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OBJECTIVE - Hepatorenal Syndrome (HRS) is a devastating form of acute kidney injury (AKI) in advanced liver disease patients with high morbidity and mortality, but phenotyping algorithms have not yet been developed using large electronic health record (EHR) databases. We evaluated and compared multiple phenotyping methods to achieve an accurate algorithm for HRS identification.
MATERIALS AND METHODS - A national retrospective cohort of patients with cirrhosis and AKI admitted to 124 Veterans Affairs hospitals was assembled from electronic health record data collected from 2005 to 2013. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. Five hundred and four hospitalizations were selected for manual chart review and served as the gold standard. Electronic Health Record based predictors were identified using structured and free text clinical data, subjected through NLP from the clinical Text Analysis Knowledge Extraction System. We explored several dimension reduction techniques for the NLP data, including newer high-throughput phenotyping and word embedding methods, and ascertained their effectiveness in identifying the phenotype without structured predictor variables. With the combined structured and NLP variables, we analyzed five phenotyping algorithms: penalized logistic regression, naïve Bayes, support vector machines, random forest, and gradient boosting. Calibration and discrimination metrics were calculated using 100 bootstrap iterations. In the final model, we report odds ratios and 95% confidence intervals.
RESULTS - The area under the receiver operating characteristic curve (AUC) for the different models ranged from 0.73 to 0.93; with penalized logistic regression having the best discriminatory performance. Calibration for logistic regression was modest, but gradient boosting and support vector machines were superior. NLP identified 6985 variables; a priori variable selection performed similarly to dimensionality reduction using high-throughput phenotyping and semantic similarity informed clustering (AUC of 0.81 - 0.82).
CONCLUSION - This study demonstrated improved phenotyping of a challenging AKI etiology, HRS, over ICD-9 coding. We also compared performance among multiple approaches to EHR-derived phenotyping, and found similar results between methods. Lastly, we showed that automated NLP dimension reduction is viable for acute illness.
Copyright © 2018 Elsevier Inc. All rights reserved.
BACKGROUND - Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease.
RESULTS - To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function.
CONCLUSIONS - Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating spatial proximity analyses into other pathogenicity prediction tools may improve accuracy for other genes and genetic diseases.
The discovery of selective inhibitors of biological target proteins is the primary goal of many drug discovery campaigns. However, this goal has proven elusive, especially for inhibitors targeting the well-conserved orthosteric adenosine triphosphate (ATP) binding pocket of kinase enzymes. The human kinome is large and it is rather difficult to profile early lead compounds against around 500 targets to gain an upfront knowledge on selectivity. Further, selectivity can change drastically during derivatization of an initial lead compound. Here, we have introduced a computational model to support the profiling of compounds early in the drug discovery pipeline. On the basis of the extensive profiled activity of 70 kinase inhibitors against 379 kinases, including 81 tyrosine kinases, we developed a quantitative structure-activity relation (QSAR) model using artificial neural networks, to predict the activity of these kinase inhibitors against the panel of 379 kinases. The model's performance in predicting activity ranges from 0.6 to 0.8 depending on the kinase, from the area under the curve (AUC) of the receiver operating characteristics (ROC). The profiler is available online at http://www.meilerlab.org/index.php/servers/show?s_id=23.
BACKGROUND - The objective of this study is to evaluate use of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) online risk calculator for estimating common outcomes after operations for gallbladder cancer and extrahepatic cholangiocarcinoma.
METHODS - Subjects from the United States Extrahepatic Biliary Malignancy Consortium (USE-BMC) who underwent operation between January 1, 2000 and December 31, 2014 at 10 academic medical centers were included in this study. Calculator estimates of risk were compared to actual outcomes.
RESULTS - The majority of patients underwent partial or major hepatectomy, Whipple procedures or extrahepatic bile duct resection. For the entire cohort, c-statistics for surgical site infection (0.635), reoperation (0.680) and readmission (0.565) were less than 0.7. The c-statistic for death was 0.740. For all outcomes the actual proportion of patients experiencing an event was much higher than the median predicted risk of that event. Similarly, the group of patients who experienced an outcome did have higher median predicted risk than those who did not.
CONCLUSIONS - The ACS NSQIP risk calculator is easy to use but requires further modifications to more accurately estimate outcomes for some patient populations and operations for which validation studies show suboptimal performance.
Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Background - Recent trials suggest procalcitonin-based guidelines can reduce antibiotic use for respiratory infections. However, the accuracy of procalcitonin to discriminate between viral and bacterial pneumonia requires further dissection.
Methods - We evaluated the association between serum procalcitonin concentration at hospital admission with pathogens detected in a multicenter prospective surveillance study of adults hospitalized with community-acquired pneumonia. Systematic pathogen testing included cultures, serology, urine antigen tests, and molecular detection. Accuracy of procalcitonin to discriminate between viral and bacterial pathogens was calculated.
