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HATK: HLA analysis toolkit.
SUMMARY: Fine-mapping human leukocyte antigen (HLA) genes involved in disease susceptibility to individual alleles or amino acid residues has been challenging. Using information regarding HLA alleles obtained from HLA typing, HLA imputation or HLA inference, our software expands the alleles to amino acid sequences using the most recent IMGT/HLA database and prepares a dataset suitable for fine-mapping analysis. Our software also provides useful functionalities, such as various association tests, visualization tools and nomenclature conversion. AVAILABILITY AND IMPLEMENTATION: https://github.com/WansonChoi/HATK.
Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial.
BACKGROUND: Cytokines are critical to human disease and are attractive therapeutic targets given their widespread influence on gene regulation and transcription. Defining the downstream regulatory mechanisms influenced by cytokines is central to defining drug and disease mechanisms. One promising strategy is to use interactions between expression quantitative trait loci (eQTLs) and cytokine levels to define target genes and mechanisms. RESULTS: In a clinical trial for anti-IL-6 in patients with systemic lupus erythematosus, we measure interferon (IFN) status, anti-IL-6 drug exposure, and whole blood genome-wide gene expression at three time points. We show that repeat transcriptomic measurements increases the number of cis eQTLs identified compared to using a single time point. We observe a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 drug exposure and find many novel interactions that have not been previously described. Finally, we find transcription factor binding motifs interrupted by eQTL interaction SNPs, which point to key regulatory mediators of these environmental stimuli and therefore potential therapeutic targets for autoimmune diseases. In particular, genes with IFN interactions are enriched for ISRE binding site motifs, while those with anti-IL-6 interactions are enriched for IRF4 motifs. CONCLUSIONS: This study highlights the potential to exploit clinical trial data to discover in vivo eQTL interactions with therapeutically relevant environmental variables.
Beliefs about medicines and adherence in women with breast cancer on adjuvant endocrine therapy.
The Beliefs about Medicines Questionnaire (BMQ) and Adherence Starts with Knowledge (ASK-12) questionnaire were originally developed and validated in Western populations to assess beliefs and barriers to medication adherence. The study aim is to validate the BMQ and ASK-12 questionnaire for use in a Singapore population with early stage breast cancer. English-speaking women on adjuvant endocrine therapy (n = 157) were recruited. The BMQ-Specific showed good internal consistency with structural validity. The internal consistency of BMQ-General and ASK-12 Behaviour scale improved with the new factor structure obtained from exploratory factor analysis. Further studies are needed to confirm these factor structures.
Use of Menopausal Hormone Therapy and Bioidentical Hormone Therapy in Australian Women 50 to 69 Years of Age: Results from a National, Cross-Sectional Study.
Menopausal Hormone Therapy (MHT) use in Australia fell by 55% from 2001 to 2005, following the release of large-scale findings on its risks and benefits. Comprehensive national data, including information on overall prevalence of MHT use as well as information on duration of use in Australia have not been reported since the 2004-5 National Health Survey, when 11% of women aged 45+ years were estimated to be current MHT users. No national data are available on prevalence of use of "bioidentical" hormone therapy (BHT). The objective of this study was to determine recent prevalence of MHT and BHT use. A cross-sectional, national, age-stratified, population survey was conducted in 2013. Eligible women, aged 50-69 years, resident in Australia were randomly sampled in 5-year age groups from the Medicare enrolment database (Australia's universal health scheme). The response rate was 22% based on return of completed questionnaires, and analyses were restricted to 4,389 women within the specified age range. The estimated population-weighted prevalence of current use of MHT was 13% (95%CI 12-14), which was broadly similar to the previously reported national figures in 2004-5, suggesting that the use of MHT in Australia has largely stabilised over the past decade. A total of 39% and 20% of current-users with an intact uterus reported use of oestrogen-progestagen MHT and oestrogen-only MHT, respectively, whereas 77% of hysterectomised current-users used oestrogen-only MHT. Almost three-quarters of current-users [population-weighted prevalence 9% (95%CI 8-10)] had used MHT for ≥5 years. In regard to BHT, estimated population-weighted prevalence of ever use was 6% (95%CI 6-7) and 2% (95%CI 2-3) for current use. The population-weighted prevalence of MHT and BHT combined, in current users in their fifties and sixties was 15% (95%CI 14-16). These data provide a recent national "snapshot" of Australian women's use of both conventional MHT and of BHT.
Improving medication adherence with adjuvant aromatase inhibitor in women with breast cancer: A randomised controlled trial to evaluate the effect of short message service (SMS) reminder.
