Project description:BackgroundBody CT scans are frequently performed for a wide variety of clinical indications, but potentially valuable biometric information typically goes unused. We investigated the prognostic ability of automated CT-based body composition biomarkers derived from previously-developed deep-learning and feature-based algorithms for predicting major cardiovascular events and overall survival in an adult screening cohort, compared with clinical parameters.MethodsMature and fully-automated CT-based algorithms with pre-defined metrics for quantifying aortic calcification, muscle density, visceral/subcutaneous fat, liver fat, and bone mineral density (BMD) were applied to a generally-healthy asymptomatic outpatient cohort of 9223 adults (mean age, 57.1 years; 5152 women) undergoing abdominal CT for routine colorectal cancer screening. Longitudinal clinical follow-up (median, 8.8 years; IQR, 5.1-11.6 years) documented subsequent major cardiovascular events or death in 19.7% (n=1831). Predictive ability of CT-based biomarkers was compared against the Framingham Risk Score (FRS) and body mass index (BMI).FindingsSignificant differences were observed for all five automated CT-based body composition measures according to adverse events (p<0.001). Univariate 5-year AUROC (with 95% CI) for automated CT-based aortic calcification, muscle density, visceral/subcutaneous fat ratio, liver density, and vertebral density for predicting death were 0.743(0.705-0.780)/0.721(0.683-0.759)/0.661(0.625-0.697)/0.619 (0.582-0.656)/0.646(0.603-0.688), respectively, compared with 0.499(0.454-0.544) for BMI and 0.688(0.650-0.727) for FRS (p<0.05 for aortic calcification vs. FRS and BMI); all trends were similar for 2-year and 10-year ROC analyses. Univariate hazard ratios (with 95% CIs) for highest-risk quartile versus others for these same CT measures were 4.53(3.82-5.37) /3.58(3.02-4.23)/2.28(1.92-2.71)/1.82(1.52-2.17)/2.73(2.31-3.23), compared with 1.36(1.13-1.64) and 2.82(2.36-3.37) for BMI and FRS, respectively. Similar significant trends were observed for cardiovascular events. Multivariate combinations of CT biomarkers further improved prediction over clinical parameters (p<0.05 for AUROCs). For example, by combining aortic calcification, muscle density, and liver density, the 2-year AUROC for predicting overall survival was 0.811 (0.761-0.860).InterpretationFully-automated quantitative tissue biomarkers derived from CT scans can outperform established clinical parameters for pre-symptomatic risk stratification for future serious adverse events, and add opportunistic value to CT scans performed for other indications.

Project description:BACKGROUND:The Australian National Bowel Cancer Screening Program (NBCSP) provides biennial immunochemical faecal occult blood test (iFOBT) screening for people aged 50-74 years. Previous work has quantified the number of colorectal cancer (CRC) deaths prevented by the NBCSP and has shown that it is cost-effective. With a 40% screening participation rate, the NBCSP is currently underutilised and could be improved by increasing program participation, but the maximum appropriate level of spending on effective interventions to increase adherence has not yet been quantified. OBJECTIVES:To estimate (i) reductions in CRC cases and deaths for 2020-2040 attributable to, and (ii) the threshold for cost-effective investment (TCEI) in, effective future interventions to improve participation in the NBCSP. METHODS:A comprehensive microsimulation model, Policy1-Bowel, was used to simulate CRC natural history and screening in Australia, considering currently reported NBCSP adherence rates, i.e. iFOBT participation (∼40%) and diagnostic colonoscopy assessment rates (∼70%). Australian residents aged 40-74 were modelled. We evaluated three scenarios: (1) diagnostic colonoscopy assessment increasing to 90%; (2) iFOBT screening participation increasing to 60% by 2020, 70% by 2030 with diagnostic assessment rates of 90%; and (3) iFOBT screening increasing to 90% by 2020 with diagnostic assessment rates of 90%. In each scenario, we estimated CRC incidence and mortality, colonoscopies, costs, and TCEI given indicative willingness-to-pay thresholds of AUD$10,000-$30,000/LYS. RESULTS:By 2040, age-standardised CRC incidence and mortality rates could be reduced from 46.2 and 13.5 per 100,000 persons, respectively, if current participation rates continued, to (1) 44.0 and 12.7, (2) 36.8 and 8.8, and (3) 31.9 and 6.5. In Scenario 2, 23,000 lives would be saved from 2020-2040 vs current participation rates. The estimated scenario-specific TCEI (Australian dollars or AUD$/year) to invest in interventions to increase participation, given a conservative willingness-to-pay threshold of AUD$10,000/LYS, was (1) AUD$14.9M, (2) AUD$72.0M, and (3) AUD$76.5M. CONCLUSION:Significant investment in evidence-based interventions could be used to improve NBCSP adherence and help realise the program's potential. Such interventions might include mass media campaigns to increase program participation, educational or awareness interventions for practitioners, and/or interventions resulting in improvements in referral pathways. Any set of interventions which achieves at least 70% iFOBT screening participation and a 90% diagnostic assessment rate while costing under AUD$72 million annually would be highly cost-effective (<AUD$10,000/LYS) and save 23,000 additional lives from 2020-2040.

