Persistent Opioid Use After Cardiac Implantable Electronic Device Procedures.

BACKGROUND: Prescription opioids are a major contributor to the ongoing epidemic of persistent opioid use (POU). The incidence of POU among opioid-naïve patients after cardiac implantable electronic device (CIED) procedures is unknown. METHODS: This retrospective cohort study used data from a national administrative claims database from 2004 to 2018 of patients undergoing CIED procedures. Adult patients were included if they were opioid-naïve during the 180-day period before the procedure and did not undergo another procedure with anesthesia in the next 180 days. POU was defined by filling an additional opioid prescription >30 days after the CIED procedure. RESULTS: Of the 143 400 patients who met the inclusion criteria, 15 316 (11%) filled an opioid prescription within 14 days of surgery. Among these patients, POU occurred in 1901 (12.4%) patients 30 to 180 days after surgery. The likelihood of developing POU was increased for patients who had a history of drug abuse (odds ratio, 1.52; P=0.005), preoperative muscle relaxant (odds ratio, 1.52; P<0.001) or benzodiazepine (odds ratio, 1.23; P=0.001) use, or opioid use in the previous 5 years (OR, 1.76; P<0.0001). POU did not differ after subcutaneous implantable cardioverter defibrillator or other CIED procedures (11.1 versus 12.4%; P=0.5). In a sensitivity analysis excluding high-risk patients who were discharged to a facility or who had a history of drug abuse or previous opioid, benzodiazepine, or muscle relaxant use, 8.9% of the remaining cohort had POU. Patients prescribed >135 mg of oral morphine equivalents had a significantly increased risk of POU. CONCLUSIONS: POU is common after CIED procedures, and 12% of patients continued to use opioids >30 days after surgery. Higher initially prescribed oral morphine equivalent doses were associated with developing POU.

Bivalirudin dosing during prolonged intermittent renal replacement therapy: a case report.

As patients transition between dialysis modalities, and from the intra- to the inter-dialytic period, medications with a narrow therapeutic index that are cleared in dialysis may require dose adjustments and close monitoring. Three cases of patients receiving bivalirudin while converting from continuous to prolonged intermittent renal replacement therapy are reported. Details provided include flow rates and ultrafiltrate volume. In these cases, it appears pre-emptive dose adjustments may be unwarranted, and clinicians should be aware of potential rebound after cessation of dialysis.

The impact of surgeon and hospital procedural volume on outcomes after aortic root replacement in the United States.

OBJECTIVE: Surgeon procedural volume for complex cardiac procedures have become important quality metrics. The objective is to determine the association of surgeon and hospital case volume on patient outcomes after an aortic root replacement for aortic root aneurysms. METHODS: From 2009 to 2014, 4629 Medicare patients underwent an aortic root replacement for a root aneurysm. Procedures were performed by 1276 surgeons at 718 hospitals. Patients with endocarditis, aortic rupture, or Type-A dissection were excluded. Procedural volume was defined as mean number of cases performed each year during the study period. The impact of hospital and surgeon volume on adjusted 30-day mortality was analyzed as a continuous variable using adjusted logistic regression with cubic splines. RESULTS: After an aortic root replacement, we observed a nonlinear reduction in the adjusted odds ratio for 30-day mortality as surgeon and hospital volume increased. Surgeons that performed approximately five cases/year and hospitals that completed approximately five cases/year had the greatest reduction in the odds of perioperative death. Patients treated at high-volume hospitals (≥4.5 cases/year) had a lower risk for 30-day postoperative stroke (hazard ratio [HR] = 0.51, p = .008), myocardial infarction (HR = 0.49, p = .016), hemodialysis (HR = 0.44, p = .005), and reoperation (HR = 0.48, p = .003). Additionally, patients treated with high-volume surgeons (≥9 cases/year) had lower risk for stroke (HR = 0.65, p = .005), hemodialysis (HR = 0.65, p = .03), sepsis (HR = 0.62, p = .03), and reoperation (HR = 0.67, p = .004). CONCLUSION: Among Medicare patients undergoing an aortic root replacement, there is a strong inverse relationship between annualized surgeon and hospital case volume and postoperative outcomes. Procedural volume is an important quality metric for this high-risk procedure.

Optimized monoclonal antibody treatment against ELTD1 for GBM in a G55 xenograft mouse model.