BACKGROUND: Medication adherence is crucial for improving clinical outcomes in the treatment of patients. We evaluate the effect of short message service (SMS) reminder on medication adherence and serum hormones in patients with breast cancer on aromatase inhibitors. METHODS: An open-label, multi-centre, prospective randomised controlled trial of SMS versus Standard Care was conducted. Medication adherence was assessed via self-report using the Simplified Medication Adherence Questionnaire at baseline, 6 month, and 1 year. Androstenedione, estradiol, and estrone were measured at baseline and 1 year. The χ2 test and mixed effects logistic regression was performed to compare medication adherence between groups. Difference in androstenedione and estrone levels were assessed using analysis of covariance, whereas χ2 test and logistic regression was used for estradiol. Analysis was based on intention-to-treat. RESULTS: A total of 244 patients were randomised to receive weekly SMS reminder (n = 123) or Standard Care (n = 121) between May 2015 and December 2018. The odds of adherence was higher at 6-month in SMS (OR = 1.78, 95% CI 1.04-3.05, p = 0.034), and not significantly different at 1-year (OR = 1.15, 95% CI: 0.67-1.96 p = 0.617). Mixed effects logistic regression analysis showed higher odds of adherence in SMS over the 1-year period (OR = 2.35, 95% CI: 1.01-5.49, p = 0.048). There was no difference in serum hormone levels between groups. CONCLUSION: SMS reminder improved medication adherence in the short-term but had no effect on serum hormones levels in the longer term. Future studies could investigate the use of tailored SMS intervention according to patient preference to improve its sustainability.
How well does the MESTT correlate with CTCAE scale for the grading of dermatological toxicities associated with oral tyrosine kinase inhibitors?
BACKGROUND: Dermatological toxicities associated with tyrosine kinase inhibitors (TKIs) are commonly graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). A new tool has been proposed by the Multinational Association for Supportive Care in Cancer (MASCC), namely the MASCC EGFRI Skin Toxicity Tool (MESTT), as a class-specific grading system. This study was designed to assess the correlation between the severity grading of the dermatological toxicities associated with TKIs using the NCI-CTCAE v4.0 and the MESTT. PATIENT AND METHODS: One hundred patients were interviewed at the National Cancer Centre Singapore with the criteria of being on erlotinib, gefitinib, lapatinib, sorafenib, or sunitinib over 2 weeks and manifested dermatological toxicities. Dermatological toxicities were graded using CTCAE and MESTT 1, respectively, by a single observer. Spearman's correlation test was performed on the results. RESULTS: Sixty-five patients (65%) experienced papulopustular rash, 72 patients (72%) had pruritus, 85 patients (85%) had xerosis, 33 patients (33%) experienced nail changes, and 24 patients (24%) had alopecia. There was significant positive correlation between the two grading systems for all investigated dermatological toxicities, namely rash (r = 0.734), pruritus (r = 0.917), xerosis (r = 0.635), and paronychia (r = 0.611) at 99% confidence level. CONCLUSION: Good correlation was observed between the scales, but there is a tendency for the MESTT tended to report higher toxicity grades for rash, xerosis, and paronychia. The MESTT was also found to be more useful to grade rash specific to TKIs and had similar usefulness for grading other studied toxicities.
Evidence-based treatment options for the management of skin toxicities associated with epidermal growth factor receptor inhibitors.
OBJECTIVE: To compile evidence from randomized controlled trials, case series, and case reports to identify the effectiveness of various therapeutic agents for the treatment and prevention of dermatologic effects secondary to epidermal growth factor receptor inhibitor (EGFRI) administration. DATA SOURCES: Literature was accessed through PubMed (2002-May 2009) and Scopus (2002-March 2009), using the terms epidermal growth factor receptor inhibitor, cetuximab, erlotinib, gefitinib, panitumumab, management, skin toxicity, and cutaneous effects. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: An evaluation of published clinical trials, case series, case reports, and clinical management guidelines that studied the treatment options for EGFRI-induced skin toxicities was performed. Studies that reported dosing regimens and treatment outcomes were included in this review. DATA SYNTHESIS: Management of EGFRI-induced skin toxicities has been documented in 2 randomized controlled trials, 3 case series, and 10 case reports in a total of 156 patients. There is strong evidence for the use of topical antibiotics to manage EGFRI skin toxicities. Controversy exists regarding the use of corticosteroids and retinoids for the management of EGFRI-induced rash. Several variables are noted among the number of case series and case reports, such as follow-up duration of the intervention, making any comparisons difficult. CONCLUSIONS: Overall, antibiotics are the most common treatment option and have the potential to reduce the severity of skin rash. Well-designed clinical studies with proper recording of relevant data on the management of EGFRI-induced dermatologic effects are needed to properly evaluate the use of various therapeutic agents. Apart from randomized controlled trials, comprehensive case reports are also important for clinical evaluation on a case-by-case basis.
