Receiver Operating Characteristic Statistics Research Articles

Extracellular Vesicles for The Diagnosis of Alzheimer's Disease and Related Dementias: A Diagnostic Accuracy Meta‐analysis

AbstractBackgroundAlzheimer’s disease, along with other cognitive disorders such as frontotemporal dementia (FTD), dementia with Lewy body (DLB) Parkinson’s disease dementia (PDD), and vascular cognitive impairment and dementia (VCD), comprise a range of conditions with similar cognitive symptoms but different pathophysiology. Currently, there is no biomarkers to distinguish them before death. The pathophysiological mechanisms differ significantly across these disorders, which implies a varied response to potential treatments. Furthermore, MCI often acts as an early phase, frequently leading to dementia, especially AD. Here, we assessed the diagnostic accuracy of biomarkers in general extracellular vesicles (EVs) and speculative CNS‐enriched EVs using the receiver operating characteristic (ROC) models to discriminate each disorder from one another or from healthy controls (HCs).MethodWe conducted a PRISMA‐guided meta‐analysis on 49 studies to evaluate the diagnostic accuracy of biomarkers in general and speculative CNS‐enriched EVs for AD, FTD, DLB, PDD, VCD, MCI, and HCs, using hierarchical bivariate modeling of ROC statistics. Sub analyses were performed across EV types, mediums (e.g., CSF, plasma, serum, urine, saliva), isolation methods, among others. We also assessed publication bias and the potential number of missing studies with the trim‐and‐fill method and other robust statistical methods.ResultsThe analyses reveal that biomarkers derived from general EVs exhibit better diagnostic accuracy and less heterogeneity, variance, and publication bias than speculative CNS‐enriched EVs for all disease comparisons.ConclusionThese findings suggest that the usage of biomarkers derived from general EVs is superior to those from speculative CNS‐enriched EVs for the diagnosis of dementia.

Addressing the Effect of Intra-Seasonal Variations in Developing Rainfall Thresholds for Landslides: An Antecedent Rainfall-Based Approach

We developed a rainfall threshold model with the objective of limiting the effects of uncertainties typically associated with them, such as a lack of robust landslide database, the selection of the contributing rain gauge, seasonal variations in rainfall patterns, and the effect of extreme rainfall conditions. With the aid of gauge-corrected satellite precipitation data and a landslide database compiled from various sources, separate rainfall thresholds were developed for two waves of the monsoon season in the Western Ghats, India. The daily vs. antecedent rainfall distributions for different scenarios of antecedent rainfall were analyzed for landslide occurrence. The different scenarios considered included 1, 2, 3, 5, 10-, 20-, 30- and 40-day antecedent rainfalls along with the monsoon antecedent defined as the cumulative rainfall from the start of the monsoon to the day prior to landslide occurrence, and the event antecedent defined as the cumulative rainfall from the start of a rainfall event to the day prior to landslide occurrence. A statistically defined critical value was used to define the thresholds for extreme rainfall conditions, while ordinary least squares and quantile regression models were compared to identify the best-fit model for the non-extreme rainfall threshold. Receiver Operating Characteristic (ROC) analysis was performed on all these models and the best model was chosen based on the efficiency values. The daily vs. monsoon antecedent threshold was the best model for the first monsoon wave, and the daily vs. event antecedent model was the best model for the second monsoon wave. A separate rainfall threshold was defined for the entire monsoon without subdivision into separate waves, and corresponding ROC statistics were compared with the former approach to analyze the efficacy of intra-seasonal variations in rainfall threshold development. The results suggest that cumulative rainfall makes a significant contribution towards landslide initiation and that intra-seasonal variations should be necessarily considered in rainfall threshold modeling.

Clinical characteristics and assessment of risk factors in patients with influenza A-induced severe pneumonia after the prevalence of SARS-CoV-2.

The aim of this study is to describe the novel epidemiological and clinical characteristics of influenza A-induced severe pneumonia occurring after the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to further assess its potential risk factors for mortality. We retrospectively studied the consecutive case series of 30 patients with confirmed influenza A-induced severe pneumonia treated in the intensive care unit at Dazhou Central Hospital in Sichuan, China, from March 1 to April 30, 2023. Logistic regression was used to analyze the independent risk factors, and receiver operating characteristic (ROC) curves were applied to evaluate the predictive efficacy of associated risk factors for mortality. The mortality rate was 33.3% in this study. Independent risk factors for mortality of patients were acute respiratory distress syndrome (ARDS) (p = 0.044) and septic shock (p = 0.012). ROC statistics for ARDS and septic shock to predict mortality in patients with influenza A-induced severe pneumonia demonstrated an area under the curve of 0.800 (sensitivity 80.0%, specificity 80.0%) and 0.825 (sensitivity 70.0%, specificity 95.0%), respectively. ARDS and septic shock were the independent risk factors for mortality in patients with influenza A-induced severe pneumonia following the end of the SARS-CoV-2 pandemic. But high level of next generation sequencing reads Aspergillus coinfection, and comorbidities did not increase death risk of the study population.

