scholarly journals Identifying Optimal Loci for the Molecular Diagnosis of Microsatellite Instability

2020 ◽  
Vol 66 (10) ◽  
pp. 1310-1318
Author(s):  
Dustin R Long ◽  
Adam Waalkes ◽  
Varun P Panicker ◽  
Ronald J Hause ◽  
Stephen J Salipante
Keyword(s):  
Microsatellite Instability ◽  
Sensitivity And Specificity ◽  
Molecular Diagnosis ◽  
Diagnostic Value ◽  
Whole Genome Sequence ◽  
Comparable Performance ◽  
Cancer Types ◽  
Microsatellite Mutation ◽  
Validation Set ◽  
Diagnostic Sensitivity And Specificity

Abstract Background Microsatellite instability (MSI) predicts oncological response to checkpoint blockade immunotherapies. Although microsatellite mutation is pathognomonic for the condition, loci have unequal diagnostic value for predicting MSI within and across cancer types. Methods To better inform molecular diagnosis of MSI, we examined 9438 tumor-normal exome pairs and 901 whole genome sequence pairs from 32 different cancer types and cataloged genome-wide microsatellite instability events. Using a statistical framework, we identified microsatellite mutations that were predictive of MSI within and across cancer types. The diagnostic accuracy of different subsets of maximally informative markers was estimated computationally using a dedicated validation set. Results Twenty-five cancer types exhibited hypermutated states consistent with MSI. Recurrently mutated microsatellites associated with MSI were identifiable in 15 cancer types, but were largely specific to individual cancer types. Cancer-specific microsatellite panels of 1 to 7 loci were needed to attain ≥95% diagnostic sensitivity and specificity for 11 cancer types, and in 8 of the cancer types, 100% sensitivity and specificity were achieved. Breast cancer required 800 loci to achieve comparable performance. We were unable to identify recurrent microsatellite mutations supporting reliable MSI diagnosis in ovarian tumors. Features associated with informative microsatellites were cataloged. Conclusions Most microsatellites informative for MSI are specific to particular cancer types, requiring the use of tissue-specific loci for optimal diagnosis. Limited numbers of markers are needed to provide accurate MSI diagnosis in most tumor types, but it is challenging to diagnose breast and ovarian cancers using predefined microsatellite locus panels.

scholarly journals Accurate Pan-Cancer Molecular Diagnosis of Microsatellite Instability by Single-Molecule Molecular Inversion Probe Capture and High-Throughput Sequencing

2018 ◽  
Vol 64 (6) ◽  
pp. 950-958 ◽  
Author(s):  
Adam Waalkes ◽  
Nahum Smith ◽  
Kelsi Penewit ◽  
Jennifer Hempelmann ◽  
Eric Q Konnick ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Sensitivity And Specificity ◽  
High Throughput ◽  
Single Molecule ◽  
High Throughput Sequencing ◽  
Diagnostic Sensitivity ◽  
Molecular Diagnostic ◽  
Cancer Types ◽  
Diagnostic Sensitivity And Specificity ◽  
Pan Cancer

Abstract BACKGROUND Microsatellite instability (MSI) is an emerging actionable phenotype in oncology that informs tumor response to immune checkpoint pathway immunotherapy. However, there remains a need for MSI diagnostics that are low cost, highly accurate, and generalizable across cancer types. We developed a method for targeted high-throughput sequencing of numerous microsatellite loci with pan-cancer informativity for MSI using single-molecule molecular inversion probes (smMIPs). METHODS We designed a smMIP panel targeting 111 loci highly informative for MSI across cancers. We developed an analytical framework taking advantage of smMIP-mediated error correction to specifically and sensitively detect instability events without the need for typing matched normal material. RESULTS Using synthetic DNA mixtures, smMIPs were sensitive to at least 1% MSI-positive cells and were highly consistent across replicates. The fraction of identified unstable microsatellites discriminated tumors exhibiting MSI from those lacking MSI with high accuracy across colorectal (100% diagnostic sensitivity and specificity), prostate (100% diagnostic sensitivity and specificity), and endometrial cancers (95.8% diagnostic sensitivity and 100% specificity). MSI-PCR, the current standard-of-care molecular diagnostic for MSI, proved equally robust for colorectal tumors but evidenced multiple false-negative results in prostate (81.8% diagnostic sensitivity and 100% specificity) and endometrial (75.0% diagnostic sensitivity and 100% specificity) tumors. CONCLUSIONS smMIP capture provides an accurate, diagnostically sensitive, and economical means to diagnose MSI across cancer types without reliance on patient-matched normal material. The assay is readily scalable to large numbers of clinical samples, enables automated and quantitative analysis of microsatellite instability, and is readily standardized across clinical laboratories.