Relative criticalness of common laboratory tests for critical value reporting.
We determined the relative strengths of association between 23 most commonly ordered laboratory tests and the adverse outcome as indicators of relative criticalness. The lowest and highest results for 23 most commonly ordered laboratory tests, 24 hours prior to death during critical care unit (CCU) stay or discharge from CCU were extracted from a publicly available CCU database (Medical Information Mart for Intensive Care-III). Following this, the Random Forest model was applied to assess the association between the laboratory results and the outcomes (death or discharge). The mean decrease in Gini coefficient for each laboratory test was then ranked as an indication of their relative importance to the outcome of a patient. In descending order, the 10 laboratory tests with the strongest association with death were: bicarbonate, phosphate, anion gap, white cell count (total), partial thromboplastin time, platelet, total calcium, chloride, glucose and INR; moreover, the strength of association was different for critically high versus low results.
Systematic review and meta-analysis of algorithms used to identify drug-induced liver injury (DILI) in health record databases.
BACKGROUND & AIMS: Drug induced liver injury (DILI) is largely underreported, leading to underestimation of its burden. Electronic detection of DILI in healthcare databases shows promise to overcome the issues of spontaneous reporting. The performance of detection algorithms may vary because of inconsistent DILI definition and detection criteria. We performed a systematic review and meta-analysis to identify the DILI detection criteria used in health record databases and determine the performance characteristics of the detection algorithms. METHODS: We searched PubMed, EMBASE and Scopus for studies that utilized laboratory threshold criteria to identify DILI cases. Validation studies were included in the meta-analysis. Data were abstracted using standardized forms and quality was assessed using modified Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) criteria. We evaluate the performance characteristics of the detection algorithm by obtaining the pooled estimate of the positive predictive value (PPV) assuming a random effects model. RESULTS: A total of 29 studies met the inclusion criteria for the systematic review; 25 of these studies (n = 35 948) had PPV estimates for performing the meta-analysis. The PPV of DILI detection algorithms was low, ranging from 1.0% to 40.2%, with a pooled estimate of 14.6% (95% CI 10.7-18.9). Algorithms that performed better had prespecified exclusion diagnoses as well as drugs of interest to minimize false positives. CONCLUSION: Algorithm performance varied with different case definitions of DILI attributed to different laboratory threshold criteria, diagnosis codes, and study drugs.
Outcome-Based Critical Result Thresholds in the Adult Patient Population.
OBJECTIVES: To derive outcome-based critical result thresholds in the adult patient population. METHODS: We extracted deidentified laboratory results and outcomes (death or discharged) of patients 18 years and older from the Medical Information Mart for Intensive Care database. The lower and upper critical result thresholds were obtained from the nearest minimum and maximum laboratory values, which corresponded to predicted probability of death at 90%. RESULTS: The critical value thresholds were sodium (<123, >153 mmol/L), potassium (<2.2, >6.6 mmol/L), bicarbonate (<15, >49 mmol/L), chloride (<82, >121 mmol/L), urea (>20 mmol/L), creatinine (>1,052 μmol/L), glucose (<1.5, >23.8 mmol/L), total calcium (<1.62, >2.95 mmol/L), magnesium (<0.37, >1.48 mmol/L), phosphate (<0.19, >2.52 mmol/L), pH (<7.22, >7.57), lactate (>5.0 mmol/L), hemoglobin (<4.6 g/dL), WBCs (>32 × 103/μL), prothrombin time (>90 seconds), and international normalized ratio (>10). CONCLUSIONS: The indirect approach described in this study is a pragmatic way to obtain threshold values that are clinically and operationally meaningful.
Comparison of laboratory threshold criteria in drug-induced liver injury detection algorithms for use in pharmacovigilance.