Glioblastoma is an aggressive brain tumour found in adults, and the therapeutic approaches available have not significantly increased patient survival. Recently, we discovered that ELTD1, an angiogenic biomarker, is highly expressed in human gliomas. Polyclonal anti-ELTD1 treatments were effective in glioma pre-clinical models, however, pAb binding is potentially promiscuous. Therefore, the aim of this study was to determine the effects of an optimized monoclonal anti-ELTD1 treatment in G55 xenograft glioma models. MRI was used to assess the effects of the treatments on animal survival, tumour volumes, perfusion rates and binding specificity. Immunohistochemistry and histology were conducted to confirm and characterize microvessel density and Notch1 levels, and to locate the molecular probes. RNA-sequencing was used to analyse the effects of the mAb treatment. Our monoclonal anti-ELTD1 treatment significantly increased animal survival, reduced tumour volumes, normalized the vasculature and showed higher binding specificity within the tumour compared with both control- and polyclonal-treated mice. Notch1 positivity staining and RNA-seq results suggested that ELTD1 has the ability to interact with and interrupt Notch1 signalling. Although little is known about ELTD1, particularly about its ligand and pathways, our data suggest that our monoclonal anti-ELTD1 antibody is a promising anti-angiogenic therapeutic in glioblastomas.

MNEMONIC: MetageNomic Experiment Mining to create an OTU Network of Inhabitant Correlations.

BACKGROUND: The number of publicly available metagenomic experiments in various environments has been rapidly growing, empowering the potential to identify similar shifts in species abundance between different experiments. This could be a potentially powerful way to interpret new experiments, by identifying common themes and causes behind changes in species abundance. RESULTS: We propose a novel framework for comparing microbial shifts between conditions. Using data from one of the largest human metagenome projects to date, the American Gut Project (AGP), we obtain differential abundance vectors for microbes using experimental condition information provided with the AGP metadata, such as patient age, dietary habits, or health status. We show it can be used to identify similar and opposing shifts in microbial species, and infer putative interactions between microbes. Our results show that groups of shifts with similar effects on microbiome can be identified and that similar dietary interventions display similar microbial abundance shifts. CONCLUSIONS: Without comparison to prior data, it is difficult for experimentalists to know if their observed changes in species abundance have been observed by others, both in their conditions and in others they would never consider comparable. Yet, this can be a very important contextual factor in interpreting the significance of a shift. We've proposed and tested an algorithmic solution to this problem, which also allows for comparing the metagenomic signature shifts between conditions in the existing body of data.

Oral Vancomycin for Secondary Prophylaxis of Clostridium difficile Infection.

OBJECTIVE: To summarize and critically appraise the evidence regarding oral vancomycin prophylaxis (OVP) to prevent recurrent Clostridium difficile infections (RCDIs), identify potential consequences of this emerging practice, and highlight future directions of study. DATA SOURCES: A MEDLINE literature search of English-language publications from 1947 through September 2018 was performed using the search terms vancomycin and C difficile and prophylaxis. Clinical trials were identified on the National Library of Medicine clinical trials registry. STUDY SELECTION AND DATA EXTRACTION: All clinical studies (n = 3) assessing oral vancomycin for secondary prophylaxis of C difficile infection (CDI) were evaluated by all authors. Other search results and references in selected publications were used for background and discussion. DATA SYNTHESIS: OVP reduced the risk of RCDI in high-risk patients taking systemic antibiotics. Variable dosing regimens and lack of safety data are limitations. OVP may have an adverse impact on the gastrointestinal microbiome, but this was not examined in the clinical studies. Relevance to Patient Care and Clinical Practice: Although current studies are limited by methodological concerns, clinicians can consider vancomycin 125 mg orally once or twice daily in high-risk patients receiving broad-spectrum antibacterial agents. Results of ongoing trials will define the most appropriate regimen and its impact on outcomes, including collateral damage. CONCLUSIONS: OVP reduces the risk of RCDIs and should be considered on a case-by-case basis. Caution is warranted before routine use is implemented because the impact on long-term outcomes has not been assessed and the optimal regimen has not been defined.

ALE: automated label extraction from GEO metadata.

