Testing For Risk Stratification Research Articles

TRANSOESOPHAGEAL ELECTROPHYSIOLOGICAL STUDY IN PEDIATRIC PATIENTS WITH VENTRICULAR PRE–EXCITATION

Abstract Introduction The transoesophageal electrophysiological study (SETE) is a simple, semi–invasive and highly reliable test for risk stratification in patients with ventricular pre–excitation. In paediatric subjects, symptoms may be nonspecific or poorly reported; hence the usefulness of the study in guiding the therapeutic strategy. The guidelines also suggest performing it in all asymptomatic patients with ventricular preexcitation above 8 years of age.Purpose of the study: to evaluate the inducibility of re–entry tachycardia at SETE in paediatric patients with ventricular pre–excitation. Materials and Methods We observed 21 patients aged between a few days of life and 12 years (average age 11 years); 14 of them had constant and 7 intermittent pre–excitations. The latter were subjected to the study as they reported dubious symptoms either due to sports activities or due to a previous diagnosis of neonatal TPS. The study was performed by carrying out the protocols of continuous atrial stimulation at increasing frequencies, programmed atrial stimulation with single, double, and triple extra stimulus and atrial stimulation with burst. Results Of the 21 patients, 8 (38.1%) were inducible. Of the 14 patients with constant ventricular pre–excitation, 5 had tachycardia upon return to the study (35.7%), 4 of which were symptomatic due to previous TPS. Therefore, only one patient with constant and asymptomatic ventricular pre–excitation was inducible. Of the 7 patients with intermittent ventricular preexcitation (documented by Holter or exercise test), 3 developed TPS at SETE (42.8%): all these patients complained of heart palpitations but did not have a documented arrhythmia. On the contrary, all patients with intermittent ventricular preexcitation and asymptomatic were found to be non–inducible. In patients in whom it was possible to calculate the effective antegrade refractory period of the anomalous pathway, shorter refractory period showed greater inducibility. Non–sustained atrial fibrillation was induced in only two patients. Conclusions SETE demonstrates a good correlation between symptoms and inducibility especially in patients with intermittent ventricular pre–excitation. In fact, if the manifest pre–excitation disappears with growth in about a third of patients, the retrograde conduction capacity of the pathway often persists. The study also allows us to identify patients with constant pre–excitation but pathway at low risk.

The Value of Adding Exosome-Based Prostate Intelliscore to Multiparametric Magnetic Resonance Imaging in Prostate Biopsy: A Retrospective Analysis

Introduction: Currently, there is limited evidence for the relationship of Exosome-based Prostate Intelliscore (EPI) and multiparametric magnetic resonance imaging (mpMRI) in stratifying risk for clinically significant prostate cancer. Using a retrospective cohort study design, we sought to characterize the relationship between these two noninvasive metrics and prostate biopsy outcome. Methods: Data were collected via electronic medical record for all patients who underwent EPI testing from 1 January 2019 to 3 February 2022 and had available medical records at a single mid-western university medical center. Positive test result was defined as >15.6 for EPI, ≥3 PI-RADS score and ≥3 + 4 Gleason Score for biopsy findings. Utility of EPI, mpMRI and combined use was characterized through calculation of sensitivity, specificity, positive predictive value, negative predictive value, and ROC analysis. Results: A total of 226 patients were identified as receiving EPI testing for risk stratification of clinically significant prostate cancer. Sensitivity for EPI was 91%, mpMRI was 90%, and the highest was combined use at 96%. With ROC analysis, AUC for EPI alone was 0.57 (95% CI, 0.47–0.67) and 0.78 (95% CI, 0.70–0.87) for mpMRI alone. With prior positive EPI result, AUC for combined use with mpMRI was 0.80 (95% CI, 0.71–0.89). Further subgroup analysis resulted in increased AUC values of EPI 0.67 (95% CI, 0.48–0.87), mpMRI 0.90 (95% CI, 0.76–1.0), and combined 0.90 (95% CI, 0.75–1.0) in the African American population. Discussion: We observed that the combined use of EPI and mpMRI led to an avoided biopsy in 43% of patients. Using both parameters increased the overall sensitivity and diagnostic accuracy in detecting clinically significant prostate cancer. The best test performance was observed in the African American cohort. Identifying optimal noninvasive tools to assess risk for prostate cancer is crucial to providing accurate and cost-effective care. Future study should utilize a prospective study design to further support the combined use of these metrics.