PURPOSE: For the purpose of pharmacovigilance, we sought to determine the best performing laboratory threshold criteria to detect drug-induced liver injury (DILI) in the electronic medical records (EMR). METHODS: We compared three commonly used liver chemistry criteria from the DILI expert working group (DEWG), DILI network (DILIN), and Council for International Organizations of Medical Sciences (CIOMS), based on hospital EMR for years 2010 and 2011 (42 176 admissions), using independent medical record review. The performance characteristics were compared in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value, accuracy, F-measure, and area under the receiver operating characteristic curve (AUROC). RESULTS: DEWG had the highest PPV (5.5%, 95% CI: 4.1%-7.2%), specificity (97.0%, 95% CI: 96.8%-97.2%), accuracy (96.8%, 95% CI: 96.6%-97.0%) and F-measure (0.099). CIOMS had the highest sensitivity (74.0%, 95% CI: 64.3%-82.3%) and AUROC (85.2%, 95% CI: 80.8%-89.7%). Besides the laboratory criteria, including additional keywords in the classification algorithm improved the PPV and F-measure to a maximum of 29.0% (95% CI: 22.3%-36.5%) and 0.379, respectively. CONCLUSIONS: More stringent criteria (DEWG and DILIN) performed better in terms of PPV, specificity, accuracy and F-measure. CIOMS performed better in terms of sensitivity. An algorithm with high sensitivity is useful in pharmacovigilance for detecting rare events and to avoid missing cases. Requiring at least two abnormal liver chemistries during hospitalization and text-word searching in the discharge summaries decreased false positives without loss in sensitivity.
Bias, Precision and Timeliness of Historical (Background) Rate Comparison Methods for Vaccine Safety Monitoring: An Empirical Multi-Database Analysis.
Using real-world data and past vaccination data, we conducted a large-scale experiment to quantify bias, precision and timeliness of different study designs to estimate historical background (expected) compared to post-vaccination (observed) rates of safety events for several vaccines. We used negative (not causally related) and positive control outcomes. The latter were synthetically generated true safety signals with incident rate ratios ranging from 1.5 to 4. Observed vs. expected analysis using within-database historical background rates is a sensitive but unspecific method for the identification of potential vaccine safety signals. Despite good discrimination, most analyses showed a tendency to overestimate risks, with 20%-100% type 1 error, but low (0% to 20%) type 2 error in the large databases included in our study. Efforts to improve the comparability of background and post-vaccine rates, including age-sex adjustment and anchoring background rates around a visit, reduced type 1 error and improved precision but residual systematic error persisted. Additionally, empirical calibration dramatically reduced type 1 to nominal but came at the cost of increasing type 2 error.
Facilitators and barriers to medication adherence with adjuvant endocrine therapy in women with breast cancer: a structural equation modelling approach.
PURPOSE: To identify a structure to explain the relationship between socio-clinico factors, necessity-concerns beliefs, and perceived barriers to adherence with adjuvant endocrine therapy (AET) amongst women with breast cancer. METHODS: Participants were 244 patients with early-stage breast cancer recruited from two tertiary hospitals from May 2015 to December 2018 who completed questionnaires on medication adherence (Simplified Medication Adherence Questionnaire), necessity-concerns beliefs (Beliefs about Medicine Questionnaire), and barriers to adherence (Adherence Starts with Knowledge Questionnaire). Socio-clinico variables were collected via interview and medical records review. Structural equation modelling was applied to examine the relationships between these variables and possible mediating effects of necessity-concerns beliefs on adherence to AET. RESULTS: The median age of the study participants was 61 (range 32-80) years and the median duration on AET was 1.6 (IQR 1.2-2.6) years. Adherence was positively associated with age (β = 0.145, 95% CI: 0.011 to 0.279, p = 0.034) and negatively associated with barriers (β = - 0.381, 95% CI: - 0.511 to - 0.251, p
Improving medication adherence with adjuvant aromatase inhibitor in women with breast cancer: study protocol of a randomised controlled trial to evaluate the effect of short message service (SMS) reminder.