BACKGROUND: NCBI's Gene Expression Omnibus (GEO) is a rich community resource containing millions of gene expression experiments from human, mouse, rat, and other model organisms. However, information about each experiment (metadata) is in the format of an open-ended, non-standardized textual description provided by the depositor. Thus, classification of experiments for meta-analysis by factors such as gender, age of the sample donor, and tissue of origin is not feasible without assigning labels to the experiments. Automated approaches are preferable for this, primarily because of the size and volume of the data to be processed, but also because it ensures standardization and consistency. While some of these labels can be extracted directly from the textual metadata, many of the data available do not contain explicit text informing the researcher about the age and gender of the subjects with the study. To bridge this gap, machine-learning methods can be trained to use the gene expression patterns associated with the text-derived labels to refine label-prediction confidence. RESULTS: Our analysis shows only 26% of metadata text contains information about gender and 21% about age. In order to ameliorate the lack of available labels for these data sets, we first extract labels from the textual metadata for each GEO RNA dataset and evaluate the performance against a gold standard of manually curated labels. We then use machine-learning methods to predict labels, based upon gene expression of the samples and compare this to the text-based method. CONCLUSION: Here we present an automated method to extract labels for age, gender, and tissue from textual metadata and GEO data using both a heuristic approach as well as machine learning. We show the two methods together improve accuracy of label assignment to GEO samples.

AutoGDC: A Python Package for DNA Methylation and Transcription Meta-Analyses.

Motivation: 0.1The Genomic Data Commons is a powerful resource which facilitates the exploration of molecular alterations across various diseases. However, utilizing this resource for meta-analysis requires many different tools to query, download, organize, and analyze the data. In order to facilitate a more rapid, simple means of analyzing DNA methylation and RNA sequencing datasets from the GDC we developed autogdc, a python package that integrates data curation and preprocessing with meta-analysis functionality into one simplified bioinformatic pipeline. Availability and Implementation: 0.2The autogdc python package is available under the GPLv3 license at along with several examples of typical use-case scenarios in the form of a jupyter notebook. The data is all originally provided by the GDC, and is therefore available under the NIH Genomic Data Sharing (GDS) and NCI GDS policies.

BioVDB: biological vector database for high-throughput gene expression meta-analysis.

High-throughput sequencing has created an exponential increase in the amount of gene expression data, much of which is freely, publicly available in repositories such as NCBI's Gene Expression Omnibus (GEO). Querying this data for patterns such as similarity and distance, however, becomes increasingly challenging as the total amount of data increases. Furthermore, vectorization of the data is commonly required in Artificial Intelligence and Machine Learning (AI/ML) approaches. We present BioVDB, a vector database for storage and analysis of gene expression data, which enhances the potential for integrating biological studies with AI/ML tools. We used a previously developed approach called Automatic Label Extraction (ALE) to extract sample labels from metadata, including age, sex, and tissue/cell-line. BioVDB stores 438,562 samples from eight microarray GEO platforms. We show that it allows for efficient querying of data using similarity search, which can also be useful for identifying and inferring missing labels of samples, and for rapid similarity analysis.

Testing clinical selection criteria for intraoperative transoesophageal echocardiography in isolated coronary artery bypass graft surgery.

Background: There is a lack of evidence associating intraoperative transoesophageal echocardiography (TOE) use with improved outcomes among coronary artery bypass graft (CABG) surgery subpopulations. Methods: This matched retrospective cohort study used a US private claims dataset to compare outcomes among different CABG surgery patient populations with vs without TOE. Statistical analyses involved exact matching on pre-selected subgroups (congestive heart failure, single vessel, and multivessel CABG) and used fine and propensity-score balanced techniques to conduct multiple matched comparisons and sensitivity analyses. Results: Of 42 249 patients undergoing isolated CABG surgery, 24 919 (59.0%) received and 17 330 (41.0%) did not receive TOE. After matching, intraoperative TOE was significantly associated with a lower, 30-day mortality: 2.63% vs 3.20% (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.71-0.92; P=0.002). In the subgroup matched comparisons, intraoperative TOE was significantly associated with a lower, 30-day mortality rate among those with congestive heart failure: 4.20% vs 5.26% (OR: 0.78; 95% CI: 0.66-0.94; P=0.007) and among those undergoing multivessel CABG with congestive heart failure: 4.23% vs 5.24% (OR: 0.80; 95% CI: 0.65-0.97; P=0.025), but not among those undergoing multivessel CABG without congestive heart failure: 1.83% vs 2.15% (OR: 0.85; 95% CI: 0.70-1.02; P=0.089, nor any of the remaining three subgroups. Conclusions: Among US adults undergoing isolated CABG surgery, intraoperative TOE was associated with improved outcomes in patients with congestive heart failure (vs without) and among patients undergoing multivessel (vs single vessel) CABG. These findings support prioritised TOE allocation to these patient populations at centres with limited TOE capabilities.

Endovascular repair of aortoiliac aneurysmal disease with the helical iliac bifurcation device and the bifurcated-bifurcated iliac bifurcation device.