Abstract PO4-07-05: Clinical evaluation of image-based risk profiling in breast cancer histopathology and comparison to an established gene expression assay

Abstract Background: Among oestrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative early breast cancer, a significant proportion of patients are categorised as intermediate risk, based on classic clinico-pathological variables, thus providing limited information to guide adjuvant chemotherapy decisions. Prognostic risk profiling is an integrated part of modern breast cancer diagnostics to provide additional risk information for this patient group. Among the established prognostic assays based on gene expression, the Prosigna assay is widely used and provides an individual risk of recurrence (ROR) score and identifies intrinsic subtypes with associated survival outcomes. Pioneering artificial intelligence-based precision diagnostics, Stratipath Breast, is a deep learning-based image analysis tool that utilises digitised histopathological whole slide images to stratify intermediate risk patients in terms of risk of recurrence. Materials and methods: The study included 234 invasive breast tumours from patients with early ER-positive HER2-negative breast cancer, clinically assessed as intermediate risk tumours and eligible for chemotherapy. All tumours had therefore previously been analysed by the Prosigna assay in clinical routine at point of diagnosis between 2020 and 2022 at the Karolinska University Hospital and Södersjukhuset, Stockholm, Sweden. Clinicopathological data including Prosigna results (ROR score, risk group and intrinsic subtype) were extracted from medical records, along with the corresponding archived haematoxylin and eosin (HE)-stained formalin-fixed paraffin-embedded tissue slides. The HE slides were subsequently digitised and analysed by the Stratipath Breast tool. The agreement between the two tests for risk stratification was evaluated in this real-world breast cancer case series. Results: The Prosigna assay classified 76 (32.5%), 110 (47.0%) and 48 (20.5%) tumours as low, intermediate and high risk, respectively. The Stratipath Breast analysis identified 116 (49.6%) tumours as low risk and 118 (50.4%) as high risk. Among Prosigna intermediate risk tumours, 52 (47.3%) were stratified as low risk and 58 (52.7%) as high risk by Stratipath Breast. The overall agreement between the two tests for low risk and high risk groups was 71.0%, with a Cohen’s linear kappa of 0.42. Twelve of the 48 Prosigna high risk cases were classified as Stratipath low risk. ROR scores were higher in the Stratipath high risk group compared to the low risk group (p < 0.001), across all cases as well as in the Prosigna intermediate group. Among the 176 histological grade (NHG) 2 tumours, 97 (55.1%) and 79 (44.9%) were stratified as Stratipath low risk and high risk, respectively, whereas 66 (37.5%), 83 (47.2%) and 27 (15.3%) were stratified as Prosigna low, intermediate and high risk, respectively. The majority of NHG1 (10 of 12) and NHG3 (37 of 46) tumours were stratified as Stratipath low risk and high risk, respectively. For both risk profiling tests, NHG and Ki67 proliferation index differed between risk groups. Conclusions: In this study of clinically assessed intermediate risk ER-positive HER2-negative breast cancer, we observed a moderate agreement between Prosigna and Stratipath Breast for low risk and high risk groups. In addition, image-based risk profiling stratified more of the NHG2 tumours as high risk. Citation Format: Stephanie Robertson, Yinxi Wang, Wenwen Sun, Emelie Karlsson, Sandy Kang Lövgren, Mattias Rantalainen, Johan Hartman. Clinical evaluation of image-based risk profiling in breast cancer histopathology and comparison to an established gene expression assay [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-07-05.

Use of the 31-Gene Expression Profile Test to Aid in the Decision of Adjuvant Treatment of Cutaneous Melanoma

