Using clinical trial data and linked administrative health data to reduce the risk of adverse events associated with the uptake of newly released drugs by older Australians: a model process

BackgroundThe study was undertaken to evaluate the contribution of a process which uses clinical trial data plus linked de-identified administrative health data to forecast potential risk of adverse events associated with the use of newly released drugs by older Australian patients. MethodsThe study uses publicly available data from the clinical trials of a newly released drug to ascertain which patient age groups, gender, comorbidities and co-medications were excluded in the trials. It then uses linked de-identified hospital morbidity and medications dispensing data to investigate the comorbidities and co-medications of patients who suffer from the target morbidity of the new drug and who are the likely target population for the drug. The clinical trial information and the linked morbidity and medication data are compared to assess which patient groups could potentially be at risk of an adverse event associated with use of the new drug. ResultsApplying the model in a retrospective real-world scenario identified that the majority of the sample group of Australian patients aged 65 years and over with the target morbidity of the newly released COX-2-selective NSAID rofecoxib also suffered from a major morbidity excluded in the trials of that drug, indicating a substantial potential risk of adverse events amongst those patients. This risk was borne out in post-release morbidity and mortality associated with use of that drug. ConclusionsClinical trial data and linked administrative health data can together support a prospective assessment of patient groups who could be at risk of an adverse event if they are prescribed a newly released drug in the context of their age, gender, comorbidities and/or co-medications. Communication of this independent risk information to prescribers has the potential to reduce adverse events in the period after the release of the new drug, which is when the risk is greatest. Note: The terms \u27adverse drug reaction\u27 and \u27adverse drug event\u27 have come to be used interchangeably in the current literature. For consistency, the authors have chosen to use the wider term \u27adverse drug event\u27 (ADE). <br /

Under-ascertainment of Aboriginality in records of cardiovascular disease in hospital morbidity and mortality data in Western Australia: a record linkage study

<p>Abstract</p> <p>Background</p> <p>Measuring the real burden of cardiovascular disease in Australian Aboriginals is complicated by under-identification of Aboriginality in administrative health data collections. Accurate data is essential to measure Australia's progress in its efforts to intervene to improve health outcomes of Australian Aboriginals. We estimated the under-ascertainment of Aboriginal status in linked morbidity and mortality databases in patients hospitalised with cardiovascular disease.</p> <p>Methods</p> <p>Persons with public hospital admissions for cardiovascular disease in Western Australia during 2000-2005 (and their 20-year admission history) or who subsequently died were identified from linkage data. The Aboriginal status flag in all records for a given individual was variously used to determine their ethnicity (index positive, and in all records both majority positive or ever positive) and stratified by region, age and gender. The index admission was the baseline comparator.</p> <p>Results</p> <p>Index cases comprised 62,692 individuals who shared a total of 778,714 hospital admissions over 20 years, of which 19,809 subsequently died. There were 3,060 (4.9%) persons identified as Aboriginal on index admission. An additional 83 (2.7%) Aboriginal cases were identified through death records, increasing to 3.7% when cases with a positive Aboriginal identifier in the majority (≥50%) of previous hospital admissions over twenty years were added and by 20.8% when those with a positive flag in any record over 20 years were incorporated. These results equated to underestimating Aboriginal status in unlinked index admission by 2.6%, 3.5% and 17.2%, respectively. Deaths classified as Aboriginal in official records would underestimate total Aboriginal deaths by 26.8% (95% Confidence Interval 24.1 to 29.6%).</p> <p>Conclusions</p> <p>Combining Aboriginal determinations in morbidity and official death records increases ascertainment of unlinked cardiovascular morbidity in Western Australian Aboriginals. Under-identification of Aboriginal status is high in death records.</p

Can we monitor heart attack in the troponin era: evidence from a population-based cohort study

<p>Abstract</p> <p>Background</p> <p>Troponins (highly sensitive biomarkers of myocardial damage) increase counts of myocardial infarction (MI) in clinical practice, but their impact on trends in admission rates for MI in National statistics is uncertain.</p> <p>Methods</p> <p>Cases coded as MI or other cardiac diagnoses in the Hospital Morbidity Data Collection (MI-HMDC) in Western Australia in 1998 and 2003 were classified using revised criteria for MI developed by an International panel convened by the American Heart Association (AHA criteria) using information on symptoms, ECGs and cardiac biomarkers abstracted from samples of medical notes. Age-sex standardized rates of MI-HMDC were compared with rates of MI based on AHA criteria including troponins (MI-AHA) or traditional biomarkers only (MI-AHAck).</p> <p>Results</p> <p>Between 1998 and 2003, rates of MI-HMDC decreased by 3.5% whereas rates of MI-AHA increased by 17%, a difference largely due to increased false-negative cases in the HMDC associated with marked increased use of troponin tests in cardiac admissions generally, and progressively lower test thresholds. In contrast, rates of MI-AHA_ckdeclined by 18%.</p> <p>Conclusions</p> <p>Increasing misclassification of MI-AHA by the HMDC may be due to reluctance by clinicians to diagnose MI based on relatively small increases in troponin levels. These influences are likely to continue. Monitoring MI using AHA criteria will require calibration of commercially available troponin tests and agreement on lower diagnostic thresholds for epidemiological studies. Declining rates of MI-AHA_ckare consistent with long-standing trends in MI in Western Australia, suggesting that neither MI-HMDC nor MI-AHA reflect the true underlying population trends in MI.</p

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features

The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom's 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia

Constitutive modeling of kinematic-hardening and damage in solder joints

Solder constitutive models are important as they are widely used in FEA simulations to predict the lifetime of soldered assemblies. This paper briefly reviews some common constitutive laws to capture creep in solder and presents work on laws capturing both kinematic hardening and damage. Inverse analysis is used to determine constants for the kinematic hardening law which match experimental creep curves. The mesh dependence of the damage law is overcome by using volume averaging and is applied to predict the crack path in a thermal cycled resistor componen

Computer simulation of crack propagation in power electronics module solder joints

A numerical modelling method for the analysis of solder joint damage and crack propagation has been described in this paper. The method is based on the disturbed state concept. Under cyclic thermal-mechanical loading conditions, the level of damage that occurs in solder joints is assumed to be a simple monotonic scalar function of the accumulated equivalent plastic strain. The increase of damage leads to crack initiation and propagation. By tracking the evolution of the damage level in solder joints, crack propagation path and rate can be simulated using Finite Element Analysis method. The discussions are focused on issues in the implementation of the method. The technique of speeding up the simulation and the mesh dependency issues are analysed. As an example of the application of this method, crack propagation in solder joints of power electronics modules under cyclic thermal-mechanical loading conditions has been analyzed and the predicted cracked area size after 3000 loading cycles is consistent with experimental results