Incremental Yield Research Articles

Abstract MP16: Incremental Diagnostic Yield of 4 Weeks versus 2 Weeks of Ambulatory Heart Rhythm Monitoring for the Detection of Subclinical Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Subclinical atrial fibrillation (AF) has been associated with greater stroke risk; however, subclinical AF can be intermittent, and hence hard to detect. Little is known about the diagnostic yield of extending electrocardiogram (ECG) monitoring beyond 2 weeks on subclinical AF detection, particularly among individuals without a clinical indication. Hypothesis: Extending ECG monitoring from 2 weeks to 4 weeks will increase detection of AF Methods: We included ARIC study participants who attended visit 6 (2016-2017), without a history of AF, and who wore a leadless, ambulatory ECG monitor (Zio® XT Patch by iRhythm Technologies Inc.) twice, each time for up to a maximum of 2 weeks. AF history was based on ARIC ascertainment (hospitalization codes through 2016, ECGs at prior ARIC visits 1-5) or self-reported AF at visit 6. AF on the Zio® XT Patch was defined as an irregularly irregular rhythm with absent P-waves lasting ≥30 seconds. Results: We included 387 ARIC participants (mean ± SD aged 79 ± 4 years, 54% female, 11% non-white race). Mean recording time was 13.3 ± 1.7 days for the first Ziopatch, 13.1 ± 2.0 for the second patch, and 26.4 ± 2.9 for the combined 4 weeks. Based on ≤2 weeks of monitoring, the prevalence of subclinical AF was 2.6% (95% CI: 1.0-4.2%; n=10); this increased to 4.4% (95% CI: 2.4-6.4%; n=17) with ≤4 weeks of monitoring. Thus, the incremental diagnostic yield of 4 weeks versus 2 weeks of monitoring was 70% (95% CI: 41.6-98.4%). The mean time to first AF episode was 10.5 ± 8.0 days with a median of 13.4 days (IQR=2.0-19.7). Cumulative yield of AF detection over the monitoring time is shown in the Figure . Conclusions: Among elderly community-dwelling individuals, extending ECG monitoring from 2 weeks to 4 weeks increased detection of AF. These findings help inform the debate on ECG screening for subclinical AF; however, more research is needed to define the optimal duration of ECG monitoring time.

Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy

Purpose:We evaluated whole-genome sequencing (WGS) as an alternative to multi-gene panel sequencing (PS) for genetic testing in dilated cardiomyopathy (DCM).Methods:Forty-two patients with familial DCM underwent PS and WGS, and detection rates of rare single nucleotide variants and small insertions/deletions in panel genes were compared. Loss-of-function variants in 406 cardiac-enriched genes were evaluated, and an assessment of structural variation was performed.Results:WGS provided broader and more uniform coverage than PS, with high concordance for rare variant detection in panel genes. WGS identified all PS-identified pathogenic or likely-pathogenic variants as well as two additional likely-pathogenic variants: one was missed by PS due to low coverage, the other was a known disease-causing variant in a gene not included on the panel. No loss-of-function variants in the extended gene set met clinical criteria for pathogenicity. One BAG3 structural variant was classified as pathogenic.Conclusions –Our data support the use of WGS for genetic testing in DCM, with high variant detection accuracy and a capacity to identify structural variants. WGS provides an opportunity to go beyond suites of established disease genes, but the incremental yield of clinically-actionable variants is limited by a paucity of genetic and functional evidence for DCM association.

Potential for Molecular Testing for Group A Streptococcus to Improve Diagnosis and Management in a High-Risk Population: A Prospective Study.

BackgroundIn high-burden settings, guidelines recommend antibiotic treatment for all suspected group A Streptococcus (GAS) infections to prevent rheumatic fever and poststreptococcal glomerulonephritis. Highly sensitive rapid GAS tests could reduce unnecessary antibiotic use in these settings.MethodsThis was a prospective study of the Xpert Xpress Strep A (Cepheid) molecular test compared with culture of throat swab samples collected at a referral hospital in northern Australia. Demographic and clinical data and results of streptococcal serology and culture were collected.ResultsOf 164 throat swab samples, 145 (88%) were eligible for inclusion; 49 (34%) were molecular test positive and 24 (17%) were culture positive for GAS. The sensitivity, specificity, and positive and negative predictive values for the molecular test versus culture were 100.0%, 79.3%, 48.8%, and 100.0%, respectively. Among 25 samples testing positive with the molecular test and negative with culture, group C or G streptococci were cultured in 2, and a plausible clinical explanation, such as pharyngotonsillitis, or rheumatic fever with positive results of streptococcal serology, was apparent in 19 instances. In 25 patients with rheumatic fever or poststreptococcal glomerulonephritis diagnoses, molecular testing nearly trebled the detection of GAS in throat swab samples, from 3 (12%) detected with culture to 8 (32%) detected with molecular testing. Reasons for “false-positive” molecular test results could include the presence of GAS below the threshold of culture detection or persistence of nonviable organisms after infection.ConclusionImplementation of molecular testing could improve antibiotic use in this high-burden setting. The incremental yield in poststreptococcal syndromes, by which time cultures are negative, has high potential in the diagnostic workup of autoimmune poststreptococcal syndromes and warrants further investigation.