scholarly journals Acute Aortic Dissection Biomarkers Identified Using Isobaric Tags for Relative and Absolute Quantitation

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Ziya Xiao ◽  
Yuan Xue ◽  
Chenling Yao ◽  
Guorong Gu ◽  
Yaping Zhang ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Sensitivity And Specificity ◽  
Acute Aortic Dissection ◽  
Roc Curves ◽  
Diagnostic Value ◽  
Serum Samples ◽  
Absolute Quantitation ◽  
Isobaric Tags ◽  
Diagnostic Sensitivity And Specificity ◽  
D Dimer

The purpose of this study was to evaluate the utility of potential serum biomarkers for acute aortic dissection (AAD) that were identified by isobaric Tags for Relative and Absolute Quantitation (iTRAQ) approaches. Serum samples from 20 AAD patients and 20 healthy volunteers were analyzed using iTRAQ technology. Protein validation was performed using samples from 120 patients with chest pain. A total of 355 proteins were identified with the iTRAQ approach; 164 proteins reached the strict quantitative standard, and 125 proteins were increased or decreased more than 1.2-fold (64 and 61 proteins were up- and downregulated, resp.). Lumican, C-reactive protein (CRP), thrombospondin-1 (TSP-1), and D-dimer were selected as candidate biomarkers for the validation tests. Receiver operating characteristic (ROC) curves show that Lumican and D-dimer have diagnostic value (area under the curves [AUCs] 0.895 and 0.891,P<0.05). For Lumican, the diagnostic sensitivity and specificity were 73.33% and 98.33%, while the corresponding values for D-dimer were 93.33% and 68.33%. For Lumican and D-dimer AAD combined diagnosis, the sensitivity and specificity were 88.33% and 95%, respectively. In conclusion, Lumican has good specificity and D-dimer has good sensitivity for the diagnosis of AAD, while the combined detection of D-dimer and Lumican has better diagnostic value.

Diagnostic Value of Non-Invasive Prenatal Screening of β-thalassemia by Cell Free Fetal DNA and Fetal NRBC

2019 ◽  
Vol 19 (2) ◽  
pp. 105-111
Author(s):  
Nadia Shafei ◽  
Mohammad Saeed Hakhamaneshi ◽  
Massoud Houshmand ◽  
Siavash Gerayeshnejad ◽  
Fardin Fathi ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
Multiple Displacement Amplification ◽  
Diagnostic Value ◽  
Diagnostic Methods ◽  
Beta Thalassemia ◽  
Non Invasive ◽  
Fetal Dna ◽  
Prenatal Diagnostic ◽  
Cell Free Fetal Dna ◽  
Invasive Techniques

Background: Beta thalassemia is a common disorder with autosomal recessive inheritance. The most prenatal diagnostic methods are the invasive techniques that have the risk of miscarriage. Now the non-invasive methods will be gradually alternative for these invasive techniques. Objective: The aim of this study is to evaluate and compare the diagnostic value of two non-invasive diagnostic methods for fetal thalassemia using cell free fetal DNA (cff-DNA) and nucleated RBC (NRBC) in one sampling community. Methods: 10 ml of blood was taken in two k3EDTA tube from 32 pregnant women (mean of gestational age = 11 weeks), who themselves and their husbands had minor thalassemia. One tube was used to enrich NRBC and other was used for cff-DNA extraction. NRBCs were isolated by MACS method and immunohistochemistry; the genome of stained cells was amplified by multiple displacement amplification (MDA) procedure. These products were used as template in b-globin segments PCR. cff-DNA was extracted by THP method and 300 bp areas were recovered from the agarose gel as fetus DNA. These DNA were used as template in touch down PCR to amplify b-globin gen. The amplified b-globin segments were sequenced and the results compared with CVS resul. Results: The data showed that sensitivity and specificity of thalassemia diagnosis by NRBC were 100% and 92% respectively and sensitivity and specificity of thalassemia diagnosis by cff-DNA were 100% and 84% respectively. Conclusion: These methods with high sensitivity can be used as screening test but due to their lower specificity than CVS, they cannot be used as diagnostic test.

