Equivalent Diagnostic Performance Research Articles

Evaluation of a Digital Handheld Hydrogen Breath Monitor to Diagnose Lactose Malabsorption: Interventional Crossover Study.

BackgroundLactose malabsorption is a common condition that affects a broad segment of the population. Clinical diagnosis based on symptom recall can be unreliable and conventional testing can be inconvenient, requiring expensive laboratory-based equipment and conduction of the testing in a clinical setting.ObjectiveThe aim of this study is to assess the performance of a digital handheld hydrogen breath monitor (GIMate) in diagnosing lactose malabsorption compared to a US Food and Drug Administration (FDA)–cleared device (H2 Check) for the same indication.MethodsAn interventional crossover study was performed in adult participants with a prior confirmed diagnosis of lactose malabsorption or a suspected history of lactose intolerance.ResultsA total of 31 participants (mean age 33.9 years) were enrolled in the study. There was 100% positive percent agreement and 100% negative percent agreement between the GIMate monitor and the H2 Check. Correlation between gastrointestinal symptoms and hydrogen values was positive at 0.82 (P<.001).ConclusionsThe digital handheld GIMate breath monitor achieved equivalent diagnostic performance to that of an FDA-cleared device in the diagnosis of lactose malabsorption.Trial RegistrationClinicalTrials.gov NCT04754724; https://clinicaltrials.gov/ct2/show/NCT04754724

Comparison of microsatellite instability detection by immunohistochemistry and molecular techniques in colorectal and endometrial cancer

DNA mismatch repair deficiency (dMMR) testing is crucial for diagnosing Lynch syndrome and detection of microsatellite unstable (MSI) tumors eligible for immunotherapy. The aim of this study was to compare the relative diagnostic performance of three molecular MSI assays: polymerase chain reaction (PCR), MSI testing by Idylla and next-generation-sequencing (NGS) on 49 tumor samples (28 colorectal and 21 endometrial adenocarcinomas) versus immunohistochemistry (IHC). Discrepancies were investigated by MLH1 methylation analysis and integrated with germline results if available. Overall, the molecular assays achieved equivalent diagnostic performance for MSI detection with area under the ROC curves (AUC) of respectively 0.91 for Idylla and PCR, and 0.93 for NGS. In colorectal cancers with tumor cell percentages ≥ 30% all three molecular assays achieved 100% sensitivity and specificity (AUC = 1) versus IHC. Also, in endometrial cancers, all three molecular assays showed equivalent diagnostic performance, albeit at a clearly lower sensitivity ranging from 58% for Idylla to 75% for NGS, corresponding to negative predictive values from 78 to 86%. PCR, Idylla and NGS show similar diagnostic performance for dMMR detection in colorectal and endometrial cancers. Molecular MSI analysis has lower sensitivity for dMMR detection in endometrial cancer indicating that combined use of both IHC and molecular methods is recommended.Clinical Trial Number/IRB: B1172020000040, Ethical Committee, AZ Delta General Hospital.

Head-to-head comparison of proprietary PPG and single-lead ECG algorithms for atrial fibrillation detection

Abstract Funding Acknowledgements Type of funding sources: None. Background Population based screening for atrial fibrillation (AF) has been suggested to reduce stroke. Photoplethysmography (PPG) deriving smartphone apps and single-lead electrocardiography (ECG) tools are attractive devices for screening due to their low cost, convenience, and accessibility. Automated algorithm analysis can serve as pre-screening or remote monitoring for AF, while confirmation on an ECG trace &amp;gt;30s is required to establish the diagnosis. This work directly compares the performance of proprietary algorithms on PPG vs single-lead ECG for the detection of AF. Purpose To evaluate and compare the diagnostic performance of a PPG-deriving smartphone app and a single-lead ECG-deriving handheld device for AF detection. Methods Patients were recruited from the cardiology ward. After obtaining written informed consent, demographic and medical information were collected. Patients were instructed to perform one measurement using a pulse-deriving smartphone app and one via a single-lead ECG handheld device. A 12-lead electrocardiogram (ECG) was collected and interpreted by a cardiologist as gold standard. Patients with atrial flutter were excluded, with additional exclusions for insufficient quality measurements and unsuccessful measurements resulting due to technical errors. Unclassified single-lead ECG measurements were handled as test-negative. Sensitivity, specificity and accuracy were calculated with respect to the reference diagnosis. McNemar’s analysis was performed to compare the sensitivity and specificity of the proprietary PPG and single-lead ECG AF detection algorithms. Results The median age in the study population (n = 300) was 70 years (interquartile range: 51-78), 56.3% were men, and the median CHA2DS2-VASc was 3 (interquartile range: 1-4) with an AF-prevalence of 32.3%. PPG signal and single‑lead ECG quality was sufficient in 272/300 (91.0%) and 278/298 (93.3%) participants, respectively. After excluding atrial flutter patients (n = 25) and insufficient quality measurements, the sensitivity and specificity were 97.6% (95% CI 93.8 to 99.3) and 94.1% (95% CI 86.8 to 98.1) for the PPG signal versus 95.7% (95% CI 91.4 to 98.3) and 91.1% (95% CI 83.2 to 96.1) for the single‑lead ECG signal, respectively. Results demonstrated a 96.4% (95% CI 93.2 to 98.3) accuracy for PPG and 94.1% (95% CI 90.4 to 96.6) for single-lead ECG. No significant differences in sensitivity (P = 0.453) or specificity (P = 0.219) between the proprietary PPG and single-lead ECG algorithms were found. Conclusion This study demonstrated equivalent diagnostic performance of PPG and single-lead ECG proprietary AF detection algorithms in smartphone apps.