BACKGROUND: Iliac branch device (IBD) treatment of common and internal iliac artery (CIA and IIA) aneurysms has been controversial in the context of available embolization techniques or off-label adjunctive procedures. Two devices exist, a straight IBD (S-IBD) and a helical IBD (H-IBD). We report our midterm results with the latter and present outcomes with a third device intended to treat disease in the presence of short CIAs termed the bifurcated-bifurcated IBD (BB-IBD). METHODS: Data were prospectively collected from IBD-treated patients with infrarenal aortoiliac or thoracoabdominal aortoiliac aneurysms. Preoperative aneurysmal characteristics were collected in accordance with the endovascular reporting standards document, including presence of IIA stenosis, CIA diameters, and the presence of an IIA aneurysm. Technical success was defined as IBD device placement, branch placement, and patency without type I or III endoleak at implantation in addition to 24 hours survival. Follow-up computed tomography scans at 1, 6 (optional), 12 months, and annually thereafter were performed and reinterventions, sac morphology changes, and endoleaks noted. Survival and patency were evaluated with life-table analyses, and differences among anatomic groups were compared with log-rank tests, whereas t-tests and Fisher exact tests were used to compare simple variables. RESULTS: Between 2003 and 2012, 138 IBD devices were placed into 130 patients (98 H-IBD and 40 BB-IBD). Median follow-up was 20.3 months (range, 1-72 months) with 30- day, 12-month, 3- and 5-year survival rates of 99%, 90%, 79%, and 62%, respectively. Technical success was 94%, and branch patency was 94.6% at 30 days and 81.8% at 5 years. Thirty-five percent (35%) of branches were placed into patients with IIA aneurysms (in addition to their proximal disease), 20% into stenotic IIAs, and 46% into iliac systems with narrow (<16 mm) CIAs. Technical success was significantly lower in patients with IIA stenosis (81.5 vs 96.4%; Fisher exact test, P = .015) but not affected by the presence of an IIA aneurysm or narrow CIA. Branch patency was similar in all groups throughout follow-up. No stent fractures or component separations were noted in the IBDs or mating devices throughout the study period. CONCLUSIONS: The H-IBD and BB-IBD configurations have high technical success and acceptable long-term patency for the treatment of CIA and IIA aneurysms, including those with challenging anatomy difficult to treat with the straight branch design.

Family history of aortic disease predicts disease patterns and progression and is a significant influence on management strategies for patients and their relatives.

BACKGROUND: While a positive family history (FH) is a known risk factor for developing an aneurysm, its association with the extent of disease has not been established. We evaluated the influence of a FH of aortic disease with respect to the pattern and distribution of aortic aneurysms in a given patient. METHODS AND RESULTS: From November 1999 to November 2011, 1263 patients were enrolled in physician-sponsored endovascular device trials to treat aortic aneurysms. Of the 555 patients who were alive and returning for follow-up, we obtained 426 (77%) family histories. Three-dimensional imaging studies were used to identify the presence of aneurysms; 36% (155/426) of patients had a FH of aortic aneurysms and 5% (21/155) had isolated intracranial aneurysms. A logistic regression model was used to compare aortic morphology between patients with a positive or negative FH for aneurysms. Patients with a positive FH of aortic aneurysms were younger at their initial aneurysm (63 vs 70 years; P < .0001), more frequently had proximal aortic involvement (root: odds ratio [OR], 5.4; P < .0001; ascending: OR, 2.9; P < .001; thoracic: OR, 2.2; P = .01) with over 50% of FH patients ultimately developing suprarenal aortic involvement (P = .0001) and had a greater incidence of bilateral iliac artery aneurysm (OR, 1.8; P = .03). CONCLUSIONS: FH is an important tool that provides insight into the expected behavior of the untreated aorta and has significant implications for the development of treatment strategies. These findings should be used to guide patient's management with regard to treatment, follow-up paradigms, genetic testing, and screening of other family members.

Timing of heparin and thrombus formation in donor lungs after cardiac death.