Expanding the clinical application of the polycystic liver disease questionnaire: determination of a clinical threshold to select patients for therapy

BackgroundPolycystic liver disease (PLD) causes symptoms resulting from cystic volume expansion. The PLD-specific questionnaire (PLD-Q) captures symptom burden. This study aims to develop a threshold to identify patients with symptoms requiring further exploration and possibly intervention. MethodsWe recruited PLD patients with completed PLD-Qs during their patient journey. We evaluated baseline PLD-Q scores in (un)treated PLD patients to determine a threshold of clinical importance. We assessed our threshold's discriminative ability with receiver operator characteristic statistics, Youden Index, sensitivity, specificity, positive and negative predictive value parameters. ResultsWe included 198 patients with a balanced proportion of treated (n=100) and untreated patients (n=98, PLD-Q scores 49 vs 19, p<0.001; median total liver volume 5827 vs 2185 ml, p<0.001). We established the PLD-Q threshold at 32 points. A score of ≥32 differentiates treated from untreated patients with an area under the ROC of 0.856, Youden Index 0.564, sensitivity of 85.0%, specificity of 71.4%, positive predictive value of 75.2%, and negative predictive value of 82.4%. Similar metrics were observed in predefined subgroups and an external cohort. ConclusionWe established the PLD-Q threshold at 32 points with high discriminative ability to identify symptomatic patients. Patients with a score ≥32 should be eligible for treatment or inclusion in trials.

An iOS-based VoiceScreen application: feasibility for use in clinical settings-a pilot study.

To elaborate the application suitable for smartphones for estimation of Acoustic Voice Quality Index (AVQI) and evaluate its usability in the clinical setting. An elaborated AVQI automatization and background noise monitoring functions were implemented into a mobile "VoiceScreen" application running the iOS operating system. A study group consisted of 103 adult individuals with normal voices (n = 30) and 73 patients with pathological voices. Voice recordings were performed in the clinical setting with "VoiceScreen" app using iPhone 8 microphones. Voices of 30 patients were recorded before and 1month after phonosurgical intervention. To evaluate the diagnostic accuracy differentiating normal and pathological voice, the receiver-operating characteristic statistics, i.e., area under the curve (AUC), sensitivity and specificity, and correct classification rate (CCR) were used. A high level of precision of AVQI in discriminating between normal and dysphonic voices was yielded with corresponding AUC = 0.937. The AVQI cutoff score of 3.4 demonstrated a sensitivity of 86.3% and specificity of 95.6% with a CCR of 89.2%. The preoperative mean value of the AVQI [6.01(SD 2.39)] in the post-phonosurgical follow-up group decreased to 2.00 (SD 1.08). No statistically significant differences (p = 0.216) between AVQI measurements in a normal voice and 1-month follow-up after phonosurgery groups were revealed. The "VoiceScreen" app represents an accurate and robust tool for voice quality measurement and demonstrates the potential to be used in clinical settings as a sensitive measure of voice changes across phonosurgical treatment outcomes.

Ultrasound assessment of bladder descent and its correlation with prolapse severity in Chinese women: a prospective multicenter study.

Translabial ultrasound is currently regarded as one of the most promising modalities in the evaluation of female pelvic organ prolapse. However, abnormal bladder descent on pelvic floor ultrasound has not been established among Chinese women. This study aimed to establish optimal cutoffs for defining bladder prolapse among Chinese women using translabial ultrasound. In this prospective multicenter study, 674 women with symptoms of lower urinary tract dysfunction and/or pelvic floor dysfunction were finally included and underwent interview, Pelvic Organ Prolapse Quantification (POP-Q) examinations and 4D translabial ultrasound. The receiver-operating characteristic (ROC) statistic was used to assess accuracy and define the optimal cutoffs. The mean patient age was 42.6 (range, 19-82)years. Multivariable analysis showed that both POP-Q assessment and translabial ultrasound findings for anterior compartment were significantly associated with prolapse symptoms. The ROC statistics suggested an optimal cutoff value of 10mm below the symphysis pubis of bladder position on Valsalva for predicting prolapse symptoms, with an area under the curve (AUC) of 0.73. Compared to translabial ultrasound, POP-Q stage showed similar accuracy for predicting prolapse symptoms (AUC: 0.74; P = 0.79), with an optimal cutoff of POP-Q stage ≥ 2. This study proposed that the descent of the bladder to ≥ 10mm below the symphysis pubis on Valsalva should be proposed as an optimal cutoff value for defining abnormal bladder prolapse on translabial ultrasound among the Chinese population. These cutoff values are nearly identical to those previously established in mainly Caucasian women.