Two-dimensional shear wave elastography and ultrasound-guided attenuation parameter for progressive non-alcoholic steatohepatitis.

We investigated the usefulness of combining two-dimensional shear wave elastography and the ultrasound-guided attenuation parameter for assessing the risk of progressive non-alcoholic steatohepatitis, defined as non-alcoholic steatohepatitis with a non-alcoholic fatty liver disease activity score of ≥4 and a fibrosis stage of ≥2. This prospective study included 202 patients with non-alcoholic fatty liver disease who underwent two-dimensional shear wave elastography, ultrasound-guided attenuation parameter, vibration-controlled transient elastography, the controlled attenuation parameter, and liver biopsy on the same day. Patients were grouped according to liver stiffness measurement using two-dimensional shear wave elastography and the attenuation coefficient, assessed using the ultrasound-guided attenuation parameter: A, low liver stiffness measurement/low attenuation coefficient; B, low liver stiffness measurement/high attenuation coefficient; C, high liver stiffness measurement/low attenuation coefficient; and D, high liver stiffness measurement/high attenuation coefficient. Two-dimensional shear wave elastography and vibration-controlled transient elastography had equivalent diagnostic performance for fibrosis. The areas under the curve of the ultrasound-guided attenuation parameter for identifying steatosis grades ≥S1, ≥S2, and S3 were 0.89, 0.91, and 0.92, respectively, which were significantly better than those of the controlled attenuation parameter (P<0.05). The percentages of progressive non-alcoholic steatohepatitis in Groups A, B, C, and D were 0.0%, 7.7%, 35.7%, and 50.0%, respectively (P<0.001). The prediction model was established as logit (p) = 0.5414 × liver stiffness measurement (kPa) + 7.791 × attenuation coefficient (dB/cm/MHz)-8.401, with area under the receiver operating characteristic curve, sensitivity, and specificity values of 0.832, 80.9%, and 74.6%, respectively; there was no significant difference from the FibroScan-aspartate aminotransferase score. Combined assessment by two-dimensional shear wave elastography and the ultrasound-guided attenuation parameter is useful for risk stratification of progressive non-alcoholic steatohepatitis and may be convenient for evaluating the necessity of specialist referral and liver biopsy.

Accelerated Post-contrast Wave-CAIPI T1 SPACE Achieves Equivalent Diagnostic Performance Compared With Standard T1 SPACE for the Detection of Brain Metastases in Clinical 3T MRI.

Background and Purpose: Brain magnetic resonance imaging (MRI) examinations using high-resolution 3D post-contrast sequences offer increased sensitivity for the detection of metastases in the central nervous system but are usually long exams. We evaluated whether the diagnostic performance of a highly accelerated Wave-controlled aliasing in parallel imaging (Wave-CAIPI) post-contrast 3D T1 SPACE sequence was non-inferior to the standard high-resolution 3D T1 SPACE sequence for the evaluation of brain metastases.Materials and Methods: Thirty-three patients undergoing evaluation for brain metastases were prospectively evaluated with a standard post-contrast 3D T1 SPACE sequence and an optimized Wave-CAIPI 3D T1 SPACE sequence, which was three times faster than the standard sequence. Two blinded neuroradiologists performed a head-to-head comparison to evaluate the visualization of pathology, perception of artifacts, and the overall diagnostic quality. Wave–CAIPI post-contrast T1 SPACE was tested for non-inferiority relative to standard T1 SPACE using a 15% non-inferiority margin.Results: Wave–CAIPI post-contrast T1 SPACE was non-inferior to the standard T1 SPACE for visualization of enhancing lesions (P < 0.01) and offered equivalent diagnostic quality performance and only marginally higher background noise compared to the standard sequence.Conclusions: Our findings suggest that Wave-CAIPI post-contrast T1 SPACE provides equivalent visualization of pathology and overall diagnostic quality with three times reduced scan time compared to the standard 3D T1 SPACE.