Chromosomal microarray analysis in fetuses with congenital anomalies of the kidney and urinary tract: A prospective cohort study and meta-analysis.

To evaluate the usefulness and incremental diagnostic yield of chromosomal microarray analysis (CMA) compared with standard karyotyping in fetuses with congenital anomalies of the kidney and urinary tract (CAKUT). A prospective cohort study and systematic review of the literature were conducted. In the prospective cohort study, 123 fetuses with CAKUT, as detected by prenatal ultrasound at our center, were enrolled and evaluated using karyotyping and CMA. In the meta-analysis, articles in PubMed and ISI Web of Knowledge databases describing copy number variations (CNVs) in prenatal cases of CAKUT were included. Among the 123 fetuses in our prospective cohort study, 13 fetuses were detected with chromosomal abnormalities or submicroscopic chromosomal abnormalities by both karyotyping and CMA. In the remaining 110 fetuses, four pathogenic CNVs in four fetuses were only detected by CMA, indicating an excess diagnostic yield of 3.6%. Six publications and our own study met the inclusion criteria for the meta-analysis. In total, 615 fetuses with CAKUT were included. The pooled data from all of the reviewed studies indicate that the incremental yield of CMA over karyotyping was 3.8%. The use of CMA provides a 3.8% incremental yield of detecting pathogenic CNVs in fetuses with CAKUT and normal karyotype.

Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study

Identification of chromosomal aneuploidies and copy number variants that are associated with fetal structural anomalies has substantial value. Although whole-exome sequencing (WES) has been applied to case series of a few selected prenatal cases, its value in routine clinical settings has not been prospectively assessed in a large unselected cohort of fetuses with structural anomalies. We therefore aimed to determine the incremental diagnostic yield (ie, the added value) of WES following uninformative results of standard investigations with karyotype testing and chromosomal microarray in an unselected cohort of sequential pregnancies showing fetal structural anomalies. In this prospective cohort study, the parents of fetuses who were found to have a structural anomaly in a prenatal ultrasound were screened for possible participation in the study. These participants were predominantly identified in or were referred to the Columbia University Carmen and John Thain Center for Prenatal Pediatrics (New York, NY, USA). Fetuses with confirmed aneuploidy or a causal pathogenic copy number variant were excluded from WES analyses. By use of WES of the fetuses and parents (parent-fetus trios), we identified genetic variants that indicated an underlying cause (diagnostic genetic variants) and genetic variants that met the criteria of bioinformatic signatures that had previously been described to be significantly enriched among diagnostic genetic variants. Between April 24, 2015, and April 19, 2017, 517 sequentially identified pregnant women found to have fetuses with a structural anomaly were screened for their eligibility for inclusion in our study. 71 (14%) couples declined testing, 87 (17%) trios were missing at least one DNA sample (from either parent or the fetus), 69 (13%) trios had a clinically relevant abnormal karyotype or chromosomal microarray finding, 51 (10%) couples did not consent to WES or withdrew consent, and five (1%) samples were not of good enough quality for analysis. DNA samples from 234 (45%) eligible trios were therefore used for analysis of the primary outcome. By use of trio sequence data, we identified diagnostic genetic variants in 24 (10%) families. Mutations with bioinformatic signatures that were indicative of pathogenicity but with insufficient evidence to be considered diagnostic were also evaluated; 46 (20%) of the 234 fetuses assessed were found to have such signatures. Our analysis of WES data in a prospective cohort of unselected fetuses with structural anomalies shows the value added by WES following the use of routine genetic tests. Our findings suggest that, in cases of fetal anomalies in which assessment with karyotype testing and chromosomal microarray fail to determine the underlying cause of a structural anomaly, WES can add clinically relevant information that could assist current management of a pregnancy. The unique challenges of WES-based prenatal diagnostics require analysis by a multidisciplinary team of perinatal practitioners and laboratory specialists. Institute for Genomic Medicine (Columbia University Irving Medical Center).