BACKGROUND: Heparin is routinely administered to brain-dead donors before cardiac arrest, although it is not universally allowed for donation after cardiac death (DCD) donors due to concerns that death may be hastened. The lack of heparin may lead to thrombosis and compromised graft function. We evaluated the impact of timing of heparin administration and thrombi formation in a DCD pig model. METHODS: Eight domestic adult pigs were administered systemic heparin (30,000 IU): four prior to cardiac arrest through intravenous injection (prearrest heparin) and four after cardiac arrest via injection into the right atrium followed by open cardiac massage (postarrest heparin). Pigs were euthanized with potassium chloride and a minimum of 5 minutes of cardiac silence allowed before organ procurement. Lungs were flushed with antegrade and retrograde Perfadex, and pulmonary preservation solution effluent was evaluated for gross thrombi. Organs were fixed in formalin, sagittally sectioned, and evaluated by a pulmonary pathologist blinded to treatment. RESULTS: Antegrade and retrograde flushes demonstrated no significant thrombi. Gross pathologic evaluation revealed no occlusive central thrombi. Scant peripheral thrombi were detected in both treatment groups. No microscopic thrombi were noted in either treatment group. CONCLUSIONS: Delayed heparin administration after cardiac death does not affect thrombus formation in an animal model of lung procurement after cardiac death. Concern about clinically significant thrombosis occurring when heparin is not given before cardiac arrest appears unfounded. These findings suggest that DCD lungs can be used regardless of antemortem heparin administration.

Risk of Stroke and Major Bleeding With Vitamin K Antagonist Use After Mitral Valve Repair.

BACKGROUND: Guidelines are discordant on the use of a vitamin K antagonist (VKA) after mitral valve repair (MVr) to reduce the risk of cerebral embolic events. We performed an observational study among patients who underwent a MVr, without perioperative atrial fibrillation, to determine the risk of cerebral ischemic and major bleeding events with or without VKA. METHODS: From 2004 to 2016, we included patients who underwent MVr, using a national administrative claims database. Those with preoperative atrial fibrillation and anticoagulant use were excluded. Patients were stratified based on the presence of a VKA. Inverse probability weighting with a Cox proportional hazard model was used. RESULTS: After MVr, 754 patients were discharged on VKA and 1462 on no-VKA. We found no difference in the cumulative incidence for embolic stroke at 180 days (VKA: 2.21% vs no-VKA: 1.50%; hazard ratio, 1.35; P = .38). However, VKA patients had a significantly increased risk for any-cause major bleeding events at 180 days (VKA: 8.58% vs no-VKA: 4.21%; hazard ratio, 2.09; P < .001). VKA patients also had increased need for a pericardiocentesis/pericardial window at 30 days after discharge (VKA: 1.13% vs no-VKA: 0.37%; hazard ratio, 3.88; P = .025). CONCLUSIONS: Our study suggests that VKA after MVr does not reduce the risk of cerebral embolic events but is associated with an increased risk of major bleeding events.

Methylation Array Signals are Predictive of Chronological Age Without Bisulfite Conversion.

DNA methylation data has been used to make "epigenetic clocks" which attempt to measure chronological and biological aging. These models rely on data derived from bisulfite-based measurements, which exploit a semi-selective deamination and a genomic reference to determine methylation states. Here, we demonstrate how another hallmark of aging, genomic instability, influences methylation measurements in both bisulfite sequencing and methylation arrays. We found that non-methylation factors lead to "pseudomethylation" signals that are both confounding of epigenetic clocks and uniquely age predictive. Quantifying these covariates in aging studies will be critical to building better clocks and designing appropriate studies of epigenetic aging.

Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor ß1 (TGFß1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

Standing on the shoulders of a giant: The legacy of Robert M. Sellers.

Robert M. Sellers, PhD, most known for his influential and highly cited Multidimensional Model of Racial Identity (MMRI), is one of the most prolific and foundational Black scholars in psychology. From racial identity theory development and measurement to conceptual and methodological innovations in studying the lived experiences of Black people, Sellers' scholarship centers on the lives of Black communities. Sellers' mentorship and contributions to the professional development of scholars and professionals of color have supported and catalyzed new intergenerational knowledge building by these scholars, ensuring a perpetuating and far-reaching legacy in psychology. In this article, we: (a) celebrate Sellers' enduring contribution to the racial identity literature and its profound impact on psychology as a discipline as well as numerous subfields of psychology, (b) outline his contributions to the racial socialization literature, (c) describe methodological innovations in racial identity and racial socialization research advanced through his scholarship, and (d) summarize his contributions in professional development and mentorship and his leadership roles. Sellers' scholarly contributions and mentorship have transformed the discipline of psychology and the social sciences broadly speaking, making him one of the most influential psychologists in the modern era. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Pediatric donor lungs for adult transplant recipients: feasibility and outcomes.