BACKGROUND: Medication adherence refers to whether a patient takes medication according to the frequency prescribed, or continues to take a prescribed medication. Inadequate adherence to medication may cause alterations in risk-benefit ratios, resulting in reduced benefits, increased risks or both, and is significantly associated with adverse clinical outcomes and higher healthcare costs. We aim to examine the effect of a computer generated short message service (SMS) reminder in improving medication adherence, and inhibiting the aromatisation process amongst breast cancer women receiving oral aromatase inhibitor therapy. METHODS/DESIGN: In this randomised controlled trial, eligible patients will be equally allocated to receive either SMS reminder or standard care. The former receives weekly SMS reminder to take medication while the latter does not receive any. The primary endpoint of medication adherence at 1-year is assessed using the Simplified Medication Adherence Questionnaire, and compared using the χ2 test. Adjustment for baseline covariate and potential confounders will be made using the logistic regression. Secondary outcomes involving estrone and androstenedione levels will be compared using the analysis of covariance, whereas the estradiol levels (
Evaluation of the myocardial deformation in the diagnosis of rejection after heart transplantation
Introduction: Heart transplantation represents main therapy for end-stage heart failure. However, survival after transplantation is limited by development of graft rejection. Endomyocardial biopsy, an invasive and expensive procedure, is gold standard technique for diagnosis of rejection. Most of biopsy complications are observed using echocardiography. Novel echocardiographic techniques, such as myocardial strain and three-dimensional reconstruction, can be useful in heart transplant patients. Purpose: To evaluate ventricular strain in heart transplant patients and association with rejection, cellular or humoral, as well as two- and three-dimensional echocardiographic parameters. Methods: Cohort of patients from heart transplant program taken to echocardiography after endomyocardial biopsy, from December 2017 to January 2020. Ventricular strain and three-dimensional left ventricle parameters were studied. Rejection results were retrieved from medical record. Qualitative variables were expressed by absolute frequency and percentages, while continuous variables by means and standard deviations. Association between rejection and variables of interest was measured by odds ratio and confidence interval of 95%, with p-value < 0.05. Results: 123 post-endomyocardial biopsy echocardiographic exams were performed in 54 patients. Eighteen exams were excluded, lasting 105 exams to be evaluated for conventional and advanced echocardiographic parameters. Male patients were 60.4%. Prevalence of cellular rejection was 8.6%, humoral rejection 12.4%, and rejection of any type 20%. There was no association between right ventricular strain and rejection, whether cellular (p = 0.118 and p = 0.227 for septum and free wall, respectively), humoral (p = 0.845 and p = 0.283, respectively), or of any type (0.504 and 0.446). There was no correlation between rejection and left ventricle global longitudinal strain, three-dimensional ejection fraction or desynchrony index. Conventional parameters associated to rejection were left ventricle posterior wall thickness [OR 1.660 (1.163; 2.370), p = 0.005] and left ventricle mass index [OR 1.027 (1.011; 1.139), p = 0.001]. Left ventricle posterior wall thickness remained significant after analysis of cellular and humoral rejection separately [OR 1.825 (1.097; 3.036), p = 0.021 and OR 1.650 (1.028; 2.648), p = 0.038, respectively]. Conclusions: There was no association between ventricular strain, three-dimensional left ventricular ejection fraction and the desynchrony index and rejection, cellular or humoral. Evidence of association of graft rejection with left ventricle posterior wall thickness and left ventricle mass index was observed.
Canadian Anaphylaxis Network-Predicting Recurrence after Emergency Presentation for Allergic REaction (CAN-PREPARE): a prospective, cohort study protocol.
INTRODUCTION: Anaphylaxis is a severe, potentially fatal multiorgan system manifestation of an allergic reaction. The highest incidence of anaphylaxis is in children and adolescents. Biphasic anaphylaxis (BA) is defined as the recurrence of allergic symptoms after resolution of an initial reaction. It has been reported to occur in 10%-20% of cases within 1-48 hours from the onset of the initial reaction. The dilemma for physicians is determining which patients with resolved anaphylaxis should be observed for BA and for how long. Guidelines for duration of postanaphylaxis monitoring vary, are based on limited evidence and can have unintended negative impacts on patient safety, quality of life and healthcare resources. The objectives of this study are to derive a prognostic model for BA and to develop a risk-scoring system that informs disposition decisions of children who present to emergency departments (ED) with anaphylaxis. METHODS AND ANALYSIS: This prospective multicentre cohort study will enrol 1682 patients from seven paediatric EDs that are members of the Paediatric Emergency Research Canada network. We will enrol patients younger than 18 years of age with an allergic reaction meeting anaphylaxis diagnostic criteria. Trained ED research assistants will screen, obtain consent and prospectively collect study data. Research assistants will follow patients during their ED visit and ascertain, in conjunction with the medical team, if the patient develops BA. A standardised follow-up survey conducted following study enrolment will determine if a biphasic reaction occurred after ED disposition. Model development will conform to the broad principles of the PROGRESS (Prognosis Research Strategy) framework and reporting will follow the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis Statement. ETHICS AND DISSEMINATION: Ethics approval has been received from all participating centres. Our dissemination plan focuses on informing clinicians, policy makers and parents of the results through publication in peer-reviewed journals and broadcasting on multiple media platforms. TRIAL REGISTRATION NUMBER: NCT05135377.