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Surgical Pathology Clinics Sep 2021Pre-analytical factors in molecular oncology diagnostics are reviewed. Issues around sample collection, storage, and transport that might affect the stability of nucleic... (Review)
Review
Pre-analytical factors in molecular oncology diagnostics are reviewed. Issues around sample collection, storage, and transport that might affect the stability of nucleic acids and the ability to perform molecular testing are addressed. In addition, molecular methods used commonly in clinical diagnostic laboratories, including newer technologies such as next-generation sequencing and digital droplet polymerase chain reaction, as well as their applications, are reviewed. Finally, we discuss considerations in designing a molecular test menu to deliver accurate and timely results in an efficient and cost-effective manner.
Topics: High-Throughput Nucleotide Sequencing; Humans; Molecular Diagnostic Techniques; Pathology, Molecular; Polymerase Chain Reaction
PubMed: 34373088
DOI: 10.1016/j.path.2021.05.001 -
American Journal of Clinical Pathology Sep 2021To develop a stochastic model relating measurement uncertainty, including reproducibility, to clinical accuracy, as demonstrated by the receiver operating characteristic...
OBJECTIVES
To develop a stochastic model relating measurement uncertainty, including reproducibility, to clinical accuracy, as demonstrated by the receiver operating characteristic curve.
METHODS
A model is developed based on the symmetric case of the well-known binormal distribution. The overall distribution is partitioned further into analytical and biological components based on assumptions derived from the Cotlove criterion. Explicit mathematical solutions are derived and further verified by Monte Carlo analyses.
RESULTS
The model demonstrates that tests with analytical error that conforms to the classic Cotlove criterion can achieve receiver operating characteristic curves with areas under the curve of 0.68 to 0.76 and Youden indices of 0.26 to 0.38 but have overall agreement for duplicate measurements of only 80% to 82%. Furthermore, the analytically accurate agreement is only 75% to 78%, and the clinically accurate agreement is only 50% to 60%.
CONCLUSIONS
The model suggests that assays may have reasonable clinical accuracy despite having reproducibility of less than 85%. Imperfect assays can substantially improve medical decision-making. The findings must be interpreted with caution given the binormal assumptions, but such assumptions are often useful as a first approximation. Practicing pathologists should feel comfortable performing semiquantitative assays shown to have a strong biological association with clinical outcome.
Topics: Allergy and Immunology; Clinical Decision-Making; Humans; Informatics; Models, Statistical; Monte Carlo Method; Pathologists; Pathology, Molecular; ROC Curve; Reproducibility of Results; Stochastic Processes; Uncertainty
PubMed: 33738478
DOI: 10.1093/ajcp/aqaa267 -
Journal of Cutaneous Pathology Jan 2021Systematic review of amended reports in surgical pathology has been recommended as a valuable exercise in promoting quality assurance and improvement. Examination of... (Review)
Review
BACKGROUND
Systematic review of amended reports in surgical pathology has been recommended as a valuable exercise in promoting quality assurance and improvement. Examination of report amendments can identify defects in the surgical pathology process and inspire new approaches to decreasing error rates and improving overall patient care.
METHODS
We performed a retrospective review of all amended dermatopathology reports over a 1.5-year period at a large academic institution.
RESULTS
During the study period, 86 amended reports out of a total 7950 skin-specific reports were issued (1.08%). Of these amended reports, about 59% (51/86) were because of non-interpretative errors (eg, wrong site, chin vs shin, etc.) while 41% (35/86) were diagnostic misinterpretations. Of these 35, 24 were considered major diagnostic changes while six were minor. Five amendments provided additional diagnostic information. Of those amended reports with diagnostic misinterpretations, 14/35 involved melanocytic lesions, 8/35 involved non-melanoma skin cancers or keratinocyte atypia, 10/35 were inflammatory lesions and 3/35 involved other tumors.
CONCLUSION
Our review points to several quality improvement areas that can be targeted to potentially avoid diagnostic errors in dermatopathology, including standardizing certain anatomic sites to prevent misidentification and seeking out clinicopathologic correlation in challenging melanocytic cases.
Topics: Dermatology; Health Records, Personal; Humans; Pathology, Surgical; Quality Assurance, Health Care; Retrospective Studies; Systematic Reviews as Topic
PubMed: 32740937
DOI: 10.1111/cup.13827 -
Nature Communications Mar 2024Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain...
Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.
Topics: Humans; Alzheimer Disease; Neuropathology; Plasma; Neurofibrillary Tangles; Autopsy; tau Proteins; Biomarkers; Amyloid beta-Peptides
PubMed: 38521766
DOI: 10.1038/s41467-024-46876-7 -
JAMA Neurology Dec 2022There are many known acquired risk factors for cerebral palsy (CP), but in some cases, CP is evident without risk factors (cryptogenic CP). Early CP cohort studies... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
There are many known acquired risk factors for cerebral palsy (CP), but in some cases, CP is evident without risk factors (cryptogenic CP). Early CP cohort studies report a wide range of diagnostic yields for sequence variants assessed by exome sequencing (ES) and copy number variants (CNVs) assessed by chromosomal microarray (CMA).