Melanoma is the fifth most common cancer in the United States, with over 7,000 deaths annually. Although most patients diagnosed with early-stage (stage I or II) disease have an excellent prognosis, two out of three patients who die from melanoma were initially diagnosed in early stages. Thus, additional methods to identify which patients are at risk of poor outcomes are needed. DecisionDx-Melanoma is a 31-gene expression profile (31-GEP) molecular risk stratification test that predicts an individual’s risk of recurrence or metastasis in patients with cutaneous melanoma (CM). Here, we describe a 61-year-old man who presented with a spot on his upper scalp. A biopsy confirmed malignant melanoma measuring > 3.87 mm, with ulceration and mitotic rate 2 to 3/mm2. CT, PET, and MRI scans did not reveal metastasis. Following wide local excision and sentinel lymph node biopsy, he was diagnosed with stage IIB CM. Due to the presence of high-risk features, 31-GEP testing was ordered, which revealed Class 2B (high-risk) CM. Due to the high-risk 31-GEP result, the patient was treated off-label with nivolumab for 1 year and received follow-up surveillance scans every 3 months for 3 years. At his last follow-up in April 2022, scans continued to show no recurrent or metastatic disease. The patient continues dermatologic screening every 6 months. The 31-GEP test provides valuable additional information to help clinicians make personalized, risk-based treatment and surveillance plans for patients with CM.

Evaluation of dual p16/Ki-67 immunostaining on anal cytology specimens.

Dual immunostaining for p16/Ki67 is FDA-approved for use on liquid-based cervical cytology specimens; however, the utility of dual staining in anal cytology especially for ASCUS risk stratification is not well established. We investigated dual staining performance on anal cytology specimens and correlated with subsequent cytologic interpretation, high-risk HPV status, and anal biopsy results. Dual staining for p16/Ki-67 was performed on all liquid-based anal cytology specimens from December 2021 to June 2022 (n = 43). Three patients had high grade squamous intraepithelial lesion (HSIL/AIN2-3) on biopsy; dual staining was positive in all three cases. All HR-HPV negative cases were negative for dual staining. Among the 12 ASCUS samples with subsequent anal biopsy results all also had HR-HPV testing. Due to small sample size of cases with squamous intraepithelial lesion (SIL) diagnosed on biopsy, the sensitivity and positive predictive value was not calculated. However, the specificity and negative predictive value of p16/Ki-67 dual staining for SIL of any grade on biopsy were 1 (95% CI: 0.66-1) and 0.9 (95% CI: 0.65-0.97) respectively, whereas the specificity and negative predictive value of HR-HPV testing for SIL of any grade on biopsy were 0.44 (95% CI: 0.14-0.79) and 0.8 (95% CI: 0.41-0.96) respectively. Dual p16/Ki-67 staining indicates transforming HPV infection and could help serve as an ancillary test for risk stratification for atypical anal cytology specimens. Among ASCUS samples, dual staining was specific for SIL of any grade with a high negative predictive value and therefore could be useful in clinical practices with limited availability for follow-up care.

Cellular host response sepsis test for risk stratification of patients in the emergency department: A pooled analysis.

Sepsis is one of the most common, costly, and misdiagnosed conditions in U.S. emergency departments (EDs). ED providers often treat on nonspecific signs, subjective suspicion, or presumption of infection, resulting in over- and undertreatment. An increased understanding of host response has opened a new direction for sepsis diagnostics. The IntelliSep test is a U.S. Food and Drug Administration-cleared cellular host response diagnostic that could help distinguish sepsis in ED settings. Our objective was to evaluate the potential of the cellular host response test to expedite appropriate care for patients who present with signs of infection. We performed a pooled analysis of five adult (≥18 years) cohorts enrolled at seven geographically diverse U.S. sites in separate studies. Structured blinded adjudication was used to classify presence or absence of sepsis, and only patients with high confidence in the adjudicated label were included (n = 1002), defined as patients for whom there was consensus in the determination of sepsis per the Sepsis-3 and severe sepsis per the Sepsis-2 definitions between both the independent adjudication panel and the site-level physician. Among patients with signs or suspicion of infection, the test achieved similar or better performance compared to other indicators in identifying patients at high risk for sepsis (specificity > 83%) and significantly superior performance in identifying those at low risk (sensitivity > 92%; 0% sepsis-associated mortality). The test also stratified severity of illness, as shown by 30-day in-hospital mortality (p < 0.001), hospital length of stay (p < 0.01), and use of hospital resources (p < 0.001). Our data suggest that the cellular host response test provides clinically actionable results for patients at both high and low risk for sepsis and provides a rapid, objective means for risk stratification of patients with signs of infection. If integrated into standard of care, the test may help improve outcomes and reduce unnecessary antibiotic use.

BPI24-026: Utilization of ExoDx Prostate Test for Prostate Cancer Risk Stratification in the African American Population.

