Citations

Abstract IntroductionCurrently, one of the commonly used methods for disseminating electronic health record (EHR)-based phenotype algorithms is providing a narrative description of the algorithm logic, often accompanied by flowcharts. A challenge with this mode of dissemination is the potential for under-specification in the algorithm definition, which leads to ambiguity and vagueness. MethodsThis study examines incidents of under-specification that occurred during the implementation of 34 narrative phenotyping algorithms in the electronic Medical Record and Genomics (eMERGE) network. We reviewed the online communication history between algorithm developers and implementers within the Phenotype Knowledge Base (PheKB) platform, where questions could be raised and answered regarding the intended implementation of a phenotype algorithm. ResultsWe developed a taxonomy of under-specification categories via an iterative review process between two groups of annotators. Under-specifications that lead to ambiguity and vagueness were consistently found across narrative phenotype algorithms developed by all involved eMERGE sites. Discussion & ConclusionOur findings highlight that under-specification is an impediment to the accuracy and efficiency of the implementation of current narrative phenotyping algorithms, and we propose approaches for mitigating these issues and improved methods for disseminating EHR phenotyping algorithms.

Abstract Rationale To improve disease outcomes in idiopathic pulmonary fibrosis (IPF), it is essential to understand its early pathophysiology so that it can be targeted therapeutically. Objectives Perform three-dimensional assessment of the IPF lung microstructure using stereology and multiresolution computed tomography (CT) imaging. Methods Explanted lungs from patients with IPF (n = 8) and donor control subjects (n = 8) were inflated with air and frozen. CT scans were used to assess large airways. Unbiased, systematic uniform random samples (n = 8/lung) were scanned with microCT for stereological assessment of small airways (count number, and measure airway wall and lumen area) and parenchymal fibrosis (volume fraction of tissue, alveolar surface area, and septal wall thickness). Measurements and Main Results The total number of airways on clinical CT was greater in IPF lungs than control lungs (P < 0.01), owing to an increase in the wall (P < 0.05) and lumen area (P < 0.05) resulting in more visible airways with a lumen larger than 2 mm. In IPF tissue samples without microscopic fibrosis, assessed by the volume fraction of tissue using microCT, there was a reduction in the number of the terminal (P < 0.01) and transitional (P < 0.001) bronchioles, and an increase in terminal bronchiole wall area (P < 0.001) compared with control lungs. In IPF tissue samples with microscopic parenchymal fibrosis, terminal bronchioles had increased airway wall thickness (P < 0.05) and dilated airway lumens (P < 0.001) leading to honeycomb cyst formations. Conclusions This study has important implications for the current thinking on how the lung tissue is remodeled in IPF and highlights small airways as a potential target to modify IPF outcomes.

Current guidelines suggest screening all patients with idiopathic pulmonary arterial hypertension for genetic aberrations, particularly mutations in Bone Morphogenic Protein Receptor Type II (BMPR2), the gene most commonly implicated in the pathogenesis of PAH. Herein, we present a novel technique used to identify a pathogenic germline BMPR2 alteration in a 36‐year‐old female and family members with hereditary pulmonary arterial hypertension who each screened negative by standard cytogenetics and molecular genetics testing.

Background: Quantitative End-Tidal CO2 (PETCO2) measurement during cardiac arrest is recommended for monitoring the CPR quality to detect ROSC. While low ETC02 can reflect suboptimal CPR quality and increases in ETC02 are often associated with ROSC the significance of high values of PETCO2 without ROSC remain unclear. Objectives: To describe the population of OHCA victims with high PETCO2 (>50 mm Hg) during ongoing resuscitation including demographics, rhythm characteristics, occurrence of ROSC, the later occurrence of field termination of resuscitation and the presumed etiology. Methods: An observational analysis of adult OHCAs with available PETCO2 data occurring between Oct 2010 and Nov 2014 at two sites involved in the Save Hearts in Arizona Registry and Education (SHARE) quality improvement program. CPR and PETCO2 data were recorded using ZOLL E and X Series EMS monitors. PETCO2 is reported as the mean value for each minute. The cardiac rhythm and the presence of ROSC were determined for each minute using EMS provider reports, vital signs, ECG, and accelerometer data. The first recorded minute of PETCO2 and minutes with ROSC were excluded. Results: Study population included 654 OHCAs with PETCO2 data, 96 cases (58% male, age median 65 (IQR 54-75)) with at least 1 min of high PETCO2 in the absence of ROSC were identified. Of these, 31 (32%) had ROSC at least once during their resuscitation. Cases were of presumed cardiac etiology in 81 (84%), while 12% and 4% had presumed respiratory and other etiologies, respectively. A total of 322 minutes of PETCO2 >50 mm Hg in the absence of ROSC were identified. The mean PETC02 value was 67 (IQR 54-75). Of these 296 minutes (92%) occurred during PEA. Despite high PETCO2, resuscitation was terminated in the field in 21 (22%) patients. Only one subject survived to hospital discharge. Conclusions: In this observational study, high PETCO2 was frequently found during resuscitation without ROSC and PEA was the most common cardiac rhythm. Further study is warranted to determine the significance and possible reasons for this finding.

