of the European Organization for Research and Treatment of Cancer (EORTC) Colorectal Cancer-specific Quality Of Life Questionnaire (QLQ-CR29)., Materials and Methods: We studied 93 patients recruited from University Malaya and Universiti Kebangsaan Medical Centers, Kuala Lumpur, Malaysia using a self-administered method. Tools included QLQ-C30, QLQ-CR29 and Karnofsky Performance Scales (KPS). Statistical analyses included Cronbach's alpha, test-retest correlations, multi-traits scaling and known-groups comparisons. A p value ≤ 0.05 was considered significant., Results: The internal consistency coefficients for body image, urinary frequency, blood and mucus and stool frequency scales were acceptable (Cronbach's alpha α ≥ 0.65). However, the coefficients were low for the blood and mucus and stool frequency scales in patients with a stoma bag (α = 0.46). Test-retest correlation coefficients were moderate to high (range: r = 0.51 to 1.00) for most of the scales except anxiety, urinary frequency, buttock pain, hair loss, stoma care related problems, and dyspareunia (r ≤ 0.49). Convergent and discriminant validities were achieved in all scales. Patients with a stoma reported significantly higher symptoms of blood and mucus in the stool, flatulence, faecal incontinence, sore skin, and embarrassment due to the frequent need to change the stoma bag (p < 0.05) compared to patients without stoma. None of the scales distinguished between patients based on the KPS scores. There were no overlaps between scales in the QLQ-C30 and QLQ-CR29 (r < 0.40)., Conclusions: the BM version of the QLQ-CR29 indicated acceptable psychometric properties in most of the scales similar to original validation study. This questionnaire could be used to complement the QLQ-C30 in assessing HRQOL among BM speaking population with colorectal cancer.

Background and Aims: Colorectal cancer is the second most frequent cancer in Malaysia. We aimed to assess the validity and reliability of the Malaysian Chinese version of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire core (QLQ-C30) in patients with colorectal cancer., Materials and Methods: Translated versions of the QLQ-C30 were obtained from the EORTC. A cross sectional study design was used to obtain data from patients receiving treatment at two teaching hospitals in Kuala Lumpur, Malaysia. The Malaysian Chinese version of QLQ-C30 was self-administered in 96 patients while the Karnofsky Performance Scales (KPS) was generated by attending surgeons. Statistical analysis included reliability, convergent, discriminate validity, and known-groups comparisons. Statistical significance was based on p value ≤0.05., Results: The internal consistencies of the Malaysian Chinese version were acceptable [Cronbach's alpha (α≥ 0.70)] in the global health status/overall quality of life (GHS/QOL), functioning scales except cognitive scale (α≤0.32) in all levels of analysis, and social/family functioning scale (α=0.63) in patients without a stoma. All questionnaire items fulfilled the criteria for convergent and discriminant validity except question number 5, with correlation with role (r = 0.62) and social/family (r = 0.41) functioning higher than with physical functioning scales (r = 0.34). The test-retest coefficients in the GHS/QOL, functioning scales and in most of the symptoms scales were moderate to high (r = 0.58 to 1.00). Patients with a stoma reported statistically significant lower physical functioning (p=0.015), social/family functioning (p=0.013), and higher constipation (p=0.010) and financial difficulty (p=0.037) compared to patients without stoma. There was no significant difference between patients with high and low KPS scores., Conclusions: Malaysian Chinese version of the QLQ-C30 is a valid and reliable measure of HRQOL in patients with colorectal cancer.