Non-hyperaemic pressure ratios to guide percutaneous coronary intervention.

The use of fractional flow reserve (FFR) in guiding revascularisation improves patient outcomes and has been well-established in clinical guidelines. Despite this, the uptake of FFR has been limited, likely attributable to the perceived increase in procedural time and use of hyperaemic agents that can cause patient discomfort. This has led to the development of instantaneous wave-free ratio (iFR), an alternative non-hyperaemic pressure ratio (NHPR). Since its inception, the use of iFR has been supported by an increasing body of evidence and is now guideline recommended. More recently, other commercially available NHPRs including diastolic hyperaemia-free ratio and resting full-cycle ratio have emerged. Studies have demonstrated that these indices, in addition to mean distal coronary artery pressure to mean aortic pressure ratio, are mathematically analogous (with specific nuances) to iFR. Additionally, there is increasing data demonstrating the equivalent diagnostic performance of alternative NHPRs in comparison with iFR and FFR. These NHPRs are now integral within most current pressure wire systems and are commonly available in the catheter laboratory. It is therefore key to understand the fundamental differences and evidence for NHPRs to guide appropriate clinical decision-making.

Comparison of percentage changes in quantitative diffusion parameters for assessing pathological complete response to neoadjuvant therapy in locally advanced rectal cancer: a meta-analysis.

To evaluate and compare the diagnostic performance of percentage changes in apparent diffusion coefficient (∆ADC%) and slow diffusion coefficient (∆D%) for assessing pathological complete response (pCR) to neoadjuvant therapy in patients with locally advanced rectal cancer (LARC). A systematic search in PubMed, EMBASE, the Web of Science, and the Cochrane Library was performed to retrieve related original studies. For each parameter (∆ADC% and ∆D%), we pooled the sensitivity, specificity and calculated the area under summary receiver operating characteristic curve (AUROC) values. Meta-regression and subgroup analyses were performed to explore heterogeneity among the studies on ∆ADC%. 15 original studies (804 patients with 805 lesions, 15 studies on ∆ADC%, 4 of the studies both on ∆ADC% and ∆D%) were included. pCR was observed in 213 lesions (26.46%). For the assessment of pCR, the pooled sensitivity, specificity and AUROC of ∆ADC% were 0.83 (95% confidence intervals [CI] 0.76, 0.89), 0.74 (95% CI 0.66, 0.81), 0.87 (95% CI 0.83, 0.89), and ∆D% were 0.70 (95% CI 0.52, 0.84), 0.81 (95% CI 0.65, 0.90), 0.81 (95% CI 0.77, 0.84), respectively. In the four studies on the both metrics, ∆ADC% yielded an equivalent diagnostic performance (AUROC 0.80 [95% CI 0.76, 0.83]) to ∆D%, but lower than in the studies (n = 11) only on ∆ADC% (AUROC 0.88 [95% CI 0.85, 0.91]). Meta-regression and subgroup analyses showed no significant factors affecting heterogeneity. Our meta-analysis confirms that ∆ADC% could reliably evaluate pCR in patients with LARC after neoadjuvant therapy. ∆D% may not be superior to ∆ADC%, which deserves further investigation.

CT colonography with spectral filtration and advanced modeled iterative reconstruction in the third-generation dual-source CT: image quality, radiation dose and performance in clinical utility

To evaluate image quality, radiation dose and its diagnostic performance in clinical utility of CT colonography (CTC) applying spectral filtration and advanced modeled iterative reconstruction (ADMIRE) techniques in third-generation dual-source CT. A total of 125 patients for screening or diagnostic purposes underwent CTC at 120kVp standard dose (120kVp-STD) with filtered-back projection reconstruction (FBP) in supine position, then at a tin-filtered 150 kVp low dose (Sn150kVp-LD) and a tin-filtered 100 kVp ultra-low dose (Sn100kVp-ULD) with ADMIRE reconstruction in prone position. Radiation metrics were recorded. Objective and subjective image qualities were compared, and the diagnostic performance was assessed for both colonic and extracolonic findings using CTC reporting and data system (C-RADS). The effective dose was significantly lower for Sn150kVp-LD and Sn100kVp-ULD than 120kVp-STD protocol, resulting in 22.5% and 87.5% reductions (1.55±0.30 and 0.25±0.07 mSv vs. 2.00±0.52 mSv; both p<0.01), respectively. Image noise and signal-to-noise ratio were improved significantly for Sn150kVp-LD with ADMIRE compared with 120kVp-STD, both of which had similar excellent 2D and 3D subjective image quality with equivalent diagnostic performance. Sn100kVp-ULD with ADMIRE had decreased subjective image quality and significant different C-RADS extracolonic-score (E-score) compared with 120kVp-STD, however, C-RADS colonic-score (C-score) of that showed no significantly difference. Sn150kVp and Sn100kVp with ADMIRE reconstruction provide an alternative low dose CTC strategy and could be feasible in clinical screening or diagnostic scenarios.

