Faculty Bibliography

BACKGROUND:Circulating free DNA sequencing (cfDNA-Seq) can portray cancer genome landscapes, but highly sensitive and specific technologies are necessary to accurately detect mutations with often low variant frequencies. METHODS:We developed a customizable hybrid-capture cfDNA-Seq technology using off-the-shelf molecular barcodes and a novel duplex DNA molecule identification tool for enhanced error correction. RESULTS:mutations originating from clonal hematopoiesis. Furthermore, cfDNA-Seq off-target read analysis allowed simultaneous genome-wide copy number profile reconstruction in 20 of 28 cases. Copy number profiles were validated by low-coverage whole-genome sequencing. CONCLUSIONS:This error-corrected, ultradeep cfDNA-Seq technology with a customizable target region and publicly available bioinformatics tools enables broad insights into cancer genomes and evolution. CLINICALTRIALSGOV IDENTIFIER/UNASSIGNED:NCT02112357.

BACKGROUND:Use of computed tomography pulmonary angiography (CTPA) in the assessment of pulmonary embolism (PE) has markedly increased over the past two decades. While this technology has improved the accuracy of radiological testing for PE, CTPA also carries the risk of substantial iatrogenic harm. Each CTPA carries a 14% risk of contrast-induced nephropathy and a lifetime malignancy risk that can be as high as 2.76%. The appropriate use of CTPA can be estimated by monitoring the CTPA yield, the percentage of tests positive for PE. This is the first study to propose and validate a computerized method for measuring the CTPA yield in the emergency department (ED). OBJECTIVE:The objective of our study was to assess the validity of a novel computerized method of calculating the CTPA yield in the ED. METHODS:The electronic health record databases at two tertiary care academic hospitals were queried for CTPA orders completed in the ED over 1-month periods. These visits were linked with an inpatient admission with a discharge diagnosis of PE based on the International Classification of Diseases codes. The computerized the CTPA yield was calculated as the number of CTPA orders with an associated inpatient discharge diagnosis of PE divided by the total number of orders for completed CTPA. This computerized method was then validated by 2 independent reviewers performing a manual chart review, which included reading the free-text radiology reports for each CTPA. RESULTS:A total of 349 CTPA orders were completed during the 1-month periods at the two institutions. Of them, acute PE was diagnosed on CTPA in 28 studies, with a CTPA yield of 7.7%. The computerized method correctly identified 27 of 28 scans positive for PE. The one discordant scan was tied to a patient who was discharged directly from the ED and, as a result, never received an inpatient discharge diagnosis. CONCLUSIONS:This is the first successful validation study of a computerized method for calculating the CTPA yield in the ED. This method for data extraction allows for an accurate determination of the CTPA yield and is more efficient than manual chart review. With this ability, health care systems can monitor the appropriate use of CTPA and the effect of interventions to reduce overuse and decrease preventable iatrogenic harm.

Certain cancers pave way for other primary cancers to emerge with genetic disturbances serving as a common denominator as demonstrated by our male patient who developed prostate cancer within three months of being diagnosed with breast cancer despite being negative for the major genetic mutations, BRCA1 and BRCA2 and having a negative family history for cancers. Here we examine overlapping major and minor contributing risk factors and the limitations of the most current screening guidelines.

Background Coronary artery calcium (CAC) predicts cardiovascular disease (CVD) events; however, less is known about how its prognostic implications vary by race/ethnicity. Methods and Results A total of 38 277 whites, 1621 Asians, 977 blacks, and 1349 Hispanics from the CAC Consortium (mean age 55 years, 35% women) were followed over a median of 11.7 years. Modeling CAC in continuous and categorical (CAC=0; CAC 1-99; CAC 100-399; CAC ≥400) forms, we assessed its predictive value for all-cause and CVD mortality by race/ethnicity using Cox proportional hazards and Fine and Gray competing-risk regression, respectively. We also assessed the impact of race/ethnicity on risk within individual CAC strata, using whites as the reference. Models were adjusted for traditional cardiovascular risk factors. Increased CAC was associated with higher total and CVD mortality risk in all race/ethnicity groups, including Asians. However, the risk gradient with increasing CAC was more pronounced in blacks and Hispanics. In Fine and Gray subdistribution hazards models adjusted for traditional cardiovascular risk factors and CAC (continuous), blacks (subdistribution hazard ratio 3.4, 95% confidence interval, 2.5-4.8) and Hispanics (subdistribution hazard ratio 2.3, 95% confidence interval, 1.6-3.2) showed greater risk of CVD mortality when compared with whites, while Asians had risk similar to whites. These race/ethnic differences persisted when CAC=0. Conclusions CAC predicts all-cause and CVD mortality in all studied race/ethnicity groups, including Asians and Hispanics, who may be poorly represented by the Pooled Cohort Equations. Blacks and Hispanics may have greater mortality risk compared with whites and Asians after adjusting for atherosclerosis burden, with potential implications for US race/ethnic healthcare disparities research.