Cost-effectiveness of urine-based tuberculosis screening in hospitalised patients with HIV in Africa: a microsimulation modelling study.

Testing urine improves the number of tuberculosis diagnoses made among patients in hospital with HIV. In conjunction with the two-country randomised Rapid Urine-based Screening for Tuberculosis to Reduce AIDS-related Mortality in Hospitalised Patients in Africa (STAMP) trial, we used a microsimulation model to estimate the effects on clinical outcomes and the cost-effectiveness of adding urine-based tuberculosis screening to sputum screening for hospitalised patients with HIV. We compared two tuberculosis screening strategies used irrespective of symptoms among hospitalised patients with HIV in Malawi and South Africa: a GeneXpert assay (Cepheid, Sunnyvale, CA, USA) for Mycobacterium tuberculosis and rifampicin resistance (Xpert) in sputum samples (standard of care) versus sputum Xpert combined with a lateral flow assay for M tuberculosis lipoarabinomannan in urine (Determine TB-LAM Ag test, Abbott, Waltham, MA, USA [formerly Alere]; TB-LAM) and concentrated urine Xpert (intervention). A cohort of simulated patients was modelled using selected characteristics of participants, tuberculosis diagnostic yields, and use of hospital resources in the STAMP trial. We calibrated 2-month model outputs to the STAMP trial results and projected clinical and economic outcomes at 2 years, 5 years, and over a lifetime. We judged the intervention to be cost-effective if the incremental cost-effectiveness ratio (ICER) was less than US$750/year of life saved (YLS) in Malawi and $940/YLS in South Africa. A modified intervention of adding only TB-LAM to the standard of care was also evaluated. We did a budget impact analysis of countrywide implementation of the intervention. The intervention increased life expectancy by 0·5-1·2 years and was cost-effective, with an ICER of $450/YLS in Malawi and $840/YLS in South Africa. The ICERs decreased over time. At lifetime horizon, the intervention remained cost-effective under nearly all modelled assumptions. The modified intervention was at least as cost-effective as the intervention (ICERs $420/YLS in Malawi and $810/YLS in South Africa). Over 5 years, the intervention would save around 51 000 years of life in Malawi and around 171 000 years of life in South Africa. Health-care expenditure for screened individuals was estimated to increase by $37 million (10·8%) and $261 million (2·8%), respectively. Urine-based tuberculosis screening of all hospitalised patients with HIV could increase life expectancy and be cost-effective in resource-limited settings. Urine TB-LAM is especially attractive because of high incremental diagnostic yield and low additional cost compared with sputum Xpert, making a compelling case for expanding its use to all hospitalised patients with HIV in areas with high HIV burden and endemic tuberculosis. UK Medical Research Council, UK Department for International Development, Wellcome Trust, US National Institutes of Health, Royal College of Physicians, Massachusetts General Hospital.

The importance of multiple samples in mycobacterial recovery: A 10-year retrospective study

Instead of the three samples previously recommended, the World Health Organization considered that two sputum samples are sufficient for the diagnosis of pulmonary tuberculosis. Our goal is to evaluate the value of multiple samples in the microscopic and cultural examination of Mycobacterium tuberculosis complex (MTBc) and nontuberculous mycobacteria (NTM). Through a 10-year retrospective study, including 38,887 sputum samples from 11,676 patients, the relative contribution of each sputum specimen for acid-fast bacilli detection and mycobacteria isolation was determined by calculating the yield of the first sample and the incremental yield of the second, third, and more than three samples. With regard to patients with MTBc isolation, we found that 95.2% (435/457) of the cases could be detected in the first and second smear and 97.9% (659/673) in the first and second culture, with a very low increment of the third sample, corresponding to 3.1% (14/457) in smear and 1.3% (9/673) in culture. Among patients with an NTM strain, the percentage of cases detected in the first and second smear and culture was 69% (20/29) and 86.5% (316/365), respectively. In these patients, we found an increment yield of the third sample of 20.7% (6/29) for smear and 10.5% (38/365) for culture. The incremental yield of third and above-third sample for NTM detection was of 31% (9/29) in smear and 13.5% (49 of 365) in culture. We found an added value of multiple samples in NTM recovery. However, our findings suggest that only two samples are required for the diagnosis of pulmonary tuberculosis.

Augmented Endoscopy for Surveillance of Colonic Inflammatory Bowel Disease: Systematic Review With Network Meta-analysis.