Clinical Usefulness of 18F-FC119S Positron-Emission Tomography as an Auxiliary Diagnostic Method for Dementia: An Open-Label, Single-Dose, Evaluator-Blind Clinical Trial

Background and PurposeThe aim of this study was to determine the diagnostic performance and safety of a new 18F-labeled amyloid tracer, 18F-FC119S.MethodsThis study prospectively recruited 105 participants, comprising 53 with Alzheimer's disease (AD) patients, 16 patients with dementia other than AD (non-AD), and 36 healthy controls (HCs). In the first screening visit, the Seoul Neuropsychological Screening Battery cognitive function test was given to the dementia group, while HC subjects completed the Korean version of the Mini Mental State Examination. Individuals underwent 18F-FC119S PET, 18F-fluorodeoxyglucose (FDG) PET, and brain MRI. The diagnostic performance of 18F-FC119S PET for AD was compared to a historical control (comprising previously reported and currently used amyloid-beta PET agents), 18F-FDG PET, and MRI. The standardized uptake value (SUV) ratio (ratio of the cerebral cortical SUV to the cerebellar SUV) was measured for each PET data set to provide semiquantitative analysis. All adverse effects during the clinical trial periods were monitored.ResultsVisual assessments of the 18F-FC119S PET data revealed a sensitivity of 92% and a specificity of 84% in detecting AD. 18F-FC119S PET demonstrated equivalent or better diagnostic performance for AD detection than the historical control, 18F-FDG PET (sensitivity of 80.0% and specificity of 76.0%), and MRI (sensitivity of 98.0% and specificity of 50.0%). The SUV ratios differed significantly between AD patients and the other groups, at 1.44±0.17 (mean±SD) for AD, 1.24±0.09 for non-AD, and 1.21±0.08 for HC. No clinically significant adverse effects occurred during the trial periods.Conclusions18F-FC119S PET provides high sensitivity and specificity in detecting AD and therefore may be considered a useful diagnostic tool for AD.

Contrast-enhanced CT and texture analysis of mass-forming pancreatitis and cancer in the pancreatic head

Objective: To explore the value of contrast-enhanced CT combined with texture analysis in differentiating pancreatic cancer from mass-forming pancreatitis in pancreatic head. Methods: A retrospective study collected 21 patients with pancreatic head mass-forming pancreatitis confirmed by surgery or biopsy and 47 patients with pancreatic ductal adenocarcinoma confirmed by surgery. The patients visited the Affiliated Hospital of Nanjing University of Chinese Medicine and the First Affiliated Hospital of Wannan Medical College between January 2014 and December 2017. Gender, age and CT findings were collected. The parenchymal phase was selected for texture analysis. The minimum absolute shrinkage and selection operator (LASSO) method was applied for dimensionality reduction.Two independent sample t-tests or Mann-Whitney U test were used for continuous variables based on the Shapiro-Wilks normality test results. Categorical variables were tested by Chi-square or Fisher test. By multivariable regression analysis, CT findings, CT texture analysis, CT findings combined with texture analysis prediction models were established. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of individual indicators and each prediction model. The Delong test was used to compare the area under the curve (AUC) of each model. Results: The CT findings prediction model consisted of CT value of lesion on pancreatic parenchymal phase and pancreatic duct penetrating sign. The texture analysis prediction model consists of root mean square and low grey level run emphasis_angle135. The AUC of them were not statistically different (Z=0.150,P>0.05). The combined predictive model had the better diagnostic performance (AUC 0.944, sensitivity 83.0%, specificity 95.2%, +LR 17.43, -LR 0.18) than CT sign prediction model (Z=2.008, P<0.05) and texture analysis prediction model(Z=2.236, P<0.05) were significantly different. Conclusions: The CT findings model and the texture analysis model have equivalent diagnostic performance in the differentiation of mass-forming pancreatitis and pancreatic cancer. The enhanced CT combined with texture analysis model has the best diagnostic efficiency and can further improve the diagnostic ability.

The diagnostic value of texture analysis in predicting WHO grades of meningiomas based on ADC maps: an attempt using decision tree and decision forest.

