Kronos: a workflow assembler for genome analytics and informatics.

BackgroundThe field of next-generation sequencing informatics has matured to a point where algorithmic advances in sequence alignment and individual feature detection methods have stabilized. Practical and robust implementation of complex analytical workflows (where such tools are structured into "best practices" for automated analysis of next-generation sequencing datasets) still requires significant programming investment and expertise.ResultsWe present Kronos, a software platform for facilitating the development and execution of modular, auditable, and distributable bioinformatics workflows. Kronos obviates the need for explicit coding of workflows by compiling a text configuration file into executable Python applications. Making analysis modules would still require programming. The framework of each workflow includes a run manager to execute the encoded workflows locally (or on a cluster or cloud), parallelize tasks, and log all runtime events. The resulting workflows are highly modular and configurable by construction, facilitating flexible and extensible meta-applications that can be modified easily through configuration file editing. The workflows are fully encoded for ease of distribution and can be instantiated on external systems, a step toward reproducible research and comparative analyses. We introduce a framework for building Kronos components that function as shareable, modular nodes in Kronos workflows.ConclusionsThe Kronos platform provides a standard framework for developers to implement custom tools, reuse existing tools, and contribute to the community at large. Kronos is shipped with both Docker and Amazon Web Services Machine Images. It is free, open source, and available through the Python Package Index and at https://github.com/jtaghiyar/kronos

B-Type Natriuretic Peptide in the Critically Ill with Acute Kidney Injury

Introduction. Acute kidney injury (AKI) is common in the intensive care unit (ICU) and associated with poor outcome. Plasma B-type natriuretic peptide (BNP) is a biomarker related to myocardial overload, and is elevated in some ICU patients. There is a high prevalence of both cardiac and renal dysfunction in ICU patients. Aims. To investigate whether plasma BNP levels in the first 48 hours were associated with AKI in ICU patients. Methods. We studied a cohort of 34 consecutive ICU patients. Primary outcome was presence of AKI on presentation, or during ICU stay. Results. For patients with AKI on presentation, BNP was statistically higher at 24 and 48 hours than No-AKI patients (865 versus 148 pg/mL; 1380 versus 131 pg/mL). For patients developing AKI during 48 hours, BNP was statistically higher at 0, 24 and 48 hours than No-AKI patients (510 versus 197 pg/mL; 552 versus 124 pg/mL; 949 versus 104 pg/mL). Conclusion. Critically ill patients with AKI on presentation or during ICU stay have higher levels of the cardiac biomarker BNP relative to No-AKI patients. Elevated levels of plasma BNP may help identify patients with elevated risk of AKI in the ICU setting. The mechanism for this cardiorenal connection requires further investigation

Access to

Introduction. Acute kidney injury (AKI) is common in the intensive care unit (ICU) and associated with poor outcome. Plasma B-type natriuretic peptide (BNP) is a biomarker related to myocardial overload, and is elevated in some ICU patients. There is a high prevalence of both cardiac and renal dysfunction in ICU patients. Aims. To investigate whether plasma BNP levels in the first 48 hours were associated with AKI in ICU patients. Methods. We studied a cohort of 34 consecutive ICU patients. Primary outcome was presence of AKI on presentation, or during ICU stay. Results. For patients with AKI on presentation, BNP was statistically higher at 24 and 48 hours than No-AKI patients (865 versus 148 pg/mL; 1380 versus 131 pg/mL). For patients developing AKI during 48 hours, BNP was statistically higher at 0, 24 and 48 hours than No-AKI patients (510 versus 197 pg/mL; 552 versus 124 pg/mL; 949 versus 104 pg/mL). Conclusion. Critically ill patients with AKI on presentation or during ICU stay have higher levels of the cardiac biomarker BNP relative to No-AKI patients. Elevated levels of plasma BNP may help identify patients with elevated risk of AKI in the ICU setting. The mechanism for this cardiorenal connection requires further investigation

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Purpose Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets

Neoadjuvant nivolumab in early-stage non–small cell lung cancer (NSCLC): Five-year outcomes.