OBJECTIVE
To synthesize the emerging CP genetics literature and address the question of what percentage of individuals with CP have a genetic disorder via ES and CMA.
DATA SOURCES
Searched articles were indexed by PubMed with relevant queries pertaining to CP and ES/CMA (query date, March 15, 2022).
STUDY SELECTION
Inclusion criteria were as follows: primary research study, case series with 10 or more nonrelated individuals, CP diagnosis, and ES and/or CMA data used for genetic evaluation. Nonblinded review was performed.
DATA EXTRACTION AND SYNTHESIS
Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for assessing data quality and validity. Data were extracted by a single observer.
MAIN OUTCOMES AND MEASURES
A separate meta-analysis was performed for each modality (ES, CMA). The primary outcome was proportion/molecular diagnostic yield (number of patients with a discovered genetic disorder divided by the total number of patients in the cohort), evaluated via meta-analysis of single proportions using random-effects logistic regression. A subgroup meta-analysis was conducted, using risk factor classification as a subgroup. A forest plot was used to display diagnostic yields of individual studies.
RESULTS
In the meta-analysis of ES yield in CP, the overall diagnostic yield of ES among the cohorts (15 study cohorts comprising 2419 individuals from 11 articles) was 23% (95% CI, 15%-34%). The diagnostic yield across cryptogenic CP cohorts was 35% (95% CI, 27%-45%), compared with 7% (95% CI, 4%-12%) across cohorts with known risk factors (noncryptogenic CP). In the meta-analysis of CMA yield in CP, the diagnostic yield of CMA among the cohorts (5 study cohorts comprising 294 individuals from 5 articles) was 5% (95% CI, 2%-12%).
CONCLUSIONS AND RELEVANCE
Results of this systematic review and meta-analysis suggest that for individuals with cryptogenic CP, ES followed by CMA to identify molecular disorders may be warranted.
Topics: Humans; Pathology, Molecular; Cerebral Palsy; Microarray Analysis; Exome Sequencing; DNA Copy Number Variations
PubMed: 36279113
DOI: 10.1001/jamaneurol.2022.3549 -
European Journal of Human Genetics :... Feb 2024Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers...
Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 101 carriers of (likely) pathogenic variants in ten different genes, 57 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached <40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70-100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures.
Topics: Humans; Pathology, Molecular; Neurodevelopmental Disorders; DNA Methylation; Biomarkers
PubMed: 37872275
DOI: 10.1038/s41431-023-01474-x -
European Radiology Dec 2023Accurate prediction of preoperative occult peritoneal metastasis (OPM) is critical to selecting appropriate therapeutic regimen for gastric cancer (GC). Considering the...
OBJECTIVE
Accurate prediction of preoperative occult peritoneal metastasis (OPM) is critical to selecting appropriate therapeutic regimen for gastric cancer (GC). Considering the clinical practicability, we develop and validate a visible nomogram that integrates the CT images and clinicopathological parameters for the individual preoperative prediction of OPM in GC.
METHODS
This retrospective study included 520 patients who underwent staged laparoscopic exploration or peritoneal lavage cytology (PLC) examination. Univariate and multivariate logistic regression results were used to screen model predictors and construct nomograms of OPM risk. The performance of the model was detected by using ROC, accuracy, and C-index. The bootstrap resampling method was considered internal validation of the model. The Delong test was used to evaluate the difference in AUC between the two models.
RESULTS
Grade 2 mural stratification, tumor thickness, and the Lauren classification diffuse were significant predictors of OPM (p < 0.05). The nomogram of these three factors (compared with the original model) showed a higher predictive effect (p < 0.001). The area under the curve (AUC) of the model was 0.830 (95% CI 0.788-0.873), and the internally validated AUC of 1000 bootstrap samples was 0.826 (95% CI 0.756-0.870). The sensitivity, specificity, and accuracy were 76.0%, 78.8%, and 78.3%, respectively.
CONCLUSIONS
CT phenotype-based nomogram demonstrates favorable discrimination and calibration, and it can be conveniently used for preoperative individual risk rating of OPM in GC.
CLINICAL RELEVANCE STATEMENT
In this study, the preoperative OPM prediction model based on CT images (mural stratification, tumor thickness) combined with pathological parameters (the Lauren classification) showed excellent predictive ability in GC, and it is also suitable for clinicians to use rather than limited to professional radiologists.
KEY POINTS
• Nomogram based on CT image analysis can effectively predict occult peritoneal metastasis in gastric cancer (training area under the curve (AUC) = 0.830 and bootstrap AUC = 0.826). • Nomogram model combined with CT features performed better than the original model (established using only clinicopathological parameters) in differentiating occult peritoneal metastasis of gastric cancer.