The preoperative prediction of the WHO grade of a meningioma is important for further treatment plans. This study aimed to assess whether texture analysis (TA) based on apparent diffusion coefficient (ADC) maps could non-invasively classify meningiomas accurately using tree classifiers. A pathology database was reviewed to identify meningioma patients who underwent tumour resection in our hospital with preoperative routine MRI scanning and diffusion-weighted imaging (DWI) between January 2011 and August 2017. A total of 152 meningioma patients with 421 preoperative ADC maps were included. Four categories of features, namely, clinical features, morphological features, average ADC values and texture features, were extracted. Three machine learning classifiers, namely, classic decision tree, conditional inference tree and decision forest, were built on these features from the training dataset. Then the performance of each classifier was evaluated and compared with the diagnosis made by two neuro-radiologists. The ADC value alone was unable to distinguish three WHO grades of meningiomas. The machine learning classifiers based on clinical, morphological features and ADC value could achieve equivalent diagnostic performance (accuracy = 62.96%) compared to two experienced neuro-radiologists (accuracy = 61.11% and 62.04%). Upon analysis, the decision forest that was built with 23 selected texture features and the ADC value from the training dataset achieved the best diagnostic performance in the testing dataset (kappa = 0.64, accuracy = 79.51%). Decision forest with the ADC value and ADC map-based texture features is a promising multiclass classifier that could potentially provide more precise diagnosis and aid diagnosis in the near future. • A precise preoperative prediction of the WHO grade of a meningioma brings benefits to further treatment plans. • Machine learning models based on clinical, morphological features and ADC value could achieve equivalent diagnostic performance compared to experienced neuroradiologists. • The decision forest model built with 23 selected texture features and the ADC value achieved the best diagnostic performance (kappa = 0.64, accuracy = 79.51%).

18F-FDG and 68Ga-somatostatin analogs PET/CT in patients with Merkel cell carcinoma: a comparison study

BackgroundMerkel cell carcinoma (MCC) is an aggressive neuroendocrine skin tumor. Currently, 18F-fluoro-deoxy-glucose (18F-FDG) PET/CT is the functional imaging modality of choice. Few data are available on the use of 68Ga-somatostatin analogs. The aim of our study was to evaluate and compare the diagnostic performance of 18F-FDG and 68Ga-somatostatin analog PET/CT in MCC patients.ResultsFifteen patients (12 males, 3 females; median age 73 years; range 41–81 years) with histologically proven MCC (4 with unknown primary lesion) who underwent both 18F-FDG and 68Ga-somatostatin analog PET/CT for staging, re-staging, or treatment response assessment were retrospectively evaluated. Results of both studies were qualitatively analyzed and compared on a patient- and lesion-based analysis, using histology or clinical/radiological follow-up as reference standard for final diagnosis. According to final diagnosis, 8/15 patients had at least one MCC lesion and 7/15 had no evidence of disease. On a patient-based analysis, 18F-FDG and 68Ga-somatostatin analogs correctly classified as positive 8/8 (100% sensitivity) patients and as negative 6/7 (85.7% specificity) and 5/7 (71.4% specificity) patients, respectively, with no significant difference. On a lesion-based analysis, 18F-FDG detected 67/75 lesions (89%) and 68Ga-somatostatin analogs 69/75 (92%), with no significant difference. In four patients with unknown primary MCC, both tracers failed to identify the primary MCC site.ConclusionsOur preliminary data suggest that 18F-FDG and 68Ga-somatostatin analog PET/CT provide good and equivalent diagnostic performance, adding interesting insights into the complex MCC biology. However, these results do not suggest that 18F-FDG PET/CT should be replaced by 68Ga-somatostatin receptor imaging, which should be performed in addition, according to clinical indication, to the perspective of “personalized medicine.”

Choice of serum tumor markers in patients with small cell lung cancer: progastrin-releasing peptide, neuron-specific enolase, and carcinoembryonic antigen

Abstract Lung cancer is a leading cause of cancer-related deaths worldwide. It mainly consists of 2 histological types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC, including squamous cell carcinoma and adenocarcinoma). The present study aimed to assess the role of serum progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) and their combinations in the histological diagnosis of lung cancer (specially SCLC), which is of great importance for the initiation of treatment and prognostic implications. Serum ProGRP, NSE, and CEA were determined by the electrochemiluminescence immunoassay (ECLIA) in 66 patients with SCLC, 73 with adenocarcinoma, 44 with squamous cell carcinoma, 45 with non-malignant pulmonary diseases, and 50 healthy controls. Receiver operating characteristic curves were constructed to compare the predictive ability of each biochemical marker and their combined detection models to discriminate among the patients with lung cancers of different histological groups, benign pulmonary diseases and healthy individuals. In the ECLIA detection system, ProGRP showed the sensitivity and specificity for SCLC diagnosis were 71.2% and 91.1% to 93.2%, respectively. Among the markers, the largest area under the ROCs was for ProGRP in discriminating SCLC from benign pulmonary diseases, squamous cell carcinoma and adenocarcinoma (0.815, 0.859, and 0.835, respectively), which indicated that ProGRP was the most efficient marker for identifying SCLC. Besides, ProGRP and NSE exhibited almost equivalent diagnostic performance in discriminating SCLC from benign diseases. As for squamous cell carcinoma, we recommended proGRP, while for adenocarcinoma, the combination of proGRP and CEA was preferred. Remarkably, when ProGRP ≤ 66 pg/mL, CEA was of great value in diagnosing SCLC and adenocarcinoma. If CEA ≤ 5 ng/mL, the patient was at higher risk for SCLC, whereas the patient was more likely to be diagnosed with adenocarcinoma. Our study provided promising information about the diagnostic values of serum ProGRP, NSE, CEA in distinguishing SCLC from benign pulmonary diseases and NSCLC, which was of crucial clinical significance in the early diagnosis and therapy of SCLC.