BPI24-026: Utilization of ExoDx Prostate Test for Prostate Cancer Risk Stratification in the African American Population.

Comparative evaluation of non-invasive tests for risk stratification for cause specific mortality in at-risk population of hepatic fibrosis

Our study aimed to conduct a comparative evaluation of various noninvasive tests (NITs) for risk stratification in at-risk population for non-alcoholic fatty liver disease (NAFLD), focusing on cardiovascular and liver-related mortality. A total of 21,715 adults aged 40 years and older were enrolled at baseline. The mean follow-up period was 12.39 years. Three types of NITs (fibrosis-4 index [FIB-4], NAFLD fibrosis score [NFS], and steatosis-associated fibrosis estimator [SAFE] score) were used. When using the low cut-off as a 'rule-out' strategy, there were no significant differences in cardiovascular mortality between the 'rule-out' (low-risk) group and the 'rule-in' (intermediate- or high-risk) group based on FIB-4 (aHR = 1.029, P = 0.845) or NFS (aHR = 0.839, P = 0.271) classification. However, the SAFE score exhibited higher sensitivity in predicting cardiovascular mortality compared to FIB-4 or NFS (73.3% in SAFE score vs. 29.6% in FIB-4 or 21.3% in NFS). Only the SAFE score could effectively differentiate the risk between low- and intermediate- or high-risk groups for all types of mortality (all P values for aHR < 0.001). The low cutoff value of the SAFE score discriminated not only liver-related mortality but also identified the cardiovascular high-risk group in the community cohort.

Abstract 6416: Early stage endometrioid endometrial cancer recurrence risk stratification using a machine learning RNA-seq gene expression signature

Abstract Endometrioid endometrial cancer (EEC) adjuvant therapy decisions rely on risk stratification using histology, grade, stage, and lymphovascular space invasion (LVSI). Recently, molecular classification systems originating from TCGA, evaluated in GOG-210 and PORTEC-3 defined four prognostic subtypes based on POLE, MSI-H/MMR-D, and p53 alterations. Although valuable, this molecular approach still has significant limitations such as applicability to the majority of EEC patients categorized as no-specific molecular profile (NSMP) and the potential need to resolve pathogenic and prognostic heterogeneity within MMR-D, and TP53 subtypes. These unmet needs were key motivators for Tempus to develop a molecular classifier predicting distant recurrence risk in early-stage EEC with a focus on high intermediate-risk (HIR) patients. The RNA-seq-based gene expression profiler (GEP) was trained using a machine-learning pipeline with TCGA data which resulted in a 24 gene signature that classifies EEC patients as molecular risk (MR) high or low (MR-high, MR-low). The GEP MR test was then evaluated on a de-identified cohort of EEC patients (N=1037) from Tempus to test associations with known pathologic or molecular prognostic features. The GEP-MR risk predictor showed significant enrichment of MR high-risk in G3 versus G1/2 histology (p-value &amp;lt; 5e-8). A high correlation was found between the MR score and copy number alteration score (t-test p-value &amp;lt; 1e-5). Next, a clinical evaluation was performed in an early-stage EEC case-control cohort of patients with documented recurrence or no recurrence event at four years (N=109), from Stanford. In the entire cohort, the MR-high group had a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=4.8, N=109). Next, we performed a subgroup analysis in the clinically important HIR patients. In this subgroup, the MR-high group had a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=8.0, N=56). Lastly, given the significance of genomic biomarkers in the evolution of EEC FIGO staging, we stratified outcomes by the established TCGA subtypes as a reference standard and performed a subgroup analysis in patients classified as having no specific molecular profile (NSMP). Among patients who were NSMP, the MR-high group showed a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=7.92, N=67). These evaluation studies demonstrate the performance of the GEP MR test in early-stage EEC distant recurrence risk stratification, specifically HIR patients, necessitating further studies to validate the test for clinical use in informing adjuvant clinical management. Citation Format: Rafi Pelossof, Talal Ahmed, Seung Won Hyun, Chithra Sangali, Ben Terdich, Calvin Chao, Michael Toboni, Casey Cosgrove, Elizabeth Kidd, Brook Howitt, Timothy Taxter. Early stage endometrioid endometrial cancer recurrence risk stratification using a machine learning RNA-seq gene expression signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6416.

Postmortem genetic analysis following sudden cardiac death : Background, approach, and future

Sudden cardiac death (SCD) is defined as an unexpected, nontraumatic death with apossible cardiac or unknown cause. The lowest incidence is observed in infancy and childhood (1per 100,000), and the incidence is approximately 50per 100,000 in the middle-aged population, reaching aplateau around the age of 80 (200 per100,000). While most SCD cases occur in older people with coronary artery disease, there is apredominance of monogenetic and polygenetic diseases in the young. Postmortem genetic analysis (molecular autopsy) using next-generation sequencing reveals adefinite pathogenic genetic alteration, which can explain SCD of young patients in near 20% of the cases. Hence, postmortem genetic analysis has become an important tool to unravel the inheritable cause of death. Furthermore, early identification of apathogenic genetic sequence variant in the deceased is crucial to reduce risk in relatives due to preventive personalized measures. Postmortem genetic analysis forms together with the clinical assessment the basis for early identification of at-risk relatives. Anew guideline for the management of ventricular arrhythmias and prevention of sudden death was recently published by the European Society of Cardiology. The new recommendations give genetic testing, also in deceased patients amuch higher priority reflecting increasing relevance of genetic testing for diagnostic evaluation, risk stratification and prevention.

Safety-Net Primary Care and Endocrinology Clinicians’ Knowledge and Perspectives on Screening for Nonalcoholic Fatty Liver Disease: A Mixed-Methods Evaluation

ObjectiveClinical guidelines have expanded the indications for nonalcoholic fatty liver disease (NAFLD) screening to type 2 diabetes mellitus and obesity, which are conditions common in populations who receive care in urban safety-net settings. This study aimed to evaluate safety-net primary care and endocrinology clinicians’ knowledge of NAFLD, determine barriers and facilitators to screening, and examine perspectives on the use of electronic health record tools for risk assessment. MethodsSequential explanatory mixed methods using survey and qualitative interviews with primary care, primary care subspecialty, and endocrinology clinicians in an urban safety-net health care system. ResultsA total of 109 participants completed the survey (36.5% response rate), and 13 participated in interviews. Most respondents underestimated or did not know the prevalence of NAFLD (68%), did not use the recommended noninvasive tests for risk stratification (65%), and few were comfortable with screening for (27%) or managing (17%) NAFLD. Endocrinologists had greater knowledge of risk factors but lower rates of comfort and more often felt that screening was not their responsibility. The qualitative themes included the following: (1) lack of knowledge about screening, (2) concern for underdiagnosing NAFLD, (3) perception of severity impacts beliefs about screening, (4) screening should occur in primary care but is not normative practice, (5) concerns exist about benefit, (6) competing demands with a complex population hinder screening, and (7) a need for easier ways to integrate screening into practice. ConclusionKnowledge gaps may hamper uptake of new guidelines for NAFLD screening in primary care and endocrinology clinics in an urban safety-net health care system. Implementation strategies focused on training and educating clinicians and informed by behavioral economics may increase screening.

Prostate cancer management in Southeast Asian countries: a survey of clinical practice patterns.

Prostate cancer (PC) has a serious public health impact, and its incidence is rising due to the aging population. There is limited evidence and consensus to guide the management of PC in Southeast Asia (SEA). We present real-world data on clinical practice patterns in SEA for advanced PC care. A paper-based survey was used to identify clinical practice patterns and obtain consensus among the panelists. The survey included the demographics of the panelists, the use of clinical guidelines, and clinical practice patterns in the management of advanced PC in SEA. Most panelists (81%) voted prostate-specific antigen (PSA) as the most effective test for early PC diagnosis and risk stratification. Nearly 44% of panelists agreed that prostate-specific membrane antigen positron emission tomography-computed tomography imaging for PC diagnostic and staging information aids local and systemic therapy decisions. The majority of the panel preferred abiraterone acetate (67%) or docetaxel (44%) as first-line therapy for symptomatic mCRPC patients. Abiraterone acetate (50%) is preferred over docetaxel as a first-line treatment in metastatic castration-sensitive prostate cancer patients with high-volume disease. However, the panel did not support the use of abiraterone acetate in non-metastatic castration-resistant prostate cancer (nmCRPC) patients. Apalutamide (75%) is the preferred treatment option for patients with nmCRPC. The cost and availability of modern treatments and technologies are important factors influencing therapeutic decisions. All panelists supported the use of generic versions of approved therapies. The survey results reflect real-world management of advanced PC in a SEA country. These findings could be used to guide local clinical practices and highlight the financial challenges of modern healthcare.

Integrative interpretation of cardiopulmonary exercise tests for cardiovascular risk stratification: a machine learning approach

Abstract Background and objectives Cardiopulmonary exercise testing (CPET) remains underutilized for cardiovascular (CV) risk assessment. Integrative interpretation of CPET results may improve characterization of cardiorespiratory fitness and assessment of CV risk. Therefore, we explored the clinical value of CPET-based phenomapping for CV risk stratification. Methods We retrospectively retrieved clinical data from 2280 patients with diverse CV risk (47.9% female) who underwent maximal CPET by cycle ergometry. We derived 18 key CPET indices as well as data on fatal and non-fatal CV events (median follow-up time: 5.3 years). Next, an unsupervised clustering algorithm (Gaussian Mixture modelling) subdivided the cohort in sex-specific phenogroups solely based on differences in CPET metrics. Clinical characteristics were compared across CPET phenogroups and their multivariable-adjusted association with future CV events was determined. Results 8 of the 18 CPET metrics were excluded from clustering due to high collinearity (i.e. an absolute Pearson correlation coefficient &amp;gt;0.8). Based on the remaining 10 CPET variables, the clustering algorithm subdivided the cohort in four male and four female CPET phenogroups. In both males and females, the phenogroups differed significantly in age, BMI, spirometric and CPET measurements and prevalence of hypertension, intake of antihypertensive and lipid-lowering drugs, CV disease and CV surgery (P&amp;lt;0.05 for trends). During follow-up, 278 males and 109 females experienced a CV event (43.9 and 16.2 events per 1000 years of follow-up, respectively). Compared to male phenogroup 1, male phenogroups 3 and 4 presented higher risk for incident CV events (multivariable-adjusted hazard ratio: 1.97 and 1.62; P≤0.027). Significant differences in risk for future CV events between the female phenogroups disappeared after adjustment for confounders. Conclusion Integrative CPET-based phenogrouping adequately stratified patients according to their risk for future CV events. Such phenomapping may facilitate comprehensive evaluation of CPET results and steer future CV risk management.Study flow and findings

Abstract 18015: Cardiopulmonary Exercise Testing Parameters-Based Phenogroups of Patients With Heart Failure With Reduced Ejection Fraction Using an Unsupervised Machine Learning Algorithm

Introduction: Although cardiopulmonary exercise testing (CPET) is the standard test for functional capacity and risk stratification in patients with HFrEF, the integrative use of different CPET parameters for prognostication is warranted. Hypothesis: A differential prognostication of HFrEF phenogroups can be achieved by means of an unsupervised machine learning algorithm of CPET parameters. Methods: We reviewed medical records of 1,067 patients with HFrEF (EF ≤ 40%) undergoing CPET from 12/2012 to 9/2020. Patients with hypotensive or bradycardic response during exercise were excluded. Unsupervised machine learning using partition around medoids (PAM) algorithm was used to create clusters based on CPET parameters. Primary outcome was LVAD/heart transplant-free survival. Kaplan-Meier plots along with log-rank test and multivariable Cox regression analysis with adjustment for co-morbidities, age, smoking, and LVEF were used to compare prognosis across clusters. Results: Among 935 patients with HFrEF included in the algorithm (mean age 56±12 years, EF 24±8%, 73% men, and 73% with RER &gt; 1.05), 329 (35 %) patients had adverse events (median follow up time 964 days). Using the PAM algorithm, we created 3 clusters using CPET parameters. Median (IQR) of age (53 [43-62], 58 [50-64] and 61 [54-68] years for cluster 1,2, and 3, respectively) and LVEF (30 [22-25], 25 [19-30] and 21 [16-26] % for cluster 1,2, and 3, respectively) were significantly different ( P &lt;0.001). No differences in sex of BMI were observed. Co-morbidities burden was higher in cluster 2 and 3, compared to cluster 1 ( Figure 1A) . Compared to cluster 1, cluster 2 and 3 had worse LVAD/heart transplant-free survival (adjusted HR 2.15 [95% CI 1.46-3.17] and 5.68 [95% CI 3.89-8.30], respectively; Figure 1B ). Conclusions: Patients with HFrEF could be risk-stratified into low-, medium- and high-risk using PAM algorithm solely based on CPET parameters that tracked with increasing comorbidity burden.

Methylation Biology of a Blood-Based MDS Risk Stratification Test

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies associated with a myriad of deleterious outcomes and a 5-year relative survival of 37%. MDS risk stratification is key for optimal treatment decisions. We previously demonstrated that methylation-based markers may help stratify MDS risk and achieved comparable performance relative to IPSS-R (the Revised International Prognostic Scoring System) by assessing the risk prediction ability of a classifier trained with features from either Bone Marrow (BM) whole-genome bisulfite sequencing (WGBS) or serum targeted methylation (TM) sequencing. Here, we elucidate the biological underpinnings of the methylation-based classifier and explore the survival stratification performance of our previously reported classifier. Methods: Utilizing datasets from BM WGBS and matched Serum TM sequencing of 127 patients with MDS (N=104) and secondary AML (N=23), we delineated the features used by the classifier by identifying differentially methylated regions (DMRs) that distinguished patients with overall survival of &amp;gt;3 years from those with &amp;lt;3 years. Our approach also included a functional enrichment and driver gene analysis associated with these DMRs, as well as cluster analysis across patients. We performed further evaluations of the survival outcomes of our BM WGBS and matched Serum TM prognostic classifier using concordance indices and log-rank tests. Results: Our analysis revealed 7,742 DMRs in BM WGBS and 14,093 DMRs in the Serum TM that significantly separated the long and short-term survival groups. Unsupervised hierarchical clustering of differential methylation patterns in both BM WGBS and Serum TM highlighted three distinctive subgroups of samples: short-term survivors, long-term survivors, and a group with intermediate survival outcomes. Notably, the short-term survivor group exhibited extensive hypermethylation across a majority of DMRs, which were linked to key biological pathways including calcium signaling, cAMP, MAPK, Rap1, and PI3K-Akt. Enrichment analysis of the BM WGBS DMRs between individuals with &amp;lt;3 and &amp;gt;3 years of survival underscored the differential hypermethylation of promoters, CpG islands, and CpG shores in association with worse survival outcomes. Our analysis of BM WGBS DMR driver genes via Hypergeometric Optimization of Motif EnRichment (HOMER) revealed potential contributors to differential survival outcomes, including known genes associated with MDS/AML, such as EWS/FLI-1, ERG, Pu.1, and RUNX1. Both pathway and driver gene analysis recapitulated previously known drivers of MDS to AML progression. The methylation classifier achieved comparable risk stratification performance for both BM WGBS comparing with IPSS-R (C-index: 0.69 [95% CI: 0.61-0.77] for methylation vs 0.71 [95% CI: 0.64-0.77] for IPSS-R) and Serum TM (C-index: 0.68 [95% CI: 0.60-0.75] for methylation vs. 0.70 [95% CI: 0.63-0.78] for IPSS-R). At a specificity threshold of 0.8, both BM WGBS and Serum TM prognostic classifiers were able to stratify between predicted short and predicted long survivors (BM WGBS HR: 2.83, p&amp;lt;0.0001; Serum TM HR: 3.01, p=0.0008). Conclusions: Our findings generated biological insights into the methylation-based risk stratification of MDS, shedding light on the specific genomic features and biological pathways that underlie these methylation patterns. We also demonstrated that methylation-based MDS risk stratification performs comparably with IPSS-R. These insights not only expand our understanding of the complexity of MDS, but also reinforce the potential of methylation-based sequencing as a viable, possibly less-invasive, alternative for MDS risk stratification compared to traditional IPSS-R methods.

Clinical Utility of the 31-Gene Expression Profile Test on the Management of Cutaneous Melanoma by Nurse Practitioners and Physician Assistants.

The 31-gene expression profile (31-GEP) can predict the risk of recurrence and metastasis in cutaneous melanoma (CM). We assessed the viewpoints and use of 31-GEP testing by physician assistants (PAs) and nurse practitioners (NPs) for patients with CM. NPs and PAs (n = 369) completed an 18-question online survey about their viewpoints and use of the 31-GEP risk-stratification test. Most practitioners (n = 334, 90.5%) felt prognostic testing improved patient care and would recommend the 31-GEP to a colleague (n = 333, 90.2%) or a friend or family member (n = 289, 78.3%) who was diagnosed with CM. The 31-GEP test was used by 176 respondents in the preceding 12 months (53%). Among users of the 31-GEP test, 78% stated that the results would impact follow-up schedule and referral, 66% overall treatment decisions, 62% sentinel lymph node biopsy recommendations, and 50% surveillance imaging. In thin tumors (≤ 1 mm), 82% of 31-GEP users and 44% of nonusers stated that the 31-GEP results would impact their treatment plan decisions. The 31-GEP test significantly impacts treatment plans in CM, particularly for thin and stage I melanomas. Importantly, even nonusers stated that 31-GEP test results would impact treatment plans as well as recommendations to a friend or family member.

Non-albumin proteinuria marks tubular involvement and is associated with arterial stiffness in subjects affected by severe obesity

IntroductionObesity is a well-established risk factor for kidney disease, and tubular damage can play a pivotal role in the development of obesity-related kidney damage. This study aimed to investigate the pathophysiological pathways involved in the development of non-albumin proteinuria (NAP), a marker of tubular involvement, in a cohort of subjects with severe obesity and preserved kidney function. MethodsA total of 106 subjects with BMI ≥ 35 kg/m2 in waiting list for bariatric surgery underwent blood chemistry analysis including metabolic and lipid profile, vascular tests for cardiovascular risk stratification and a comprehensive assessment of kidney function, including renal resistive index (RRI) and NAP measurement. ResultsNineteen patients with ACR ≥ 30 mg/g regardless of NAP values (ALB+), nineteen with NAP≥ 150 mg/g and albuminuria < 30 mg/g (iNAP) and sixty-eight without proteinuria (No-P) were found. Both ALB+ and iNAP groups exhibited a higher prevalence of hypertension and anti-hypertensive treatment compared to No-P, while the prevalence of diabetes was similar between groups. Concerning lipid profile, no differences in total, HDL and LDL cholesterol were found, while ALB+ patients had higher serum triglyceride levels than the other two groups. RRI and carotid-femoral pulse wave velocity (cf-PWV) was significantly higher in ALB+ and iNAP groups compared to No-P. Remarkably, cf-PWV remained still significant after adjustment for age, sex and MBP (p = 0.0004). In overall population, a multiple regression analysis showed that cf-PWV was an independent determinant of NAP in a model including age, sex, glycated hemoglobin, systolic and mean blood pressure (R2 =0.17, p = 0.031). ConclusioniNAP subjects showed increased arterial stiffness comparable to that observed in ALB+ group, suggesting that they may represent a subgroup at higher cardiovascular risk, often unrecognized in clinical practice.

A guide to conducting systematic reviews of clinical laboratory tests.

Clinical laboratory professionals have an instrumental role in supporting clinical decision making with theoptimal use of laboratory testing for screening, risk stratification, diagnostic, prognostic, treatment selection and monitoring of different states of health and disease. Delivering evidence-based laboratory medicine relies on review of available data and literature. The information derived, supports many national policies to improve patient care through clinical practice guidelines or best practice recommendations. The quality, validity and bias of this literature is variable. Hence, there is a need to collate similar studies and data and analyse them critically. Systematic review, thus, becomes the most important source of evidence. A systematic review, unlike a scoping or narrative review, involves a thorough understanding of the procedure involved and a stepwise methodology. There are nuances that need some consideration for laboratory medicine systematic reviews. The purpose of this article is to describe theprocess of performing a systematic review in the field oflaboratory medicine, describing the available methodologies, tools and software packages that can be used to facilitate this process.

Addendum. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Care in Diabetes-2023. Diabetes Care 2023;46(Suppl. 1):S49-S67.

Addendum. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Care in Diabetes-2023. Diabetes Care 2023;46(Suppl. 1):S49-S67.

Exercise Stress Test in The Assessment of Brugada Syndrome Patients

Brugada syndrome (BS) is a genetic channelopathy, clinically characterized by an increased risk of sudden cardiac death. The diagnosis requires a typical electrocardiographic pattern, and data on risk stratification are limited in the literature. The aim of this study was to conduct a review on the importance of exercise stress test (EST) in risk stratification in BS. Articles were searched in the PubMed, Scielo and Google Scholar databases. From the 200 articles retrieved, eight were included, with a total [...]