Results - Among 1735 patients, pathogens were identified in 645 (37%), including 169 (10%) with typical bacteria, 67 (4%) with atypical bacteria, and 409 (24%) with viruses only. Median procalcitonin concentration was lower with viral pathogens (0.09 ng/mL; interquartile range [IQR], <0.05-0.54 ng/mL) than atypical bacteria (0.20 ng/mL; IQR, <0.05-0.87 ng/mL; P = .05), and typical bacteria (2.5 ng/mL; IQR, 0.29-12.2 ng/mL; P < .01). Procalcitonin discriminated bacterial pathogens, including typical and atypical bacteria, from viral pathogens with an area under the receiver operating characteristic (ROC) curve of 0.73 (95% confidence interval [CI], .69-.77). A procalcitonin threshold of 0.1 ng/mL resulted in 80.9% (95% CI, 75.3%-85.7%) sensitivity and 51.6% (95% CI, 46.6%-56.5%) specificity for identification of any bacterial pathogen. Procalcitonin discriminated between typical bacteria and the combined group of viruses and atypical bacteria with an area under the ROC curve of 0.79 (95% CI, .75-.82).
Conclusions - No procalcitonin threshold perfectly discriminated between viral and bacterial pathogens, but higher procalcitonin strongly correlated with increased probability of bacterial pathogens, particularly typical bacteria.
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: email@example.com.
BACKGROUND & AIMS - There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)-few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes.
METHODS - We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center.
RESULTS - We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P = .001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553-26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330-28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132-25.12).
CONCLUSIONS - In an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
Multiple different schemes are used to assess surgical resection margins in orthopedic pathology, but which is optimal for reporting resection margin status of osteosarcoma is uncertain. Moreover, the minimum tumor clearance (metric width of resection margin) necessary for local control is not well defined. In this investigation, the American Joint Committee on Cancer (AJCC) R system, Musculoskeletal Tumor Society (MSTS) system, and margin distance method for reporting resection margin status were compared in a series of 186 high-grade osteosarcomas. Hazard ratios for local recurrence for each resection margin category were compared with other categories within each margin assessment scheme to assess discriminatory ability. Cross-model comparisons of regression coefficients from parametric survival and logistic regression models were also performed. Predictive accuracy of each margin assessment scheme for determining 2-year local recurrence-free survival was evaluated by comparing the areas under receiver-operating characteristic curves generated from logistic regression analyses. Concordance with clinical outcomes was also calculated. Both the MSTS and margin distance schemes showed significantly greater predictive accuracy and concordance with observed outcomes than the AJCC R system. A margin distance of ≥2 mm significantly decreased the risk of local recurrence. Results were similar after adjustment for confounding prognostic factors (anatomic site, macroscopic lymphovascular invasion, and chemotherapy status). Therefore, surgical resection margins for osteosarcoma should be reported using either the MSTS or margin distance method instead of the AJCC R system.
Purpose - Progression rate of age-related macular degeneration (AMD) varies substantially, yet its association with genetic variation has not been widely examined.
Methods - We tested whether progression rate from intermediate AMD to geographic atrophy (GA) or choroidal neovascularization (CNV) was correlated with genotype at seven single nucleotide polymorphisms (SNPs) in the four genes most strongly associated with risk of advanced AMD. Cox proportional hazards survival models examined the association between progression time and SNP genotype while adjusting for age and sex and accounting for variable follow-up time, right censored data, and repeated measures (left and right eyes).
Results - Progression rate varied with the number of risk alleles at the CFH:rs10737680 but not the CFH:rs1061170 (Y402H) SNP; individuals with two risk alleles progressed faster than those with one allele (hazard ratio [HR] = 1.61, 95% confidence interval [CI] = 1.08-2.40, P < 0.02, n = 547 eyes), although this was not significant after Bonferroni correction. This signal was likely driven by an association at the correlated protective variant, CFH:rs6677604, which tags the CFHR1-3 deletion; individuals with at least one protective allele progressed more slowly. Considering GA and CNV separately showed that the effect of CFH:rs10737680 was stronger for progression to CNV.
Conclusions - Results support previous findings that AMD progression rate is influenced by CFH, and suggest that variants within CFH may have different effects on risk versus progression. However, since CFH:rs10737680 was not significant after Bonferroni correction and explained only a relatively small portion of variation in progression rate beyond that explained by age, we suggest that additional factors contribute to progression.
Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.
INTRODUCTION - The incidence of pulmonary nodules is increasing with the movement toward screening for lung cancer by low-dose computed tomography. Given the large number of benign nodules detected by computed tomography, an adjunctive test capable of distinguishing malignant from benign nodules would benefit practitioners. The ability of the EarlyCDT-Lung blood test (Oncimmune Ltd., Nottingham, United Kingdom) to make this distinction by measuring autoantibodies to seven tumor-associated antigens was evaluated in a prospective registry.
METHODS - Of the members of a cohort of 1987 individuals with Health Insurance Portability and Accountability Act authorization, those with pulmonary nodules detected, imaging, and pathology reports were reviewed. All patients for whom a nodule was identified within 6 months of testing by EarlyCDT-Lung were included. The additivity of the test to nodule size and nodule-based risk models was explored.
RESULTS - A total of 451 patients (32%) had at least one nodule, leading to 296 eligible patients after exclusions, with a lung cancer prevalence of 25%. In 4- to 20-mm nodules, a positive test result represented a greater than twofold increased relative risk for development of lung cancer as compared with a negative test result. Also, when the "both-positive rule" for combining binary tests was used, adding EarlyCDT-Lung to risk models improved diagnostic performance with high specificity (>92%) and positive predictive value (>70%).
CONCLUSIONS - A positive autoantibody test result reflects a significant increased risk for malignancy in lung nodules 4 to 20 mm in largest diameter. These data confirm that EarlyCDT-Lung may add value to the armamentarium of the practitioner in assessing the risk for malignancy in indeterminate pulmonary nodules.
Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.