Breast cancer identification via modeling of peripherally circulating miRNAs.

Prolonged life expectancy in humans has been accompanied by an increase in the prevalence of cancers. Breast cancer (BC) is the leading cause of cancer-related deaths. It accounts for one-fourth of all diagnosed cancers and affects one in eight females worldwide. Given the high BC prevalence, there is a practical need for demographic screening of the disease. In the present study, we re-analyzed a large microRNA (miRNA) expression dataset (GSE73002), with the goal of optimizing miRNA biomarker selection using neural network cascade (NNC) modeling. Our results identified numerous candidate miRNA biomarkers that are technically suitable for BC detection. We combined three miRNAs (miR-1246, miR-6756-5p, and miR-8073) into a single panel to generate an NNC model, which successfully detected BC with 97.1% accuracy in an independent validation cohort comprising 429 BC patients and 895 healthy controls. In contrast, at least seven miRNAs were merged in a multiple linear regression model to obtain equivalent diagnostic performance (96.4% accuracy in the independent validation set). Our findings suggested that suitable modeling can effectively reduce the number of miRNAs required in a biomarker panel without compromising prediction accuracy, thereby increasing the technical possibility of early detection of BC.

Targeted sequencing reveals complex, phenotype-correlated genotypes in cystic fibrosis

BackgroundCystic fibrosis (CF) is one of the most common life-threatening genetic disorders. Around 2000 variants in the CFTR gene have been identified, with some proportion known to be pathogenic and 300 disease-causing mutations have been characterized in detail by CFTR2 database, which complicates its analysis with conventional methods.MethodsWe conducted next-generation sequencing (NGS) in a cohort of 89 adult patients negative for p.Phe508del homozygosity. Complete clinical and demographic information were available for 84 patients.ResultsBy combining MLPA with NGS, we identified disease-causing alleles in all the CF patients. Importantly, in 10% of cases, standard bioinformatics pipelines were inefficient in identifying causative mutations. Class IV-V mutations were observed in 38 (45%) cases, predominantly ones with pancreatic sufficient CF disease; rest of the patients had Class I-III mutations. Diabetes was seen only in patients homozygous for class I-III mutations. We found that 12% of the patients were heterozygous for more than two pathogenic CFTR mutations. Two patients were observed with p.[Arg1070Gln, Ser466*] complex allele which was associated with milder pulmonary obstructions (FVC 107 and 109% versus 67%, CI 95%: 63-72%; FEV 90 and 111% versus 47%, CI 95%: 37-48%). For the first time p.[Phe508del, Leu467Phe] complex allele was reported, observed in four patients (5%).ConclusionNGS can be a more information-gaining technology compared to standard methods. Combined with its equivalent diagnostic performance, it can therefore be implemented in the clinical practice, although careful validation is still required.

Diagnostic performance of point-of-care and central laboratory cardiac troponin assays in an emergency department.

Early diagnosis of myocardial infarction (MI) with cardiac troponin (cTn) assays at the point-of-care (POC) is suggested to shorten turn-around-time in the emergency department (ED). The present study aimed at comparing the diagnostic performance of two POC cTn assays with that of a central laboratory high-sensitivity (hs) method, under routine ED conditions. In 2,163 non-selected ED patients suspected for MI, the diagnostic performance of the POC troponin I (TnI), troponin T (TnT), and hs-TnT assay for the prediction of MI was evaluated based on receiver operating characteristic (ROC) analyses and compared with the performance based on the manufacturers’ cut-offs. Due to an observed association between renal function as determined by estimated glomerular filtration rate (eGFR) and cTn concentrations, all analyses were stratified by renal function. In patients with normal renal function (eGFR > 60 mL/min/1.73m2), POC and hs assays showed a comparable diagnostic performance as quantified by the area under the ROC curve (AUC) of about 0.88. The ROC-derived optimal cut-off (OCO) levels for the different cTn assays clearly changed with decreasing kidney function. Impaired kidney function required OCO to be three to five times higher to achieve a comparable performance. Particularly cTnT concentrations were strongly associated with renal function. The three cTn assays demonstrated equivalent diagnostic performance in ED-patients admitted with suspected ACS in relation to the release diagnosis, supporting the use of POC testing in this setting. The present results implicate that application of eGFR-specific OCOs may decrease false-positives among patients with impaired renal function. Providing individual cut-offs depending on patients’ eGFR might be an appropriate add-on tool to improve specificity in the diagnosis of MI.