Oxidative stress biomarkers in fetal growth restriction with and without preeclampsia.

Oxidative stress as observed in fetal growth restriction (FGR) and preeclampsia (PE) can be identified by decreased levels of systemic free thiols (FT) and increased levels of plasma ischemia-modified albumin (IMA), which may serve as biomarkers in maternal blood for pregnancy complications. We evaluate the performance of oxidative stress-associated potential biomarkers for FGR and PE, and their relationship with clinical characteristics. A prospective clinical pilot study was performed in healthy controls and women with pregnancies complicated by severe FGR with or without PE. Blood samples were taken directly after inclusion and analyzed for FT; IMA; soluble FMS-like tyrosine kinase-1 (sFlt-1); placenta growth factor (PlGF); and biomarkers like leptin and soluble receptors for advanced glycation end products (sRAGE). Placentas were examined microscopically. Descriptive statistics and receiver operating characteristics statistics were performed. Mothers with both severe FGR and PE had significantly reduced FT levels (p<0.001) and PlGF levels (p<0.001), and increased levels of plasma IMA (p<0.05), sFlt (p<0.001), leptin (p<0.05) and sRAGE (p<0.01) compared to women with FGR only. Systemic FT levels were significantly inversely associated with blood pressure (p<0.01) and plasma IMA (p<0.001), leptin (p=0.01) and sRAGE (p<0.001). Systemic FT and leptin showed significant discriminative ability to differentiate mothers with both FGR and PE from mothers with uncomplicated pregnancies or pregnancies complicated by FGR only. There is a significant discriminative capacity of FT, IMA, leptin and sRAGE that harbor potential as biomarkers of pregnancies complicated by combined FGR and PE.

Impact of tapered-shaped left ventricular outflow tract on permanent pacemaker implantation after the third-generation balloon-expandable valve implantation

Abstract Background In the era of transcatheter aortic valve implantation (TAVI) for patients with lower surgical risk, conduction disturbances requiring permanent pacemaker implantation (PPI) after TAVI remain a serious concern. The association between tapered-shaped left ventricular outflow tract (LVOT) and PPI after TAVI has not been elucidated. Purposes This study sought to identify predictors for PPI after TAVI with the third-generation balloon-expandable valve, with focus on LVOT morphology. Methods Of 272 consecutive patients treated with the third-generation balloon-expandable valve, 256 patients without previous PPI or bicuspid valve were retrospectively analyzed. Results PPI was implanted after TAVI in 20 (7.8%) patients. Patients requiring PPI had smaller LVOT area (356.3 mm2 vs. 399.4 mm2, p=0.011). Moreover, receiver-operating characteristic (ROC) statistics showed that LVOT area /annulus area possessed significantly higher predictive ability than LVOT area (area under the curve: 0.91 [95% confidence interval [CI]: 0.84 to 0.95] vs. 0.67 [95% CI: 0.57 to 0.77], p&amp;lt;0.001). Multivariable analysis revealed LVOT area /annulus area (odds ratio [OR]: 1.93 [95% CI: 1.38–2.71]; p&amp;lt;0.001 per % of decreasing), the difference between membranous septum length and implantation depth (ΔMSID) (OR: 6.82 [95% CI 2.39–19.48]; p&amp;lt;0.001 per mm of decreasing) and pre-existing complete right bundle branch block (CRBBB) (OR: 32.38 [95% CI 2.30–455.63]; p=0.002) as independent predictors of PPI. Further analysis using ROC statistics revealed LVOT area / annulus area of 88.5% and ΔMSID of 1.8 mm as the optimal cutoff points for prediction of PPI after the third-generation balloon-expandable valve implantation, with high negative predictive values of 98.1% and 99.0%, respectively. Figure shows the PPI rates stratified by the number of following predictors: LVOT area /annulus area &amp;lt;88.5%, ΔMSID &amp;lt;1.8 mm and pre-existing CRBBB. Patients with 2 or more predictors had significantly higher PPI rates than those with 1 or less predictor (67% [18 of 27 patients] vs. 1% [2 of 229 patients], p&amp;lt;0.001). Conclusions LVOT area /annulus area, ΔMSID and pre-existing CRBBB were identified as powerful independent predictors for PPI after TAVI. Higher valve implantation is important to prevent excessive PPI especially for patients with pre-procedural tapered-shaped LVOT, short membranous septum or pre-existing CRBBB. PPI rates stratified by predictors Funding Acknowledgement Type of funding source: None

The Evaluation of Prognostic Scores in Spontaneous Intracerebral Hemorrhage in an Asian Population: A Retrospective Study

ObjectiveClinical grading scales used for prognostication in spontaneous intracerebral hemorrhage facilitate informed-decision making for resource-intensive interventions. Numerous clinical prognostic scores are available for spontaneous intracerebral hemorrhage. However, these have not been validated well in Asian patients, and the most appropriate scoring system remains debatable. We evaluated the utility of clinical scores in prognosticating 30-day mortality and 90-day functional outcome in patients with spontaneous intracerebral hemorrhage. Materials and MethodsWe conducted a retrospective review of all patients with spontaneous intracerebral hemorrhage admitted to our tertiary center from December 2014 to May 2016. Data on clinical presentation, imaging, and outcomes were extracted from electronic medical records using a standardized form. The data were analyzed for predictors of outcomes. Performance of prognostic scales was compared using receiver-operator characteristic statistics. ResultsA total of 297 patients were included in the study. Mean age was 60.1 (SD 15.2) years and 190 (64.0%) were male. Thirty-two (10.8%) cases died within 30 days and 177 (62.8%) cases had poor functional outcome (modified Rankin scale of 3 or more) at 90 days. Dialysis dependency (OR=33.54, 95%CI=4.21–325.26, p=0.002), Glasgow coma scale (OR=0.76, 95%CI=0.64–0.88, p=0.001), hematoma volume (OR=1.02, 95%CI=1.00–1.04, p=0.027), and surgical evacuation (OR=0.15, 95%CI=0.02–0.66, p=0.024) were independent predictors for 30-day mortality. The original ICH score (0.862) and the ICH-Grading Scale (0.781) had the highest c-statistic for 30-day mortality and 90-day poor functional outcome respectively. ConclusionsCurrent prognostic scores performed acceptable-to-good in our patient cohort. Future studies may be useful to investigate the utility of these scores in clinical decision-making.

The Screening Value Of ESS, SACS, BQ, And SBQ On Obstructive Sleep Apnea In Patients With Chronic Obstructive Pulmonary Disease.

ObjectiveTo compare the performance of Epworth sleepiness scale (ESS), sleep apnea clinical score (SACS), Berlin questionnaire (BQ), and STOP-BANG questionnaire (SBQ) in screening for obstructive sleep apnea (OSA) in patients with chronic obstructive pulmonary disease (COPD).MethodsA total of 431 patients were analyzed. All subjects completed lung function test, ESS, SACS, BQ, and SBQ survey and overnight polysomnography (PSG). According to lung function and PSG results, participants were divided into COPD with OSA group (OVS, AHI ≥5) and without OSA group (AHI <5). The value of ESS, SACS, BQ, and SBQ was compared in predicting OSA in patients with COPD by receiver-operating characteristic (ROC) curve statistics.ResultsOf the 431 subjects, there were 96 cases in COPD without OSA group, and 335 cases in OVS group including 183, 96, and 56 cases of COPD combined with mild, moderate or severe OSA. In predicting different degrees of severity of OSA in patients with COPD, the value of ESS was poor with all the values of area under the curve (AUC) < 0.7. SACS and BQ had moderate predictive value in screening for severe OSA with the value of AUC of 0.750, 0.735 respectively. However, the SBQ performed best in predicting various degrees of OSA. For screening mild OSA (AHI ≥5), the ROC statistics recommended the cut-off score of SBQ >2 was considered high risk of OSA; the sensitivity, specificity, and AUC were 92.8%, 40.6%, and 0.723 respectively, the odds ratio (OR) was 2.161. When AHI ≥15, AUC for SBQ was 0.737. In predicting severe OSA (AHI ≥30), the ROC curve showed cut-off point, sensitivity, specificity, and AUC for SBQ was >4, 66.1%, 82.1%, and 0.824 respectively; the positive and negative likelihood ratio was 3.70, 0.41 separately, the OR was 2.977.ConclusionSBQ performed better than ESS, SACS, and BQ in predicting OSA in patients with COPD.

Exploring the feasibility of the combination of acoustic voice quality index and glottal function index for voice pathology screening.

The aim of this study was to explore the diagnostic value of the combination of Acoustic Voice Quality Index (AVQI) and Glottal Function Index (GFI) as a screening tool for voice disorders, and to compare the AVQI measurements obtained using oral and smartphone (SP) microphones. A study group consisted of 183 adult individuals including 86 subjects with normal voice and 97 patients with pathological voice. Voice recordings were performed simultaneously with an oral AKG Perception 220 and SP iPhone 6s microphones. To evaluate the diagnostic accuracy differentiating normal and pathological voice, the receiver-operating characteristic statistics [area under curve (AUC), positive and negative likelihood ratios (LR+ and LR-)], and correct classification rate (CCR) were used. The AVQI cut-off scores of 3.31 for oral and 3.32 for SP microphones were associated with very good test accuracy (AUC = 0.857 and AUC = 0.818), resulting in balance between sensitivity and specificity (70.0% vs 86.0% and 70% vs 87.0%). The CCR reached 78%. The combined AVQI and GFI cut-off scores of 6.65 for oral and 7.1 for SP microphones corresponded with excellent test accuracy (AUC = 0.976 and AUC = 0.965) and sensitivity and specificity (93.0% vs 93.0% and 91.0% vs 94%). Very respectable levels of LR+ and LR- both for oral microphone (13.3 and 0.08) and for SP microphone (15.6 and 0.10) voice recordings were achieved. CCRs of 93% and 92% confirmed the results of ROC statistics. Combination of AVQI and GFI measurements significantly improved diagnostic accuracy in differentiating normal vs pathological voice.