8537 Background: Neoadjuvant (neoadj) immune checkpoint blockade (ICB) with anti-PD-1 therapy has shown increasing promise for early stage NSCLC, with long-term clinical outcomes still maturing. Our group reported the first phase I/II trial of neoadj nivolumab (nivo) in resectable NSCLC, finding therapy to be safe and feasible. We now present final clinical results from this cohort, representing the longest follow up data for neoadj anti-PD-1 to date. Methods: Two doses of neoadj nivo (3 mg/kg) were given prior to resection in 21 patients (pts) with resectable NSCLC. 5-year (yr) follow-up data, including recurrence-free survival (RFS), overall survival (OS) and association with pathologic response were tabulated. Event time distributions were estimated with the Kaplan-Meier method. All p-values are two-sided with 0.05 significance level. Results: At a median follow up of 63 months, 3-, 4- and 5-yr survival rates were 85, 80, and 80% respectively. RFS rates at 3-, 4- and 5-yrs were 65, 60, and 60% respectively. As previously reported, major pathologic response (MPR: ≤10% viable tumor) was 45%, and pathologic complete response (pCR) rate was 10%. The hazard ratio (HR) for pathologic down-staging was in the direction of improved RFS, without meeting statistical significance (HR 0.36, 95% CI 0.07-1.75, p = 0.2). RFS HR estimates for MPR and an alternative pathologic cut-off of less than 50% residual tumor (RT), were 0.61, (95% CI 0.15-2.44, p = 0.48) and 0.36, (95% CI 0.09-1.51, p = 0.16) respectively. The direction of the effect of pre-treatment PD-L1 positivity (≥1%) was to improve RFS (HR 0.36, 95% CI 0.07-1.85, p = 0.22). At 5-yr follow up, 8 of 9 (89%) pts with MPR were alive and no cancer deaths have occurred. Amongst pts with MPR, 1/9 pts had a cancer recurrence in the mediastinum treated successfully with definitive chemoradiotherapy. Both pts with pCR are alive and without recurrence. Patterns of all recurrences in this cohort are summarized in table 1. No long-term immune-related adverse events have occurred other than one G3 dermatologic event. Conclusions: The 5-yr clinical outcomes for neoadj nivo in resectable NSCLC compare favorably to historical trends. MPR trended toward improved RFS, while definitive conclusions are limited by our cohort size and overall low recurrence rate. Thresholds of %RT beyond pCR and MPR in this setting should be explored in larger prospective studies. PD-L1 expression may play a role in predicting long-term response, but larger prospective studies are needed. Clinical trial information: NCT02259621. [Table: see text] </jats:p

Abstract 544: Recurrent DICER1 hotspot mutations in endometrial cancer and their impact on microRNA biogenesis

Abstract Alternation in genes associated with microRNA (miRNA) biogenesis pathway may lead to miRNA dysregulation, and is implicated in a variety of human malignancies. Previously our group identified recurrent somatic “hotspot” mutations (E1705, D1709, D1810, E1813) in a critical miRNA-processing gene, DICER1, in rare sex cord-stromal tumors. During miRNA biogenesis, the two RNase III domains of DICER1 form an intramolecular dimer, which leads to the cleavage of the precursor miRNA (pre-miRNA) hairpin and generate mature 5p and 3p miRNAs from 5’ and 3’ arms of the precursor hairpin respectively. Studies have shown that the hotspot mutations in the RNase IIIb metal binding domain could impair DICER1's ability to generate mature 5p miRNAs, leading to global loss of 5p miRNAs. Recently, in collaboration with The Cancer Genome Atlas (TCGA), we identified DICER1 hotspot mutations in a small subset of endometrial cancer from TCGA cohort (6/248) as well as our own tumor bank (6/307), suggesting disruption of DICER1 is implicated in a common malignancy. We also found an additional recurrent mutation G1809R and demonstrated that it has similar detrimental effects on miRNA biogenesis as hotspot mutations through deep sequencing and realtime PCR. Using Illumina Miseq targeted resequencing and Sanger sequencing, we observed biallelic DICER1 mutations in RNase IIIb domain in some but not all cases. miRNA deep sequencing confirmed that 5p miRNAs are decreased in both cell line models and endometrial tumors with hotspot mutations. Bioinformatic analysis of RNA sequencing profiles from TCGA dataset predicted hotspot DICER1 mutations to have greater functional impact than non-hotspot DICER1 mutations on gene expression. The oncogenic properties of DICER1 hotspot mutations are currently under investigation. Citation Format: Jiamin Chen, Yemin Wang, Melissa McConechy, Michael Anglesio, Janine Senz, Winnie Yang, Jamie Rosner, Andy Chu, Grace Cheng, Gregg Morin, David Huntsman. Recurrent DICER1 hotspot mutations in endometrial cancer and their impact on microRNA biogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 544. doi:10.1158/1538-7445.AM2014-544</jats:p