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- Identification of novel DNA methylation prognostic biomarkers for AML with normal cytogeneticsPublication . Cardoso, Cândida; Pestana, Daniel; Gokuladhas, Sreemol; Marreiros, Ana; Justin M. O'Sullivan; Binnie, Alexandra; Teotónio Fernandes, Mónica Alexandra; Castelo-Branco, PedroPURPOSE AML is a hematologic cancer that is clinically heterogeneous, with a wide range of clinical outcomes. DNA methylation changes are a hallmark of AML but are not routinely used as a criterion for risk stratification. The aim of this study was to explore DNA methylation markers that could risk stratify patients with cytogenetically normal AML (CN-AML), currently classified as intermediate-risk.MATERIALS AND METHODSDNA methylation profiles in whole blood samples from 77 patients with CN-AML in The Cancer Genome Atlas (LAML cohort) were analyzed. Individual 5'-cytosine-phosphate-guanine-3' (CpG) sites were assessed for their ability to predict overall survival. The output was validated using DNA methylation profiles from bone marrow samples of 79 patients with CN-AML in a separate data set from the Gene Expression Omnibus.RESULTSIn the training set, using DNA methylation data derived from the 450K array, we identified 2,549 CpG sites that could potentially distinguish patients with CN-AML with an adverse prognosis (intermediate-poor) from those with a more favorable prognosis (intermediate-favorable) independent of age. Of these, 25 CpGs showed consistent prognostic potential across both the 450K and 27K array platforms. In a separate validation data set, nine of these 25 CpGs exhibited statistically significant differences in 2-year survival. These nine validated CpGs formed the basis for a combined prognostic biomarker panel, which includes an 8-CpG Somatic Panel and the methylation status of cg23947872. This panel displayed strong predictive ability for 2-year survival, 2-year progression-free survival, and complete remission in the validation cohort.CONCLUSIONThis study highlights DNA methylation profiling as a promising approach to enhance risk stratification in patients with CN-AML, potentially offering a pathway to more personalized treatment strategies.
- The burden of COVID-19 care in community and academic intensive care units in Ontario, Canada: a retrospective cohort studyPublication . Pestana, Daniel; Joshi, Divya; Duan, Erick; Fowler, Robert; Tsang, Jennifer; Binnie, AlexandraDuring the COVID-19 pandemic, neighbourhoods with high material deprivation and high proportions of racialized Canadians were disproportionately affected by COVID-19. Many of these neighbourhoods were served by community hospitals. We sought to compare the burden of COVID-19 care in community and academic intensive care units (ICUs) in Ontario, Canada. We included all adult patients admitted to Ontario ICUs with COVID-19 between 1 March 2020 and 31 July 2021 in a retrospective cohort study. We compared patient volumes, demographics, interventions, and outcomes between community hospital corporations (CHCs) and academic hospital corporations (AHCs). During the first three waves of the pandemic, 9,651 adult ICU admissions for COVID-19 were reported across 72 hospital corporations in Ontario: 6,902 (71.5%) in CHCs and 2,749 (28.5%) in AHCs. Days of ICU care per baseline ICU bed were highest in large CHCs ([ 10 baseline ICU beds) relative to AHCs and small CHCs (median [interquartile range], 73.7 [53.8–110.6] vs 42.2 [32.7–71.8] vs 21.4 [7.2–40.3]; Kruskal–Wallis test, P \ 0.001). Among direct ICU admissions, CHC patients had greater severity of illness whereas among transfer ICU admissions, AHC patients were more severely ill. In a multivariable logistic regression model, mortality was similar among patients with index admission to a CHC or AHC; however, patients with index admission to an AHC were more likely to receive extracorporeal membrane oxygenation (adjusted odds ratio, 6.16; 95% confidence interval, 4.72 to 8.11). During the pandemic, Ontario’s large CHCs provided significantly more days of ICU COVID-19 care per baseline ICU bed compared with AHCs and small CHCs. Equipping large CHCs to handle ICU surges during future emerging disease outbreaks should be a priority for pandemic preparedness.
- Association of epigenetic age and outcome in critically Ill patientsPublication . Sharma-Oates, Archana; Sullivan, Jack; Pestana, Daniel; Santos, Claudia C. dos; Binnie, Alexandra; Lord, Janet M.OBJECTIVES: DNA methylation can be used to determine an individual’s biological age, as opposed to chronological age, an indicator of underlying health status. This study aimed to assess epigenetic age in critically ill patients with and without sepsis to determine if higher epigenetic age is associated with admission diagnosis or mortality. DESIGN: Secondary analysis of whole blood DNA methylation data generated from a nested case–control study of critically ill septic and nonseptic patients. SETTING: Four tertiary care hospitals in Canada. INTERVENTIONS: None. PATIENTS: Critically ill patients with and without sepsis. MEASUREMENTS AND MAIN RESULTS: Epigenetic age was derived from DNA methylation data using the Hannum and PhenoAge algorithms and deviation from the patient’s chronological age in years was determined. Of the 66 patients with sepsis, 34 were male (51.5%), the mean age was 65.03 years and 25 patients (37.8%) died before discharge. Of the 68 nonseptic patients, 47 were male (69.1%), the mean age was 64.92 years and 25 (36.7%) died before discharge. Epigenetic age calculated using the PhenoAge algorithm showed a significant age acceleration of 4.97 years in septic patients (p = 0.045), but no significant acceleration in nonseptic patients. Epigenetic age calculated using the Hannum algorithm showed no significant acceleration in the septic or nonseptic patients. Similarly, in the combined septic and nonseptic cohorts, nonsurvivors showed an epigenetic age acceleration of 7.62 years (p = 0.004) using the PhenoAge algorithm while survivors showed no significant age acceleration. Survivor status was not associated with age acceleration using the Hannum algorithm.