Considering the high risk of dysplasia and cancer in inflammatory bowel disease [IBD], surveillance is advocated. However, international guidelines do not reach a uniform recommendation on the way to perform surveillance. We performed a systematic review with a meta-analysis to assess the best endoscopic surveillance strategy in colonic IBD. The systematic review was performed in PubMed/MEDLINE, EMBASE, SCOPUS, and Cochrane databases to identify studies comparing white light endoscopy [WLE] and augmented endoscopy [AE] in the detection of dysplasia/neoplasia in colonic IBD. A sub-analysis between dye-spray chromoendoscopy [DCE], narrow-band imaging [NBI], I-SCAN, full-spectrum endoscopy [FUSE], and auto-fluorescence imaging [AFI] was also performed. Furthermore, a meta-regression and a network meta-analysis were also performed. A total of 27 studies [6167 IBD patients with 2024 dysplastic lesions] met the inclusion criteria. There was no publication bias. AE showed a higher likelihood of detecting dysplasia than WLE (19.3% vs 8.5%, odds ratio [OR] = 2.036), with an incremental yield [IY] of 10.8%. DCE [OR = 2.605] and AFI [OR = 3.055] had higher likelihood of detecting dysplasia than WLE; otherwise, I-SCAN [OR = 1.096], NBI [OR = 0.650], and FUSE [OR = 1.118] were not superior to WLE. Dysplasia was found in 1256/7267 targeted biopsies [17.3%] and in 363/110 040 random biopsies [0.33%] [OR = 66.559, IY = 16.9%]. Meta-regression found no variable impacting on the efficacy of AE techniques. Network meta-analysis identified a significant superiority of DCE to WLE in detecting dysplasia [OR 2.12], but no other single technique was found to be superior to all others in dysplasia detection. DCE was associated with higher likelihood of discovering dysplastic lesions than WLE. Chromoendoscopy is the best supported endoscopic technique for IBD surveillance.

894: Can we predict yield of Chromosomal Microarray in intrauterine growth restriction according to clinical parameters?

Intrauterine growth restriction (IUGR) is a condition in which the fetus fails to achieve its full growth potential. There are various etiologies for IUGR including placental factors, infections, maternal chronic conditions and genetic causes. We aimed to evaluate the yield of Chromosomal Microarray Analysis in different clinical scenarios as well as in pregnancies in which short lone bones were the major finding. Our cohort included 246 cases of pregnancies. In 182 cases IUGR was the prominent feature while in 64 cases fetal short long bones were the prominent feature. CMA analysis was performed for all cases between January 2016 to March 2018. Data were retrieved from the Israeli national database and from patient medical records. In 130 cases data regarding the clinical and familial background and prenatal work-up performed during the pregnancy were available for sub analysis. Data collection is ongoing The mean gestational age at diagnosis was 31.5± 9.4 weeks. The mean measured percentile was 3.8 ± 2.4. In 14 out of 246 cases (5.7%) CMA result was pathogenic/likely pathogenic. In 3 cases (1.2%) a microdeletion/duplication with low penetrance was detected and in 23 cases (9.3%) variables of unknown clinical significance were detected. There were 2 cases of trisomy 18, one case of trisomy 21, one case of triploidy and 10 cases of microdeletions/microduplications 5 of which were detectable by karyotype. In pregnancies in which short long bones were the prominent finding, CMA was positive in 4 cases (6.25% ). In IUGR only cases there were 10 pathological CMA results (5.5%). The yield of CMA was significantly higher for cases with pathological echocardiogram (p=0.003).And was close to reaching clinical significance for IUGR pregnancies, in which the lowest measured percentile was below 1 (p=0.057). There was no significant difference for other parameters such as maternal illness, familial background of genetic conditions, obstetrics history, and prenatal work-up. The yield of CMA for IUGR is 5.7% and is higher in cases with pathological echocardiogram results and in pregnancies in which measured percentiles were below the 1. Other parameters did not reach clinical significance; however, data collection is ongoing, hence the power of such analysis will improve and may reflect additional contributing parameters. The incremental yield of CMA over karyotyping in our cohort karyotype was 64.28%.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Wide-area transepithelial sampling with computer-assisted 3-dimensional analysis (WATS) markedly improves detection of esophageal dysplasia and Barrett's esophagus: analysis from a prospective multicenter community-based study.

SummaryThe 4-quadrant forceps biopsy (FB) protocol for identifying Barrett's esophagus (BE) and esophageal dysplasia (ED) suffers from poor sensitivity due to significant sampling error. We investigated the benefit of wide-area transepithelial sampling with 3-dimensional computer-assisted analysis (WATS) used adjunctively to the combination of random and targeted FB in the detection of ED, and as a secondary outcome, BE. In this multicenter prospective trial, community endoscopists at 21 sites utilized WATS as an adjunct to both targeted and random FB in patients undergoing BE screening and surveillance. Investigators alternated taking FB and WATS samples first. WATS specimens were analyzed at CDx Diagnostics (Suffern, NY) while FB samples were analyzed by each site's regular pathologists. Data were de-identified and then aggregated for analysis. Of 12,899 patients enrolled, FB identified 88 cases of ED, and WATS detected an additional 213 cases missed by FB. These 213 cases represented an absolute increase of 1.65%, raising the yield from 0.68% to 2.33%. Adding WATS to FB increased the overall detection of ED by 242% (95% CI: 191%–315%). Fewer than 61 patients needed to be tested with WATS to identify an additional case of ED. The combination of random and targeted FB identified 1,684 cases of BE, and WATS detected an additional 2,570 BE cases. The absolute incremental yield of adding WATS to FB is 19.9%, increasing the rate of detection from 13.1% to 33%. Adding WATS to FB increased the overall detection of BE by 153% (95% CI: 144–162%). The number needed to test with WATS in order to detect an additional case of BE was 5. Whether FB or WATS was done first did not impact the results. In this study, comprised of the largest series of patients evaluated with WATS, adjunctive use of the technique with targeted and random FB markedly improved the detection of both ED and BE. These results underscore the shortcomings of FB in detecting BE-associated neoplasia, which can potentially impact the management and clinical outcomes of these patients.

Same-day colon capsule endoscopy is a viable means to assess unexplored colonic segments after incomplete colonoscopy in selected patients.

Same-day colon capsule endoscopy (CCE) immediately following incomplete optical colonoscopy (OC) would have a number of advantages for patients, while also presenting unique procedural challenges including the effect of sedation on capsule propulsion and patient tolerance of protracted preparation and fasting. The aim of this article is to prospectively assess the efficacy of same-day CCE after incomplete OC in an unselected patient cohort. This was an observational, prospective, single-centre study of CCE post-incomplete colonoscopies. Patients with an incomplete OC for any reason other than obstruction or inadequate bowel preparation were recruited. CCE was performed after a minimum of a one-hour fast. Once the patient was fully alert, intravenous metoclopramide was administered after capsule ingestion when possible, and a standard CCE booster protocol was then followed. Relevant clinical information was recorded. CCE completion rates, findings and their impact, and adverse events were noted. Fifty patients were recruited, mean age = 57 years and 66% (n = 32) were female. Seventy-six per cent (n = 38) of CCEs were complete; however, full colonic views were obtained in 84% (n = 42) of cases. Patients > 50 years of age were five times more likely to have an incomplete CCE and there was also a trend towards known comorbidities associated with hypomobility having reduced excretion rates. Overall diagnostic yield for CCE in the unexplored segments was 74% (n = 37), with 26% (n = 13) of patients requiring significant changes in management based on CCE findings. The overall incremental yield was 38%. CCE findings were normal 26% (n = 13), polyps 38% (n = 19), inflammation 22% (n = 11), diverticular disease 25 (n = 12), angiodysplasia 3% (n = 1) and cancer 3% (n = 1). Significant small bowel findings were found in three (6%) cases, including Crohn's disease and a neuroendocrine tumour. A major adverse event occurred in one patient (2%), related to capsule retention. Same-day CCE is a viable alternative means to assess unexplored segments of the colon after incomplete OC in selected patients.

Endoscopic ultrasound-guided through-the-needle microforceps biopsy in the evaluation of pancreatic cystic lesions: a multicenter study.

Background and study aims Accurate diagnosis and classification of pancreatic cysts (PCs) remains a challenge. The aims of this study were to: (1) evaluate the safety and technical success of a novel microforceps for EUS-guided through-the-needle biopsy (TTNB) of PCs; and (2) assess its diagnostic yield for mucinous PCs when compared to FNA cyst fluid analysis and cytology. Patients and methods This was a multicenter retrospective analysis of 47 patients who underwent EUS-FNA and TTNB for PCs between January 2014 and June 2017. Technical success was defined as acquisition of a specimen adequate for cytologic or histological evaluation. Cyst fluid carcinoembryonic antigen (CEA) was used to initially categorize cysts as non-mucinous (CEA < 192 ng/mL) or mucinous (CEA ