{"title":"Explainable epigenetic aging clocks: an overview of existing AI models and approaches.","authors":"Adiv A Johnson, Maxim N Shokhirev","doi":"10.1080/14737159.2026.2693031","DOIUrl":"10.1080/14737159.2026.2693031","url":null,"abstract":"<p><strong>Introduction: </strong>There is a growing demand to make epigenetic aging clocks that are interpretable and actionable. Here, we identify and describe explainable artificial intelligence (XAI) epigenetic clocks that convert CpGs into higher-level abstractions using deep learning.</p><p><strong>Areas covered: </strong>By combing through PubMed, this narrative review identifies six different XAI clocks: XAI-AGE, DL-XAI, EpInflammAge, PathwayAge, EXP.REACTOME, and EXP.TFT. XAI-AGE, DL-XAI, PathwayAge, EXP.REACTOME, and EXP.TFT provide explainability by leveraging the fact that a subset of DNA methylation sites are annotated to genes. From here, genes are converted into biological pathways or a protein-protein interaction network. Conversely, the XAI clock EpInflammAge works by taking methylation-based predictors of circulating chemokines and cytokines - referred to as synthetic proxies - and feeding these as inputs into a deep learning model.</p><p><strong>Expert opinion: </strong>By evaluating and comparing extant XAI clocks, it is clear that explainability is compatible with the ability to make accurate age predictions that are associated with meaningful health signals. The pathway- or network-level models are, however, more difficult to interpret and less actionable than the XAI clock based on synthetic proxies. Explainability and actionability could be improved by only incorporating robust estimators of well-understood biomarkers or by exclusively including tangible, easy-to-understand biological pathways.</p>","PeriodicalId":12113,"journal":{"name":"Expert Review of Molecular Diagnostics","volume":" ","pages":"695-707"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Diagnostic performance of circulating cell-free DNA as a minimally invasive biomarker for breast cancer: a systematic review and meta-analysis of methylation, quantitative, and integrity markers.","authors":"Nouran Wael, Al-Zahraa Owid, Hiba Fadlalla","doi":"10.1080/14737159.2026.2687512","DOIUrl":"10.1080/14737159.2026.2687512","url":null,"abstract":"<p><strong>Introduction: </strong>We evaluated the diagnostic accuracy of circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) compared to tissue biopsy in breast cancer across three assay modalities.</p><p><strong>Methods: </strong>We searched PubMed, Scopus, and Cochrane for studies published from January 2014 to March 2026. Bivariate random effects models pool sensitivity, specificity, and area under the curve (AUC). Registered under (CRD420261333264).</p><p><strong>Results: </strong>Eighteen studies with 4,743 participants were included. Quantitative assays achieved the highest sensitivity of 0.930 (95% CI: 0.603-0.991), specificity of 0.899 (95% CI: 0.802-0.951), and AUC of 0.928. Methylation assays showed a sensitivity of 0.752 (95% CI: 0.595-0.862), specificity of 0.841 (95% CI: 0.737-0.908), and AUC of 0.862. Integrity assays yielded a sensitivity of 0.863 (95% CI: 0.682-0.948), specificity of 0.874 (95% CI: 0.781-0.931), and AUC of 0.927. Substantial statistical heterogeneity (I<sup>2</sup>) occurred across all subgroups. Overall certainty was low, due to case-control designs and inconsistency.</p><p><strong>Conclusion: </strong>While cfDNA cannot replace tissue biopsies, current pooled estimates demonstrate high specificity, suggesting promising potential as an adjunctive diagnostic tool. Quantitative assays show the greatest potential for optimizing patient triage. However, the overall low certainty of evidence highlights an urgent need for standardized prospective studies.</p>","PeriodicalId":12113,"journal":{"name":"Expert Review of Molecular Diagnostics","volume":" ","pages":"617-631"},"PeriodicalIF":4.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148210617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Fluid biomarkers in cerebral amyloid angiopathy: current limitations and future directions.","authors":"Marta Del Chicca, Gaia Mignani, Fabio Iannaccone, Rebecca Piccarducci, Nicola Giannini, Gloria Tognoni, Stefano Masi, Roberto Ceravolo, Gabriele Siciliano, Michelangelo Mancuso, Filippo Baldacci","doi":"10.1080/14737159.2026.2687501","DOIUrl":"10.1080/14737159.2026.2687501","url":null,"abstract":"<p><strong>Introduction: </strong>Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage and cognitive decline in older adults. Current diagnosis relies mainly on neuroimaging, which lacks pathophysiological specificity.</p><p><strong>Areas covered: </strong>This narrative review summarizes evidence on cerebrospinal fluid (CSF) and plasma biomarkers in sporadic CAA. In CSF, CAA is typically associated with reduced Aβ42 and Aβ42/Aβ40 ratio, although similar alterations are observed in Alzheimer's disease (AD), limiting diagnostic specificity. Lower Aβ40 levels may reflect vascular amyloid deposition and appear more characteristic of CAA, but alone provide insufficient discrimination. Plasma biomarker studies have yielded inconsistent findings due to methodological and population heterogeneity. Nevertheless, amyloid isoforms, phosphorylated tau species, and neurofilament light chain (NfL) show potential, with NfL correlating with imaging markers and disease burden. The increasing need to distinguish CAA from AD and other cerebral small vessel diseases has driven growing interest in fluid biomarkers.</p><p><strong>Expert opinion: </strong>Despite promising findings, no fluid biomarker currently demonstrates sufficient specificity or validation for routine clinical use in CAA. Significant overlap with AD pathology remains a major limitation. Large longitudinal real-world studies are needed to determine the diagnostic, prognostic, and incremental clinical value of fluid biomarkers in CAA.</p>","PeriodicalId":12113,"journal":{"name":"Expert Review of Molecular Diagnostics","volume":" ","pages":"561-586"},"PeriodicalIF":4.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Olusegun O Soge, Helen Fifer, Sarah Alexander, Sarah N Buss
{"title":"Diagnostics and novel laboratory approaches to combat <i>Neisseria gonorrhoeae</i> antimicrobial resistance.","authors":"Olusegun O Soge, Helen Fifer, Sarah Alexander, Sarah N Buss","doi":"10.1080/14737159.2026.2689689","DOIUrl":"10.1080/14737159.2026.2689689","url":null,"abstract":"<p><strong>Introduction: </strong><i>Neisseria gonorrhoeae</i> (gonococcus, GC) has developed resistance to all antimicrobials recommended for gonorrhea treatment, owing to its genetic plasticity and capacity to acquire antimicrobial resistance (AMR). This review examines the crucial role of diagnostics and novel laboratory approaches in mitigating the spread of GC-AMR and in preserving the long-term effectiveness of current and future antimicrobials for gonorrhea.</p><p><strong>Areas covered: </strong>Recent advances in diagnostics and novel laboratory approaches for detection of GC-AMR, enhancing GC-AMR surveillance and clinical management of gonorrhea.</p><p><strong>Expert opinion: </strong>The rapid emergence and global dissemination of multidrug-resistant GC including ceftriaxone-resistant strains poses a grave challenge to current gonorrhea control and prevention strategies. The implementation of rapid diagnostics and novel laboratory approaches can, when used appropriately, support the rapid detection of GC-AMR, ensure timely treatment, reduce transmission, and preserve last-line antibiotics by enabling resistance-guided therapy. These diagnostics and novel laboratory approaches are also crucial for the early detection of emerging resistance to antimicrobials recently approved by the FDA, and other antimicrobials currently under development and anticipated for future clinical use. Integrating culture-based GC-AMR surveillance with rapid molecular assays targeting genetic determinants of AMR offers a comprehensive approach for robust monitoring and timely response to the ever-evolving GC-AMR.</p>","PeriodicalId":12113,"journal":{"name":"Expert Review of Molecular Diagnostics","volume":" ","pages":"587-603"},"PeriodicalIF":4.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Milan Perovic, Bojana Salovic, Sonja Zafirović, Ana Nikolic, Vladimir Gerginić, Emina Sudar-Milovanović, Esma R Isenovic
{"title":"The estradiol-to-oocyte ratio as a predictor of ART outcomes: evidence and implications in PCOS.","authors":"Milan Perovic, Bojana Salovic, Sonja Zafirović, Ana Nikolic, Vladimir Gerginić, Emina Sudar-Milovanović, Esma R Isenovic","doi":"10.1080/14737159.2026.2682326","DOIUrl":"10.1080/14737159.2026.2682326","url":null,"abstract":"<p><strong>Introduction: </strong>Polycystic ovary syndrome (PCOS) is an endocrine disease involving reproductive dysfunction, with anovulation and diminished oocyte quality, and is related to endometrial dysfunction. Estradiol-to-oocyte ratio (EOR) surfaced as a measure of success in reproductive effects in PCOS during assisted reproductive technical expertise.</p><p><strong>Areas covered: </strong>This review provides a comprehensive summary of current evidence on EOR, its physiological significance, relationship with oocyte maturation, and impact on embryo viability in IVF. We will explore molecular mechanisms of EOR's action in follicular development, integrating data from imaging technologies and biomarker studies. It also discusses its clinical utility in optimizing individualized fertility treatment and improving reproductive prognoses for PCOS patients during IVF.</p><p><strong>Expert opinion: </strong>EOR may empower IVF specialists by enabling more refined assessments, helping them make more personalized and confident treatment decisions for patients (embryo transfer and subsequent cycle protocol). It provides guidance for treatment adjustments in subsequent cycles, especially when prior responses were high in quantity but suboptimal in quality. Incorporating EOR into clinical practice complements clinical expertise and supports the balance between efficacy and safety in managing PCOS-related infertility.</p>","PeriodicalId":12113,"journal":{"name":"Expert Review of Molecular Diagnostics","volume":" ","pages":"547-559"},"PeriodicalIF":4.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neuro-axonal injury biomarker serum neurofilament light chain is associated with osteoarthritis: a dual-cohort study from NHANES and UK Biobank.","authors":"Mingxuan Liu, Huade Ma, Haidong Zhou, Kangqi Xie, Changtai Luo, Zhonglong He, Zhongxing Ning, Jihua Wei, Dianbo Yu","doi":"10.1080/14737159.2026.2690188","DOIUrl":"10.1080/14737159.2026.2690188","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) affects over half a billion people globally, representing a major public health burden. Serum neurofilament light chain (sNFL) has recently been implicated in systemic inflammation and metabolic disorders.</p><p><strong>Research design and methods: </strong>This dual-cohort study analyzed data from the National Health and Nutrition Examination Survey (NHANES) and the UK Biobank. In NHANES, sNFL was measured via a high-sensitivity immunoassay, while in UKB, NfL was quantified using the Olink Explore 3072 proteomics platform. OA was defined by self-report in NHANES, and a combination of self-report and ICD-10 hospital records in UKB. The associations were evaluated using multivariate logistic regression and RCS.</p><p><strong>Results: </strong>Higher sNFL levels were significantly associated with increased OA odds in both cohorts. In fully adjusted models, each 1-unit increase in log-transformed sNFL corresponded to 85% higher odds in NHANES [OR = 1.85, 95% CI: (1.51, 2.23)] and 28% higher odds in UKB [OR = 1.28, 95% CI: (1.21, 1.36)]. Comparing the highest to lowest quartiles, ORs were 4.41 (95% CI: 2.71, 7.13) and 1.46 (95% CI: 1.34, 1.59), respectively (both <i>p</i> for trend <0.01).</p><p><strong>Conclusions: </strong>Elevated sNFL levels are independently and consistently associated with a higher prevalence of OA across two distinct national cohorts.</p>","PeriodicalId":12113,"journal":{"name":"Expert Review of Molecular Diagnostics","volume":" ","pages":"633-641"},"PeriodicalIF":4.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matteo Rosellini, Linda Danielli, Alessandro Bibbò, Martina Musio, Costantino Ricci, Pietro Piazza, Matteo Santoni, Veronica Mollica, Francesco Massari
{"title":"KIM-1 and beyond: emerging biomarkers for adjuvant immunotherapy in clear cell renal cell carcinoma.","authors":"Matteo Rosellini, Linda Danielli, Alessandro Bibbò, Martina Musio, Costantino Ricci, Pietro Piazza, Matteo Santoni, Veronica Mollica, Francesco Massari","doi":"10.1080/14737159.2026.2687507","DOIUrl":"10.1080/14737159.2026.2687507","url":null,"abstract":"<p><strong>Introduction: </strong>Adjuvant immunotherapy has transformed the management of high-risk resected ccRCC, with pembrolizumab demonstrating improvements in DFS and OS. However, divergent outcomes across recent phase III trials highlight the limitations of clinicopathologic staging alone for guiding postoperative treatment decisions. A substantial proportion of patients may receive adjuvant therapy without deriving meaningful benefit, underscoring the urgent need for biologically informed risk stratification.</p><p><strong>Areas covered: </strong>KIM-1, a circulating biomarker derived from proximal tubular epithelium, has emerged as a promising candidate in this setting. Elevated postoperative KIM-1 levels are consistently associated with inferior oncologic outcomes and may reflect minimal residual disease. Exploratory analyses from IMmotion010 suggest a potential predictive enrichment effect for adjuvant immunotherapy benefit in patients with high baseline KIM-1. Additional biomarkers including sarcomatoid differentiation, specific genomic drivers (PBRM1, BAP1, VHL), circulating tumor DNA, epigenetic signatures, and systemic inflammatory markers, provide complementary insights into tumor biology and host-tumor interaction.</p><p><strong>Expert opinion: </strong>Although none of these biomarkers are currently validated for routine clinical decision-making, integrative models combining clinicopathologic and molecular features may enable more precise selection of patients for adjuvant immunotherapy and help reduce overtreatment in localized ccRCC.</p>","PeriodicalId":12113,"journal":{"name":"Expert Review of Molecular Diagnostics","volume":" ","pages":"605-615"},"PeriodicalIF":4.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Assessing biomarkers for patients with breast cancer who are suited for adjuvant therapy.","authors":"Emad A Rakha","doi":"10.1080/14737159.2026.2663045","DOIUrl":"10.1080/14737159.2026.2663045","url":null,"abstract":"<p><strong>Introduction: </strong>Biomarker-guided stratification is essential for optimizing adjuvant systemic therapy in early-stage breast cancer, requiring a balance between therapeutic benefit and avoidance of overtreatment.</p><p><strong>Areas covered: </strong>This review summarizes established and emerging prognostic and predictive biomarkers guiding adjuvant therapy selection. Evidence was synthesized from structured searches of PubMed, EMBASE, clinical trial databases and author expertise, focusing on morphological and molecular biomarkers, including multigene assays, protein and immune-based markers, mutation profiling, liquid biopsy and artificial intelligence (AI).</p><p><strong>Expert opinion: </strong>Although clinicopathological factors such as tumor size, grade, and nodal status remain fundamental, clinical decision-making is increasingly driven by biologically informed precision. ER and HER2 status continue to underpin prognostic and predictive assessment. In hormone receptor-positive disease, multigene assays refine recurrence risk and chemotherapy benefit, while tools such as HER2DX improve stratification in HER2-positive tumors. Immune and DNA-repair biomarkers inform targeted therapy in HER2-positive and triple-negative subtypes. Mutation profiling of <i>ESR1, PIK3CA, AKT, mTOR</i>, and <i>PTEN</i> increasingly informs targeted treatment, particularly in advanced disease. Emerging approaches, including liquid biopsy, AI, and multi-omics integration, offer dynamic insights but require prospective validation. Future progress depends on assay standardization, equitable access, and validation within adaptive clinical trial frameworks, supporting integrated molecular-clinical and AI-enhanced models for personalized therapy.</p>","PeriodicalId":12113,"journal":{"name":"Expert Review of Molecular Diagnostics","volume":" ","pages":"483-500"},"PeriodicalIF":4.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"α-synuclein PET imaging: early human evidence and the path toward clinical proof-of-concept.","authors":"Luca Filippi, Nicoletta Urbano","doi":"10.1080/14737159.2026.2675385","DOIUrl":"10.1080/14737159.2026.2675385","url":null,"abstract":"<p><strong>Introduction: </strong>Aggregation of misfolded α-synuclein is the defining pathological hallmark of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy (MSA). Despite major advances in the field of molecular neuroimaging, the <i>in vivo</i> detection of α-synuclein remains one of the most challenging goals in positron emission tomography (PET), largely due to the low abundance of aggregates, structural heterogeneity of fibrillar strains, and the need for high selectivity over other amyloid proteins.</p><p><strong>Areas covered: </strong>This Special Report summarizes advances in the development of small-molecule PET tracers targeting α-synuclein aggregates, with particular emphasis on the transition from preclinical radiotracer discovery to early clinical imaging studies. The article discusses key methodological challenges in tracer development, emerging chemical scaffolds, and the first translational efforts enabling initial human PET investigations.</p><p><strong>Expert opinion: </strong>Although no tracer is yet clinically validated, emerging evidence is consistent but still preliminary, particularly in MSA, where several compounds show regionally specific signals. However, important challenges remain, including limited sensitivity in early or prodromal disease and the need to further establish tracer specificity and biological interpretability <i>in vivo</i>. Further multicenter studies will be essential to establish α-synuclein PET as a reliable biomarker for diagnosis, patient stratification, and therapeutic monitoring.</p>","PeriodicalId":12113,"journal":{"name":"Expert Review of Molecular Diagnostics","volume":" ","pages":"453-460"},"PeriodicalIF":4.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147940687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}