scholarly journals A diabetes risk score for Qatar utilizing a novel mathematical modeling approach to identify individuals at high risk for diabetes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Susanne F. Awad ◽  
Soha R. Dargham ◽  
Amine A. Toumi ◽  
Elsy M. Dumit ◽  
Katie G. El-Nahas ◽  
...  
Keyword(s):  
High Risk ◽  
Sensitivity And Specificity ◽  
Risk Score ◽  
Area Under The Curve ◽  
Diabetes Risk ◽  
Predictive Values ◽  
Predictive Variables ◽  
Comparable Performance ◽  
Representative Random Sample ◽  
Diabetes Risk Score

AbstractWe developed a diabetes risk score using a novel analytical approach and tested its diagnostic performance to detect individuals at high risk of diabetes, by applying it to the Qatari population. A representative random sample of 5,000 Qataris selected at different time points was simulated using a diabetes mathematical model. Logistic regression was used to derive the score using age, sex, obesity, smoking, and physical inactivity as predictive variables. Performance diagnostics, validity, and potential yields of a diabetes testing program were evaluated. In 2020, the area under the curve (AUC) was 0.79 and sensitivity and specificity were 79.0% and 66.8%, respectively. Positive and negative predictive values (PPV and NPV) were 36.1% and 93.0%, with 42.0% of Qataris being at high diabetes risk. In 2030, projected AUC was 0.78 and sensitivity and specificity were 77.5% and 65.8%. PPV and NPV were 36.8% and 92.0%, with 43.0% of Qataris being at high diabetes risk. In 2050, AUC was 0.76 and sensitivity and specificity were 74.4% and 64.5%. PPV and NPV were 40.4% and 88.7%, with 45.0% of Qataris being at high diabetes risk. This model-based score demonstrated comparable performance to a data-derived score. The derived self-complete risk score provides an effective tool for initial diabetes screening, and for targeted lifestyle counselling and prevention programs.

scholarly journals Clinical significance of small molecule metabolites in the blood of patients with different types of liver injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hui Li ◽  
Yan Wang ◽  
Shizhao Ma ◽  
Chaoqun Zhang ◽  
Hua Liu ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Clinical Diagnosis ◽  
Sensitivity And Specificity ◽  
Acid Amide ◽  
Hbv Infection ◽  
Diagnostic Sensitivity ◽  
Future Research ◽  
Diagnostic Efficacy ◽  
Metabolic Markers ◽  
Diagnostic Sensitivity And Specificity

AbstractTo understand the characteristic of changes of serum metabolites between healthy people and patients with hepatitis B virus (HBV) infection at different stages of disease, and to provide reference metabolomics information for clinical diagnosis of liver disease patients. 255 patients with different stages of HBV infection were selected. 3 mL blood was collected from each patient in the morning to detect differences in serum lysophosphatidylcholine, acetyl-l-carnitine, oleic acid amide, and glycocholic acid concentrations by UFLC-IT-TOF/MS. The diagnostic values of four metabolic substances were evaluated by receiver operating characteristic (ROC) curve. The results showed that the optimal cut-off value of oleic acid amide concentration of the liver cirrhosis and HCC groups was 23.6 mg/L, with a diagnostic sensitivity of 88.9% and specificity of 70.6%. The diagnostic efficacies of the three substances were similar in the hepatitis and HCC groups, with an optimal cut-off value of 2.04 mg/L, and a diagnostic sensitivity and specificity of 100% and 47.2%, respectively. The optimal cut-off value of lecithin of the HBV-carrier and HCC groups was 132.85 mg/L, with a diagnostic sensitivity and specificity of 88.9% and 66.7%, respectively. The optimal cut-off value of oleic acid amide of the healthy and HCC groups was 129.03 mg/L, with a diagnostic sensitivity and specificity of 88.4% and 83.3%, respectively. Lysophosphatidylcholine, acetyl-l-carnitine, and oleic acid amide were potential metabolic markers of HCC. Among them, lysophosphatidylcholine was low in the blood of HCC patients, and its diagnostic efficacy was better than that of acetyl-l-carnitine and oleic acid amide, providing reference metabolomics information in clinical diagnosis and future research.