BACKGROUND: There is a limited experience using pediatric organs for adult lung transplantation (LTx), with size matching the major concern. We reviewed our experience transplanting pediatric donor lungs into adult recipients with endpoints of post-LTx complications and overall patient survival. METHODS: From 2/1990 to 12/2007, 609 adults underwent primary LTx at our institution. Thirty-eight (6.2%) patients underwent LTx with organs from pediatric donors (≤16 years). Of these, median donor age was 13 years (range: 7 to 16) and median recipient age 55 (range: 24 to 66). Endpoints analyzed included size matching accuracy, airway and pleural complications, time to extubation, intensive care unit (ICU) and hospital lengths of stay, as well as survival. RESULTS: Gross undersizing of the donor lung was present in 2/38 (5.3%) and of the donor bronchus in 11/38 (29%). Five patients (13%) experienced a major postoperative airway complication. Thoracentesis prior to discharge was necessary in 4/38 (11%) patients and chest tube reinsertion in 10/38 (26%) for pleural effusion. Median time to extubation was 2 days. ICU and hospital lengths of stay were 6 and 16 days, respectively. Kaplan-Meier survival at 30 days, 1 year, 3 years, and 5 years post-transplant was 89%, 74%, 63%, and 55%. CONCLUSIONS: Despite sizing concerns, transplantation of pediatric lungs into adult recipients is feasible. Size mismatch may predispose to higher rates of airway and pleural complications. Hospital course and overall survival appear comparable to adult-to-adult LTx, and concerns over size matching should not preclude pediatric organ use for adult candidates.

Multi-tissue DNA methylation microarray signature is predictive of gene function.

Background Transcriptional correlation networks derived from publicly available gene expression microarrays have been previously shown to be predictive of known gene functions, but less is known about the predictive capacity of correlated DNA methylation at CpG sites. Guilt-by-association co-expression methods can adapted for use with DNA methylation when a representative methylation value is created for each gene. We examine how methylation compares to expression in predicting Gene Ontology terms using both co-methylation and traditional machine learning approaches across different types of representative methylation values per gene. Methods We perform guilt-by-association gene function prediction with a suite of models called Methylation Array Network Analysis, using a network of correlated methylation values derived from over 24,000 samples. In generating the correlation matrix, the performance of different methods of collapsing probe-level data effect on the resulting gene function predictions was compared, along with the use of different regions surrounding the gene of interest. Results Using mean comethylation of a given gene to its annotated term had an overall highest prediction macro-AUC of 0.60 using mean gene body methylation, across all Gene Ontology terms. This was increased using the logistic regression approach with the highest macro-AUC of 0.82 using mean gene body methylation, compared to the naive predictor of 0.72. Conclusion Genes correlated in their methylation state are functionally related. Genes clustered in co-methylation space were enriched for chromatin state, PRC2, immune response, and development-related terms.

Volume of frail patients predicts outcome in frail patients after cardiac surgery.

OBJECTIVE: Recent data from major noncardiac surgery suggest that outcomes in frail patients are better predicted by a hospital's volume of frail patients specifically, rather than overall surgical volume. We sought to evaluate this "frailty volume-frailty outcome relationship" in patients undergoing cardiac surgery. METHODS: We studied 72,818 frail patients undergoing coronary artery bypass grafting or valve replacement surgery from 2010 to 2014 using the Nationwide Readmissions Database. Frailty was defined using the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnoses indicator. Multilevel logistic regression was used to assess the independent effect of frailty volume by quartile on mortality, surgical complications, failure to rescue, nonhome discharge, 30-day readmissions, length of stay, and hospital costs in frail patients. RESULTS: In comparing the highest volume quartiles with the lowest, both overall cardiac surgical volume and volume for frail patients were significantly associated with shorter length of stay and reduced costs. However, frailty volume was also independently associated with significantly reduced in-hospital mortality (odds ratio, 0.79; 95% confidence interval, 0.67-0.94; P = .006) and failure to rescue (odds ratio, 0.83; 95% confidence interval, 0.70-0.98; P = .03), whereas no such association was seen between overall volume and either mortality (odds ratio, 0.94; 95% confidence interval, 0.74-1.10; P = .43) or failure to rescue (odds ratio, 0.98; 95% confidence interval, 0.83-1.17; P = .85). Neither frailty volume nor overall volume showed any significant relationship with the rate of 30-day readmissions. CONCLUSIONS: In frail patients undergoing cardiac surgery, surgical volume of frail patients was a significant independent of predictor of in-hospital mortality and failure to rescue, whereas overall surgical volume was not. Thus, the "frailty volume-outcome relationship" superseded the traditional "volume-outcome relationship" in frail patients with cardiac disease.