Fecal occult blood versus DNA testing: indirect comparison in a colorectal cancer screening population.

BackgroundA multitarget stool DNA test (MSDT) that showed higher sensitivity but lower specificity than a fecal immunochemical test (FIT) for hemoglobin in one recent study from the US and Canada, is increasingly used for colorectal cancer (CRC) screening, despite its ~20-fold higher costs compared to FITs. We aimed to assess diagnostic performance of a quantitative FIT in an independent study among participants of screening colonoscopy and to compare it with the previously reported performance of MSDT.MethodsA total of 3494 participants, aged 50–84 years, who underwent screening colonoscopy in private gastroenterological practices in Germany, and who provided a stool sample before colonoscopy to be evaluated by a commercially available quantitative FIT (FOB Gold®) were included. Diagnostic performance (sensitivity, specificity) for detecting CRC or advanced precancerous lesions (APCLs) was evaluated by comparison of test results with findings at screening colonoscopy. In addition to the original cutoff, we used an adjusted cutoff yielding the same specificity as reported for the MSDT to enhance comparability.ResultsThe most advanced finding at colonoscopy was CRC and APCL in 30 (0.86%) and 359 (10.3%) cases, respectively. At a cutoff yielding the same specificity as reported for MSDT (86.6%), the sensitivities (95% CI) of the FIT for detecting CRC and APCL >1 cm were 96.7% (82.8–99.9%) and 54.3% (48.3–60.3%), respectively. These sensitivities are higher than those reported for MSDT (92.3% and 43.6%, p=0.66 and 0.003, respectively).ConclusionIn this large screening population, FIT showed equivalent or better diagnostic performance in comparison to reported performance of MSDT.

Prognostic value of basal high-sensitive cardiac troponin levels on mortality in the general population: A meta-analysis.

Interest in the use of cardiac troponin T (cTnT) and cardiac troponin I (cTnI) has expanded from diagnosis of acute myocardial infarction to risk assessment for morbidity and mortality. Although cTnT and cTnI were shown to have equivalent diagnostic performance in the setting of suspected acute myocardial infarction, potential prognostic differences are largely unexplored.The aim of this study is to quantify and compare the relationship between cTnT and cTnI, and cardiovascular and all-cause mortality in the general population.Medline, Embase, and the Cochrane Library (from inception through October 2016) were searched for prospective observational cohort studies reporting on the prognostic value of basal high-sensitive cTnT and/or cTnI levels on cardiovascular and all-cause mortality in the general population. Data on study characteristics, participants' characteristics, outcome parameters, and quality [according to the Effective Public Health Practice Project (EPHPP) "Quality Assessment Tool For Quantitative Studies] were retrieved. Hazard ratios per standard deviation increase in basal cardiac troponin level (HR per 1-SD; retrieved from the included articles or estimated) were pooled using a random-effects model.On a total of 2585 reviewed citations, 11 studies, with data on 65,019 participants, were included in the meta-analysis. Random effects pooling showed significant associations between basal cardiac troponin levels and HR for cardiovascular and all-cause mortality [HR per 1-SD 1.29 (95% confidence interval, 95% CI, 1.20-1.38) and HR per 1-SD 1.18 (95% CI, 1.11-1.26), respectively]. Stratified analyses showed higher HRs for cTnT than cTnI [cardiovascular mortality: cTnT HR per 1-SD 1.37 (95% CI, 1.23-1.52); and cTnI HR per 1-SD 1.21 (95% CI, 1.16-1.26); all-cause mortality: cTnT HR per 1-SD 1.31 (955 CI, 1.13-1.53); and cTnI HR per 1-SD 1.14 (95% CI, 1.06-1.22)]. These differences were significant (P < 0.01) in meta-regression analyses for cardiovascular mortality but did not reach statistical significance for all-cause mortality.Elevated, basal cTnT, and cTnI show robust associations with an increased risk of cardiovascular and all-cause mortality during follow-up in the general population.Systematic review registration number PROSPERO CRD42014006964.