scholarly journals Comparing the Diagnostic Value of Serum D-Dimer to CRP and IL-6 in the Diagnosis of Chronic Prosthetic Joint Infection

2020 ◽  
Vol 9 (9) ◽  
pp. 2917
Author(s):  
Thomas Ackmann ◽  
Burkhard Möllenbeck ◽  
Georg Gosheger ◽  
Jan Schwarze ◽  
Tom Schmidt-Braekling ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
Joint Infection ◽  
Revision Arthroplasty ◽  
Preoperative Assessment ◽  
Diagnostic Value ◽  
Musculoskeletal Infection ◽  
Prosthetic Joint ◽  
The Individual ◽  
Low Sensitivity ◽  
D Dimer

Introduction: D-dimer is a diagnostic criterion for periprosthetic joint infection (PJI) of the Musculoskeletal Infection Society (MSIS) in 2018. The aim of this study was to evaluate the serum D-dimer values in comparison to C-reactive protein (CRP) and interleukin-6 (IL-6) for the diagnosis of PJI. Materials and Methods: We included 119 patients (50 women, 69 men; 71 knees, 48 hips) undergoing revision arthroplasty with preoperative assessment of CRP, IL-6, and serum D-dimer. Cases were classified as infected or aseptic based on the MSIS criteria of 2018. Receiver operating curves and Youden’s index were used to define an ideal cut-off value and sensitivity and specificity for the individual parameters, and respective combinations were calculated using cross-tables. Results: The median D-dimer level (2320 vs. 1105 ng/mL; p < 0.001), the median CRP level (4.0 vs. 0.5 mg/dL; p < 0.001), and the median IL-6 level (21.0 vs. 5.0 pg/mL; p < 0.001) were significantly higher in the group of PJI compared to the group with aseptic failure. The calculated optimal cut-off values were 2750 ng/mL (AUC 0.767) for D-dimer, 1.2 mg/dL (AUC 0.914) for CRP, and 10.0 pg/mL (AUC 0.849) for IL-6. D-dimer showed a sensitivity of 38% and specificity of 94%, whereas the CRP and IL-6 had sensitivities of 88% and 76%, and specificities of 87% and 92%, respectively. Conclusion: In comparison with CRP and IL-6, serum D-dimer showed low sensitivity and specificity in our cohort. While CRP and IL-6 combination had the highest sensitivity, a combination of Il-6 and D-dimer or CRP and IL-6 had the highest specificity.

scholarly journals The diagnostic value of human epididymis protein 4 for endometrial cancer is moderate

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jing Liu ◽  
Lili Han ◽  
Zhen Jiao
Keyword(s):  
Endometrial Cancer ◽  
Sensitivity And Specificity ◽  
Diagnostic Value ◽  
Critical Value ◽  
Chief Complaint ◽  
Human Epididymis Protein 4 ◽  
Human Epididymis ◽  
Clinical Stages ◽  
Spss Software ◽  
Xinjiang Uyghur Autonomous Region

AbstractHuman epididymis protein 4 (HE4) has been used as a biomarker of endometrial cancer (EC) in clinical practice. However, there remains a lack of systemic research on the critical values of HE4 for diagnosing different clinical stages and pathological types of EC. This study investigated the accuracy of human epididymis protein 4 (HE4) in the diagnosis of EC. Patients who were hospitalized for a chief complaint of abnormal vaginal hemorrhage at Xinjiang Uyghur Autonomous Region People's Hospital between 2014 and 2019 were consecutively included. Pathological biopsy confirmed the diagnosis of EC; there were a total of 136 EC patients and 127 non-EC patients. The accuracy of HE4 in the diagnosis of EC was assessed with SPSS software. The accuracy of HE4 for diagnosing different clinical stages and pathological types of EC was also explored. The critical value of HE4 for endometrial cancer was 52.40 mmol/L, with a sensitivity of 57.35% and a specificity of 76.38%. For different stages of EC, the critical value was 36.9 mmol/L, and the sensitivity and specificity were 28% and 87.39%, respectively. For different pathological types, the critical value was 30.60 mmol/L, and the sensitivity and specificity were 93.85% and 33.33%, respectively. The diagnostic value of HE4 for EC is moderate, and the serum HE4 level cannot reflect the stage and type of EC.