Background: Previous studies have described modest correlation between end-tidal CO 2 (ETCO 2 ) and CPR quality during resuscitation of cardiac arrest patients, but it is unclear whether ETCO 2 alone can indicate CPR quality. The present study investigated whether ETCO 2 adequately identifies the quality of CPR provided during out-of-hospital cardiac resuscitation. Methods: ETCO 2 was monitored with side-stream CO 2 (Philips/Respironics) and CPR quality measured with an accelerometer-based system (E Series, ZOLL Medical) during the treatment of consecutive adult OHCA patients with presumed cardiac etiology by 2 EMS agencies in the Arizona SHARE QI Program between 10/08-06/13. Minute-by-minute ETCO 2 and CPR quality were extracted. ETCO 2 values were log transformation to achieve approximate normality. Linear mixed effect models were fitted to use (transformed) ETCO 2 level to predict four CPR variables: chest compression (CC) depth, CC rate, CC release velocity (CCRV), and ventilation rate (VR). A random intercept for each case was included and a spatial power covariance structure assumed for measurements over time. Results: 230 subjects (median age 69 yrs, 69% male) with 1581 minutes of data were studied. Transformed ETCO 2 was significant for CC depth (p< 0.0001), CCRV (p=0.003) and VR (p<0.0001), but only explained 3.7%, 2.7%, and 10.0% of the total variance for these variables, respectively. Transformed ETCO 2 was not a significant predictor for CC rate (p=0.89). The Figure illustrates the overlap in CC depth over quartiles of ETCO 2 , demonstrating that any specific ETCO 2 level could be found over a wide range of CC depths. Conclusion: In this secondary analysis, ETCO 2 was not an independent indicator of CC rate but was a weak predictor for CC depth, CCRV and VR. These findings suggest that ETCO 2 may be not be an adequate substitute for CPR quality monitoring. Future studies should investigate how ETCO 2 and CPR quality monitoring can be used in conjunction to optimize CPR.

Background: Abnormal breathing, or “gasping,” frequently occurs during cardiac arrest and has been associated with increased survival. During 9-1-1 calls, early recognition of gasping may allow dispatchers to identify OHCA and to start CPR instructions promptly. Objective: To characterize lay rescuers’ descriptions of abnormal breathing during OHCA. Methods: 9-1-1 audio recordings of 4,279 confirmed OHCAs (10/10-7/14) in Arizona were reviewed by program personnel. Terms used by lay rescuers to describe victims’ breathing were recorded in a structured database. Results: Abnormal breathing (as opposed to “not breathing”) was described in 542/4279 (13%) calls. There were 623 verbal descriptions. A total of 50 different terms were used. However, the top 8 accounted for 83% and the remaining 42 descriptions (“Other”) comprised only 17% of all terms used. “Gasping” was the most commonly used term (30%; 187/623), followed by “snoring” (15%; 95/623; Figure). Conclusion: Lay rescuers used a wide variety of terms to describe abnormal breathing in documented OHCA. However, 8 terms accounted for 83% of descriptions. Familiarizing 9-1-1 telecommunicators with the most commonly used terms may improve the accuracy of recognition and hasten the identification of OHCA.

Abstract Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values<5x10-8 as genome-wide significant, and p-values<1x10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values<1x105. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Abstract Purpose: Hepatocellular Carcinoma (HCC) is the leading cause of cancer-related mortality in Nigeria. HIV and viral hepatitis B (HBV) and C (HCV) co-infection are common in Nigeria that significantly accelerates liver disease progression including HCC. Aging-related DNA methylation signatures obtained in liquid biopsy, such as circulating cell-free DNA (ccfDNA) extracted from serum/plasma are promising minimally-invasive biomarkers that may inform HIV-associated HCC. We examined the epigenetic age acceleration (EpiAgeAccel) in ccfDNA in HCC patients with HIV. Methods: The study included three groups of participants: a) HIV positive with HCC (n=7); b) HIV positive and cancer-free (n=45); and c) HIV negative with HCC (n=33). Epigenetic age was estimated by Horvath's calculator using genome-wide ccfDNA methylation data profiled by Illumina EPIC array. EpiAgeAccel was computed as the residuals of a linear model of epigenetic age on chronological age, namely the unexplained portion of epigenetic age by chronological age. We used multiple linear regression to compare EpiAgeAccel between HIV/HCC groups, adjusting for sex, age, education, alcohol intake, and HBV/HCV infection. Results: Among HIV positive participants, there was a higher percentage of men (57% vs. 22%, p&lt;0.001), HBV infection (29% vs. 11%, p=0.004), and HCV infection (57% vs. 2%, p&lt;0.001) in the HCC group compared to the cancer-free group. EpiAgeAccel was 4.8 years higher in HIV positive patients with HCC compared to cancer-free HIV positives (p=0.02). Among HCC patients, EpiAgeAccel was 2.1 years higher in HIV positives compared to HIV negative but not statistically significant. Conclusion: Epigenetic age in ccfDNA is accelerated in HIV-positive HCC patients. EpiAgeAccel measured in ccfDNA may be developed into a surrogate biomarker for minimally invasive HCC detection among HIV-infected patients in low- and middle-income countries. Citation Format: Yinan Zheng, Claudia Hawkins, Edith Okeke, Mary Duguru, Emuobor Odeghe, Olufunmilayo Lesi, Yishu Qu, Kyeezu Kim, Brian Joyce, Jun Wang, Lewis Roberts, Demirkan Gursel, Abdulkareem Fatimah, Alani Akanmu, Godwin Imade, Jian-Jun Wei, Masha Kocherginsky, Kwang-Youn Kim, Oluwakemi Odukoya, Wasiu Adeyemo, Firas Wehbe, Chad Achenbach, Atiene Sagay, Folasade Ogunsola, Robert Murphy, Lifang Hou. Blood-Based Circulating Cell-Free DNA Epigenetic Age Is Accelerated Among HIV-Infected Patients with Hepatocellular Carcinoma in Nigeria [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 83.