Reduced Levels of Tear Lacritin Are Associated With Corneal Neuropathy in Patients With the Ocular Component of Sjögren's Syndrome.

PurposeTo determine whether levels of endogenous tear protein, lacritin, are linked to altered corneal innervation and dry eye severity in patients with Sjögren's syndrome (SS).MethodsClinical data were obtained from 10 SS and 10 age-matched controls. Enzyme-linked immunosorbent assay was used to assess total tear lacritin extracted from Schirmer strips. Western blot was used to detect active lacritin monomer (∼25 kDa), active lacritin fragment (∼12–15 kDa), and inactive tissue transglutaminase–generated lacritin (≥40 kDa). In vivo confocal microscopy was used to assess nerve fiber density (NFD) and length (NFL). Relationships between nerve morphology and tear lacritin were examined by Spearman correlation. Diagnostic performance of tear lacritin was analyzed using receiver operating characteristic.ResultsActive tear lacritin was significantly reduced in SS patients (3.72 ± 5.62 [SS] versus 18.17 ± 4.57 ng/100 ng total tear protein [controls]; P < 0.001), while inactive lacritin was increased (84.99% ± 11.15% [SS] versus 51.04% ± 12.03% [controls]; P < 0.001). Nerve fiber density (21.70 ± 18.93 vs. 31.80 ± 9.35; P = 0.03) and NFL (4.18 ± 3.44 vs. 6.54 ± 2.47; P < 0.05) were significantly decreased in SS patients compared to controls. Reduced NFL (r = 0.74, P < 0.01) and NFD (r = 0.70, P < 0.01) were highly correlated with reduced tear lacritin. Similarly, total tear lacritin was highly correlated with Schirmers (r = 0.77, P < 0.01), ocular staining (r = −0.80, P < 0.01), and corneal sensitivity (r = 0.81, P < 0.01). Tear lacritin showed equivalent or better diagnostic performance compared to traditional clinical measures for SS (100.00% sensitivity, 85.71% specificity, cutoff = 14.50 ng/100 ng tear protein).ConclusionsReduced tear lacritin levels in SS patients are highly correlated with clinical signs of dry eye, as well as decreased NFD and NFL. Lacritin and its components provide excellent diagnostic sensitivity and specificity in SS.

Magnetic Resonance Elastography for the Evaluation of Liver Fibrosis in Chronic Hepatitis B and C by Using Both Gradient-Recalled Echo and Spin-Echo Echo Planar Imaging: A Prospective Study.

Magnetic resonance elastography (MRE) with three-dimensional spin-echo echo planar imaging (3D-SE-EPI) is a newly emerging noninvasive method for assessing liver fibrosis. We hypothesized that 3D-SE-EPI might have better diagnostic accuracy than conventional two-dimensional gradient-recalled echo (2D-GRE). We prospectively included 179 consecutive patients with chronic hepatitis B (CHB) or C (CHC) who underwent both MRE and liver biopsy. Liver stiffness was measured by both 3D-SE-EPI and 2D-GRE for staging biopsy-proven liver fibrosis (using METAVIR scores). A receiver-operating characteristic analysis using the area under the receiver-operating characteristic curve (AUC) was used to compare the diagnostic performance in predicting liver fibrosis between these two techniques, and compared them to serum markers of fibrosis. The technical failure rate of 3D-SE-EPI (2.2%, n=4/179) was lower compared with 2D-GRE (8.3%, n=15/179). The stiffness measured by 3D-SE-EPI was slightly lower compared with 2D-GRE, with the mean difference of 0.57 kPa (Bland and Altman plot, 95% limits of agreement: -0.32 and 1.45 kPa). AUCs for the characterization of ≥F1, ≥F2, ≥F3, and F4 were 0.957 (95% confidence interval (CI): 0.913-0.983), 0.971 (0.932-0.991), 0.991 (0.961-0.999), and 0.979 (0.942-0.995) for 3D-SE-EPI, which was slightly higher compared with the AUCs for 2D-GRE at each fibrosis stage (0.948 (0.901-0.977), 0.959 (0.915-0.981), 0.979 (0.943-0.995), and 0.976 (0.938-0.994), respectively), although none reached statistical significance (P=0.160-0.585). In an "intention-to-diagnose" analysis, the diagnostic accuracy (the proportion of well-classified patients) by EPI (86.7-91.3%, n=169) was higher compared with GRE (80.9-82.1%, n=158) after applying optimal cutoffs. Both 3D-SE-EPI and 2D-GRE performed better than serum fibrosis markers. With respect to 2D-GRE, 3D-SE-EPI has the advantage of lower failure rate with equivalent high diagnostic performance for staging liver fibrosis in CHB/CHC patients, and thus more helpful for those challenging cases in 2D-GRE.