Low TREM1 expression in whole blood predicts anti-TNF response in inflammatory bowel disease.

BackgroundWith the changed therapeutic armamentarium for Crohn's disease (CD) and ulcerative colitis (UC), biomarkers predicting treatment response are urgently needed. We studied whole blood and mucosal expression of genes previously reported to predict outcome to anti-TNF therapy, and investigated if the signature was specific for anti-TNF agents.MethodsWe prospectively included 54 active IBD patients (24CD, 30UC) initiating anti-TNF therapy, as well as 22 CD patients initiating ustekinumab and 51 patients initiating vedolizumab (25CD, 26UC). Whole blood expression of OSM, TREM1, TNF and TNFR2 was measured prior to start of therapy using qPCR, and mucosal gene expression in inflamed biopsies using RNA-sequencing. Response was defined as endoscopic remission (SES-CD ≤ 2 at week 24 for CD and Mayo endoscopic sub-score ≤ 1 at week 10 for UC).FindingsBaseline whole blood TREM1 was downregulated in future anti-TNF responders, both in UC (FC = 0.53, p = .001) and CD (FC = 0.66, p = .007), as well as in the complete cohort (FC = 0.67, p < .001). Receiver operator characteristic statistics showed an area under the curve (AUC) of 0.78 (p = .001). A similar accuracy could be achieved with mucosal TREM1 (AUC 0.77, p = .003), which outperformed the accuracy of serum TREM1 (AUC 0.58, p = .31). Although differentially expressed in tissue, OSM, TNF and TNFR2 were not differentially expressed in whole blood. The TREM1 predictive signal was anti-TNF specific, as no changes were seen in ustekinumab and vedolizumab treated patients.InterpretationWe identified low TREM-1 as a specific biomarker for anti-TNF induced endoscopic remission. These results can aid in the selection of therapy in biologic-naïve patients.

Should Genital Hiatus/Perineal Body Be Measured at Rest or on Valsalva?

Genital hiatus (Gh) and perineal body (Pb) are part of the Pelvic Organ Prolapse Quantification assessment system, but it is unclear whether measurements should be taken at rest or on Valsalva. This study was designed to assess the predictive value of Gh and Pb measurements obtained at rest and on Valsalva for signs and symptoms of pelvic organ prolapse (POP). This is a retrospective study involving 416 women who presented to a tertiary urogynecology unit with symptoms of pelvic floor dysfunction. Genital hiatus and Pb were measured at rest and on maximal Valsalva. The strength of association between binary markers of POP and measurements of Gh/Pb was estimated using logistic regression analysis. Receiver operator characteristic statistics were used to compare predictive values of Gh and Pb measurements obtained at rest and on Valsalva. A total of 451 women were seen during the study period. Thirty-five were excluded owing to missing data, leaving 416. Fifty-four percent (n = 223) complained of POP symptoms. On examination, 80% (n = 332) had significant POP (stage 2+ in anterior or posterior compartments or stage 1+ in the central compartment). On imaging, significant POP was diagnosed in 66% (n = 275). Mean hiatal area was 22 cm (SD, 7; range, 5-49 cm) at rest and 30 cm (SD, 10; range, 11-69 cm) on Valsalva. Genital hiatus and Pb measured on Valsalva were consistently stronger predictors of prolapse symptoms and objective prolapse (by clinician examination and by ultrasound) than at Gh and Pb measured at rest. The corresponding area under the curve values were significantly larger for Gh/Pb measures on Valsalva after adjusting for multiple confounders. Genital hiatus/Pb measured on maximal Valsalva is a superior predictor of symptoms and signs of POP compared with Gh/Pb at rest.