Project description:Introduction: MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in post-transcriptional gene regulation and have recently been shown to play a role in cancer metastasis. In solid tumors, especially breast cancer, alterations in miRNA expression contribute to cancer pathogenesis, including metastasis. Considering the emerging role of miRNAs in metastasis, the identification of predictive markers is necessary to further understanding of stage-specific breast cancer development. This is a retrospective analysis that aimed to identify molecular biomarkers related to distant breast cancer metastasis development. Methods: A retrospective case cohort study was performed in 64 breast cancer patients treated during the period from 1998-2001. The case group (n=29) consisted of patients with a poor prognosis who presented with breast cancer recurrence or metastasis during follow up. The control group (n=35) consisted of a random sample of patients with a good prognosis who did not develop breast cancer recurrence or metastasis. These patient groups were stratified according to TNM clinical stage (CS) I, II and III, and the main clinical features of the patients were homogeneous. miRNA profiling was performed using formalin-fixed, paraffin-embedded tumors. Biomarkers related to metastatic potential were identified independent of clinical stage, and a cutoff point was selected based on the optimal sensitivity and specificity (ROC curve). Finally, a hazard risk analysis of these biomarkers was performed to evaluate their relation to metastatic potential. Results: miRNA expression profiling identified several miRNAs that were either specific and shared across all clinical stages (p?0.05). Among these, we identified miRNAs previously associated with cell motility (let-7 family), cell proliferation and invasion (hsa-miR-16 and has-miR-205) and distant metastasis (hsa-miR-21). In addition, hsa-miR-494 and hsa-miR-21 were up-regulated in metastatic cases of CSI and II. Furthermore, the combination of the 3 miRNAs identified for CSII (hsa-miR-494, hsa-miR-183 and hsa-miR-21) was significant and were a more effective risk marker compared to the single miRNAs. Conclusions: Women with metastatic breast cancer, especially CSII, presented up-regulated levels of miR-183, miR-494 and miR-21, which were associated with a poor prognosis. These miRNAs therefore represent new risk biomarkers of breast cancer metastasis and may be useful for future targeted therapies.

Project description:Chronic traumatic encephalopathy is a debilitating neurodegenerative disorder associated with repetitive traumatic brain injuries often sustained through prior contact sport participation. The frequency of this disorder in a diverse population, including amateur athletes, is unknown. Primary historical obituary and yearbook records were queried for 2566 autopsy cases in the Mayo Clinic Tissue Registry resulting in identification of 300 former athletes and 450 non-athletes. In these cases, neocortical tissue was screened for tau pathology with immunohistochemistry, including pathology consistent with chronic traumatic encephalopathy, blinded to exposure or demographic information. Using research infrastructure of the Rochester Epidemiology Project, a comprehensive and established medical records-linkage system of care providers in southern Minnesota and western Wisconsin, medical diagnostic billing codes pertaining to head trauma, dementia, movement disorders, substance abuse disorders and psychiatric disorders were recorded for cases and controls in a blinded manner. A total of 42 individuals had pathology consistent with, or features of, chronic traumatic encephalopathy. It was more frequent in athletes compared to non-athletes (27 cases versus 15 cases) and was largely observed in men (except for one woman). For contact sports, American football had the highest frequency of chronic traumatic encephalopathy pathology (15% of cases) and an odds ratio of 2.62 (P-value = 0.005). Cases with chronic traumatic encephalopathy pathology had higher frequencies of antemortem clinical features of dementia, psychosis, movement disorders and alcohol abuse compared to cases without chronic traumatic encephalopathy pathology. Understanding the frequency of chronic traumatic encephalopathy pathology in a large autopsy cohort with diverse exposure backgrounds provides a baseline for future prospective studies assessing the epidemiology and public health impact of chronic traumatic encephalopathy and sports-related repetitive head trauma.

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A retrospective cohort study of ‘’Early Screening Assistant’’ on improving participation and effectiveness of opportunistic screening for colorectal cancer

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