Diagnostic accuracy of serum inflammatory markers in late fracture-related infection

2018 ◽  
Vol 100-B (12) ◽  
pp. 1542-1550 ◽  
Author(s):  
J. van den Kieboom ◽  
P. Bosch ◽  
J. D. J. Plate ◽  
F. F. A. IJpma ◽  
R. Kuehl ◽  
...  
Keyword(s):  
Diagnostic Accuracy ◽  
Sensitivity And Specificity ◽  
Inflammatory Markers ◽  
Meta Analysis ◽  
Diagnostic Value ◽  
Mixed Effects Models ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Erythrocyte Sedimentation ◽  
Serum Inflammatory Markers

Aims To assess the diagnostic value of C-reactive protein (CRP), leucocyte count (LC), and erythrocyte sedimentation rate (ESR) in late fracture-related infection (FRI). Materials and Methods PubMed, Embase, and Cochrane databases were searched focusing on the diagnostic value of CRP, LC, and ESR in late FRI. Sensitivity and specificity combinations were extracted for each marker. Average estimates were obtained using bivariate mixed effects models. Results A total of 8284 articles were identified but only six were suitable for inclusion. Sensitivity of CRP ranged from 60.0% to 100.0% and specificity from 34.3% to 85.7% in all publications considered. Five articles were pooled for meta-analysis, showing a sensitivity and specificity of 77.0% and 67.9%, respectively. For LC, this was 22.9% to 72.6%, and 73.5% to 85.7%, respectively, in five articles. Four articles were pooled for meta-analysis, resulting in a 51.7% sensitivity and 67.1% specificity. For ESR, sensitivity and specificity ranged from 37.1% to 100.0% and 59.0% to 85.0%, respectively, in five articles. Three articles were pooled in meta-analysis, showing a 45.1% sensitivity and 79.3% specificity. Four articles analyzed the value of combined inflammatory markers, reporting an increased diagnostic accuracy. These results could not be pooled due to heterogeneity. Conclusion The serum inflammatory markers CRP, LC, and ESR are insufficiently accurate to diagnose late FRI, but they may be used as a suggestive sign in its diagnosis.

scholarly journals Can Serum Glypican-3 Be a Biomarker for Effective Diagnosis of Hepatocellular Carcinoma? A Meta-Analysis of the Literature

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Sheng-Li Yang ◽  
Xiefan Fang ◽  
Zao-Zao Huang ◽  
Xiang-Jie Liu ◽  
Zhi-Fan Xiong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Sensitivity And Specificity ◽  
Meta Analysis ◽  
Diagnostic Value ◽  
Healthy Individuals ◽  
Subgroup Analyses ◽  
Effective Diagnosis ◽  
Diagnostic Index

Objective. This review is to evaluate the diagnostic value of serum GPC3 for hepatocellular carcinoma (HCC) due to conflicting results reported.Methods. NCBI PubMed and Embase were comprehensively searched for studies that have used serum GPC3 level as a diagnostic index for HCC. The quality of the included studies was assessed. Subgroup analyses were conducted to evaluate the sensitivity and specificity of GPC3 as a HCC marker. Statistical analysis was performed with the software STATA version 12.0.Results. A total of 22 studies were included. The qualities of included studies were relatively poor. Among them, 18 studies have shown that serum GPC3 is a specific biomarker for HCC, and the pooled sensitivity and specificity of these studies were 69 and 93%, respectively. The other 4 studies have reported conflicting results, which were not caused by races, infection status of HBV and HCV, or assay reagents but due to one common experimental design of enrolling liver cirrhosis patients as control subjects.Conclusions. This meta-analysis indicates that serum GPC3 is elevated in HCC patients compared with healthy individuals, but more studies are needed to evaluate its effectiveness to differentially diagnose HCC and liver cirrhosis.

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