Abstract LB-220: An automated breast cancer detection assay for screening in the developing world

Abstract Introduction: Breast cancer incidence is rapidly increasing globally with 1.7 million new cases and 600,000 deaths due to the disease annually. Death due to breast cancer is four to six times more frequent in the developing world compared to the USA due to lack of early detection, definitive diagnosis, and limited access to treatment. Ultrasound imaging for early detection and ultrasound guided fine needle aspiration (FNA) of suspicious lesions followed by an automated, cartridge-based analysis of methylated genes could triage malignancies for faster pathology assessment and treatment, thus enabling better use of scarce resources. Experimental Procedures: To identify a panel of methylated DNA markers to enable sensitive and specific detection of malignant breast lesions, we screened 24 methylated genes (known to be frequently methylated in malignant breast tissue and unmethylated in normal breast tissue) by Quantitative Multiplex Methylation-Specific PCR (QM-MSP) analysis. Formalin-fixed paraffin-embedded (FFPE) sections of biopsies of both benign and malignant breast lesions from the USA, China and South Africa were analyzed. Samples were divided into Training and Test sets. The Training set consisted of 206 tissues [66 invasive ductal carcinoma (IDC), 30 ductal carcinoma in situ (DCIS), 99 benign breast disease (BBD) and 11 normal breast (NB)]. The gene panel selected in the Training set was examined in an independent Test set of tissues (n=204) [65 IDC, 29 DCIS, 99 BBD and 11 NB]. Further, we optimized the technical performance of an automated, prototype breast cancer detection cartridge system for quantitative assessment of gene methylation and tested it in pilot study using FNA samples from breast cancers. Results: Analysis of the tissues in the Training set (n=206) led to the selection of a panel of 10 genes highly methylated in malignant lesions with little or no methylation in benign lesions. For the 10-gene panel to achieve a sensitivity greater than 90%, a laboratory cutoff of 14.5 cumulative methylation (CM) units (out of a possible 10,000 units) was set. In the Training set, the 10-gene panel achieved a sensitivity of 90% and a specificity of 85% with receiver operating characteristic (ROC) statistics: ROC, AUC= 0.947. In a blinded Test set of tissue samples (n=204), with a laboratory cutoff of 14.5 CM units, the 10-gene panel achieved a sensitivity of 87% and a specificity of 89%, with ROC statistics: p&amp;lt;0.001, AUC= 0.936, and provided significant accuracy for breast cancers from three countries and all molecular subtypes. In a pilot study of FNA samples using the cartridge system, robust methylation in all ten genes was detected in malignant tumors. Conclusions: QM-MSP of breast lesions led to the selection of a panel of 10 genes methylated for detection of breast cancer. We have validated the technical performance of an automated, prototype cartridge system. The study reveals the potential of methylation markers to provide fast, accurate and automated cancer detection at a low cost in developing regions globally. Research Use Only. Not for diagnostic tests. A sponsored research agreement from Cepheid to Dr. Sukumar's Lab at Johns Hopkins University. Citation Format: Bradley M. Downs, Mary Jo Fackler, Claudia Mercado-Rodriguez, Ashley Cimino-Mathews, Chuang Chen, Jing-Ping Yuan, Eunice van den Berg, Leslie M. Cope, Susan C. Harvey, Syed Z. Ali, Suzana Tulac, Kriszten J. Kocmond, Edwin W. Lai, Brian Rhees, Mike Bates, Saraswati Sukumar. An automated breast cancer detection assay for screening in the developing world [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-220.

Optimised ARID1A immunohistochemistry is an accurate predictor of ARID1A mutational status in gynaecological cancers.

ARID1A is a tumour suppressor gene that is frequently mutated in clear cell and endometrioid carcinomas of the ovary and endometrium and is an important clinical biomarker for novel treatment approaches for patients with ARID1A defects. However, the accuracy of ARID1A immunohistochemistry (IHC) as a surrogate for mutation status has not fully been established for patient stratification in clinical trials. Here we tested whether ARID1A IHC could reliably predict ARID1A mutations identified by next‐generation sequencing. Three commercially available antibodies – EPR13501 (Abcam), D2A8U (Cell Signaling), and HPA005456 (Sigma) – were optimised for IHC using cell line models and human tissue, and screened across a cohort of 45 gynaecological tumours. IHC was scored independently by three pathologists using an immunoreactive score. ARID1A mutation status was assessed using two independent sequencing platforms and the concordance between ARID1A mutation and protein expression was evaluated using Receiver Operating Characteristic statistics. Overall, 21 ARID1A mutations were identified in 14/43 assessable tumours (33%), the majority of which were predicted to be deleterious. Mutations were identified in 6/17 (35%) ovarian clear cell carcinomas, 5/8 (63%) ovarian endometrioid carcinomas, 2/5 (40%) endometrial carcinomas, and 1/7 (14%) carcinosarcomas. ROC analysis identified greater than 95% concordance between mutation status and IHC using a modified immunoreactive score for all three antibodies allowing a definitive cut‐point for ARID1A mutant status to be calculated. Comprehensive assessment of concordance of ARID1A IHC and mutation status identified EPR13501 as an optimal antibody, with 100% concordance between ARID1A mutation status and protein expression, across different gynaecological histological subtypes. It delivered the best inter‐rater agreement between all pathologists, as well as a clear cost‐benefit advantage. This could allow patients to be accurately stratified based on their ARID1A IHC status into early phase clinical trials.

Abstract P6-03-07: An automated DNA methylation assay (QM-MSP) for rapid breast cancer diagnosis in underdeveloped countries

Abstract BACKGROUND: Underdeveloped countries reported 882,900 new cases of breast cancer and 324,000 deaths in 2012, likely to be a gross underestimation according to recent reports. Often, mammography screening is not available, primary care services are limited, and pathology and treatment services are available only in the regional hospitals. Because of the lack of access to diagnostic and treatment services, it is estimated that more than 90% of patients with breast cancer never present for medical treatment. To address this situation, an accurate, easy-to-perform diagnostic test appropriate for use in remote clinics is desperately needed. Johns Hopkins (JH) and Cepheid partnered to translate a robust Quantitative Multiplex Methylation-Specific PCR (QM-MSP) assay to an automated, cartridge-based system that provides quantitative measures of DNA methylation within hours of fine needle aspiration or core biopsy of image-detected suspicious lesions. METHODS: With a goal of discriminating malignant from benign breast disease with high sensitivity and specificity, we evaluated 24 breast cancer-specific DNA methylation markers (selected through comprehensive methylome analysis) in 119 invasive ductal carcinomas and 186 benign breast tissues. QM-MSP was performed on sections of formalin-fixed paraffin-embedded (FFPE) tissues to quantify DNA methylation. The dynamic range and performance of quantitative methylation detection was tested using a subset of 9 genes in the cartridge-based system. RESULTS: QM-MSP was performed in a Training set consisting of 93 tissues [n=43 IDC, n=50 benign lesions (25 usual ductal hyperplasia, UDH, and 25 papilloma)] from the US. We selected 9 DNA markers significantly (p&amp;lt;0.05) more methylated in malignant compared to benign lesions, which had low or no methylation. An independent Test set consisted of benign (n=26) and malignant (n=10) tissues (mostly Caucasian; JH Test Set). As a panel, the 9 markers were significantly more methylated in malignant than benign tissue (p&amp;lt;0.001), revealing a sensitivity of 90% and specificity of 92%, using a laboratory cutoff of 9.5 CMI units (900 unit scale) based on receiver operator characteristic statistics (ROC; p&amp;lt;0.0001, AUC=0.977). To determine if the markers characterized in the JH Test Set could perform as well in samples from a different geography, the panel was tested on 176 tissues from Wuhan, China (China Test Set). In this cohort (66 IDC and 110 benign tissues - 49 fibroadenoma, 19 benign cyst, 12 UDH, 30 papilloma), sensitivity was 89% and specificity was 89% for detection of breast cancer with ROC AUC=0.945. An advanced version of the cartridge with up to 12 methylated DNA markers is under development, thus far showing robust signals in cancer and low background in benign tissues. Current work at JH is focused on optimizing the technical performance of the cartridge. CONCLUSIONS: We identified a panel of methylated DNA markers that discriminate malignant from benign breast lesions and built a prototype automated cartridge-based assay with promising sensitivity and specificity for breast cancer. Such an assay has the potential to aid in specimen triage in the pathology lab and provide fast, low cost and accurate diagnosis of breast cancer in LMIC settings. Citation Format: Fackler MJ, Downs BM, Mercado-Rodriguez C, Cimino-Mathews A, Chen C, Yuan J, Cope LM, Kohlway A, Kocmond K, Lai E, Weidler J, Visvanathan K, Umbricht CB, Harvey S, Wolff AC, Bates M, Sukumar S. An automated DNA methylation assay (QM-MSP) for rapid breast cancer diagnosis in underdeveloped countries [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-07.

Prolapse assessment supine and standing: do we need different cutoffs for "significant prolapse"?

Translabial ultrasound (TLUS) has shown good correlations between clinical examination and imaging findings in the supine position, and limits of normality have been described. This is not the case for imaging in the standing position. This study was designed to test the hypothesis that different cutoff values are required for imaging in the standing position. This was a retrospective study carried out in a tertiary urogynecological unit in women presenting with symptoms of lower urinary tract and pelvic floor dysfunction between August 2013 and December 2015. All women underwent a standardized interview, 4D TLUS and a POP-Q assessment. Organ descent on ultrasound was measured relative to the postero-inferior margin of the symphysis pubis (SP) on maximal Valsalva in the supine and standing positions. Receiver operator characteristic (ROC) statistics were used to determine optimal cutoffs for "normal" pelvic organ support. We assessed 243 data sets. Mean patient age was 57 years. Prolapse symptoms were reported by 59.2%, and POP of stage ≥ 2 was found in 82.3%. On analysing imaging data sets obtained in the standing position, we obtained similar cutoff values to those established previously for supine imaging, using ROC statistics. The levator hiatus distended significantly more on Valsalva in the standing position compared with supine, and on ROC analysis we identified a new optimal cutoff of 29 cm2. Established cutoffs for supine imaging of organ descent are suitable for imaging in the standing position. Hiatal distensibility may require a higher cutoff of 29 cm2.

Saliva Urea Nitrogen Continuously Reflects Blood Urea Nitrogen after Acute Kidney Injury Diagnosis and Management: Longitudinal Observational Data from a Collaborative, International, Prospective, Multicenter Study

Background: Acute kidney injury (AKI) is a growing global concern and often reversible. Saliva urea nitrogen (SUN) measured by a dipstick may allow rapid diagnosis. We studied longitudinal agreement between SUN and blood urea nitrogen (BUN) and the diagnostic performance of both. Methods: Agreement between SUN and BUN and diagnostic performance to diagnose AKI severity in AKI patients in the United States and Brazil were studied. Bland-Altman analysis and linear mixed effects models were employed to test the agreement between SUN and BUN. Receiver operating characteristics statistics were used to test the diagnostic performance to diagnose AKI severity. Results: We found an underestimation of BUN by SUN, decreasing with increasing BUN levels in 37 studied patients, consistent on all observation days. The diagnostic performance of SUN (AUC 0.81, 95% CI 0.63-0.98) was comparable to BUN (AUC 0.85, 95% CI 0.71-0.98). Conclusion: SUN reflects BUN especially in severe AKI. It also allows monitoring treatment responses. Video Journal Club ‘Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=445041.

What is abnormal uterine descent on translabial ultrasound?

Ultrasound is increasingly used in evaluating women with pelvic floor dysfunction, including quantification of pelvic organ prolapse (POP). The aim of this study was to define the optimal cutoff for uterine descent on translabial ultrasound (TLUS) to predict symptoms of prolapse. This was a retrospective study of patients seen for lower urinary tract symptoms and/or POP at a tertiary urogynecological center. All patients underwent a standardized interview, 4D TLUS and the International Continence Society Pelvic Organ Prolapse Quantification system (ICS POP-Q) assessment. Pelvic organ descent on US was measured relative to the posteroinferior margin of the symphysis pubis (SP) on maximum Valsalva. Receiver operator characteristic (ROC) statistics was used to determine the optimal cutoff. We assessed 538 data sets. Mean patient age was 53years (range 18-88). Prolapse symptoms were reported by 263 (49%). Clinically significant POP, i.e., ICS POP-Q stage ≥2 was found in 74.5%. This comprised a cystocele in 322, uterine prolapse in 63, enterocele in ten, and rectocele in 280 women. On TLUS, mean uterine position on Valsalva was 14.3mm above the SP. Prolapse symptoms were strongly associated with uterine descent (20.7mm vs 7.6mm, P < 0.001). Using ROC statistics with and without excluding women with a dominant prolapse in other compartments, +15mm was found to be the optimal cutoff for predicting symptoms of prolapse, with areas under the curve of 0.68 and 0.74, respectively. An optimal cutoff to predict prolapse symptoms due to uterine descent is a cervix descending to 15mm above the symphysis pubis on maximum Valsalva.

Predicting Endoscopic Disease Activity in Crohn's Disease: A New and Validated Noninvasive Disease Activity Index (The Utrecht Activity Index).

Mucosal healing is presently considered one of the primary goals in treatment of Crohn's disease (CD), but this can only be confirmed by endoscopy. We aimed to design and validate a new disease activity index based on a combination of clinical characteristics and readily available laboratory parameters, which reliably predicts the presence and severity of endoscopic disease activity in patients with CD. Thirteen clinical characteristics and laboratory variables were selected for analysis. Endoscopic disease activity was assessed by the Crohn's disease Endoscopic Index of Severity. A linear regression model was based on 93 ileocolonoscopies performed in 82 patients with CD and internally validated by bootstrap resampling. Subsequently, the newly developed model was validated in a cohort of 99 patients. The number of liquid stools during 1 day × 0.25 + C-reactive protein (in milligrams per liter) × 0.1 + platelet count (× 10(9)/L) × 0.01 + fecal calprotectin (in milligrams per liter) × 0.001 - mean platelet volume (in femtoliters) × 0.2 optimally predicted the severity of endoscopic disease activity (bootstrap adjusted R2 = 0.50). The model demonstrated good agreement in the external validation (r = 0.7), especially for (ileo)colonic CD (r = 0.8). Using receiver operator characteristic statistics, a cutoff point of 3 on the new index indicated endoscopic disease activity with a sensitivity of 80% and a specificity of 92%. This newly developed, noninvasive, index was found to reliably predict endoscopic disease activity in patients with CD. This tool can facilitate clinical decision making and might prove valuable in clinical trials.