Topics: Humans; Stomach Neoplasms; Retrospective Studies; Peritoneal Neoplasms; Cytology; Nomograms; Tomography, X-Ray Computed
PubMed: 37414883
DOI: 10.1007/s00330-023-09854-z -
The American Journal of Pathology Oct 2021Significant advances in artificial intelligence (AI), deep learning, and other machine-learning approaches have been made in recent years, with applications found in... (Review)
Review
Significant advances in artificial intelligence (AI), deep learning, and other machine-learning approaches have been made in recent years, with applications found in almost every industry, including health care. AI is capable of completing a spectrum of mundane to complex medically oriented tasks previously performed only by boarded physicians, most recently assisting with the detection of cancers difficult to find on histopathology slides. Although computers will likely not replace pathologists any time soon, properly designed AI-based tools hold great potential for increasing workflow efficiency and diagnostic accuracy in pathology. Recent trends, such as data augmentation, crowdsourcing for generating annotated data sets, and unsupervised learning with molecular and/or clinical outcomes versus human diagnoses as a source of ground truth, are eliminating the direct role of pathologists in algorithm development. Proper integration of AI-based systems into anatomic-pathology practice will necessarily require fully digital imaging platforms, an overhaul of legacy information-technology infrastructures, modification of laboratory/pathologist workflows, appropriate reimbursement/cost-offsetting models, and ultimately, the active participation of pathologists to encourage buy-in and oversight. Regulations tailored to the nature and limitations of AI are currently in development and, when instituted, are expected to promote safe and effective use. This review addresses the challenges in AI development, deployment, and regulation to be overcome prior to its widespread adoption in anatomic pathology.
Topics: Artificial Intelligence; Cloud Computing; Humans; Pathologists; Pathology; Practice Patterns, Physicians'; Social Control, Formal
PubMed: 33245914
DOI: 10.1016/j.ajpath.2020.10.018 -
ACS Applied Bio Materials Oct 2023Sensitive, rapid, and portable molecular diagnostics is the future of disease surveillance, containment, and therapy. The recent SARS-CoV-2 pandemic has reminded us of... (Review)
Review
Sensitive, rapid, and portable molecular diagnostics is the future of disease surveillance, containment, and therapy. The recent SARS-CoV-2 pandemic has reminded us of the vulnerability of lives from ever-evolving pathogens. At the same time, it has provided opportunities to bridge the gap by translating basic molecular biology into therapeutic tools. One such molecular biology technique is CRISPR (clustered regularly interspaced short palindromic repeat) which has revolutionized the field of molecular diagnostics at the need of the hour. The use of CRISPR-Cas systems has been widespread in biology research due to the ease of performing genetic manipulations. In 2012, CRISPR-Cas systems were, for the first time, shown to be reprogrammable, i.e., capable of performing sequence-specific gene editing. This discovery catapulted the field of CRISPR-Cas research and opened many unexplored avenues in the field of gene editing, from basic research to therapeutics. One such field that benefitted greatly from this discovery was molecular diagnostics, as using CRISPR-Cas technologies enabled existing diagnostic methods to become more sensitive, accurate, and portable, a necessity in disease control. This Review aims to capture some of the trajectories and advances made in this arena and provides a comprehensive understanding of the methods and their potential use as point-of-care diagnostics.
Topics: Pathology, Molecular; Gene Editing; CRISPR-Cas Systems; Genetic Therapy; Point-of-Care Testing
PubMed: 37788375
DOI: 10.1021/acsabm.3c00439 -
International Journal of Medical... 2020The advantages of atomic force microscopy (AFM) in biological research are its high imaging resolution, sensitivity, and ability to operate in physiological conditions.... (Review)
Review
The advantages of atomic force microscopy (AFM) in biological research are its high imaging resolution, sensitivity, and ability to operate in physiological conditions. Over the past decades, rigorous studies have been performed to determine the potential applications of AFM techniques in disease diagnosis and prognosis. Many pathological conditions are accompanied by alterations in the morphology, adhesion properties, mechanical compliances, and molecular composition of cells and tissues. The accurate determination of such alterations can be utilized as a diagnostic and prognostic marker. Alteration in cell morphology represents changes in cell structure and membrane proteins induced by pathologic progression of diseases. Mechanical compliances are also modulated by the active rearrangements of cytoskeleton or extracellular matrix triggered by disease pathogenesis. In addition, adhesion is a critical step in the progression of many diseases including infectious and neurodegenerative diseases. Recent advances in AFM techniques have demonstrated their ability to obtain molecular composition as well as topographic information. The quantitative characterization of molecular alteration in biological specimens in terms of disease progression provides a new avenue to understand the underlying mechanisms of disease onset and progression. In this review, we have highlighted the application of diverse AFM techniques in pathological investigations.
Topics: Biomechanical Phenomena; Cell Adhesion; Cytoskeleton; Diabetes Mellitus, Type 2; Extracellular Matrix; Humans; Image Processing, Computer-Assisted; Inflammation; Membrane Proteins; Microscopy, Atomic Force; Molecular Imaging; Pathology, Clinical; Pathology, Molecular
PubMed: 32308537
DOI: 10.7150/ijms.41805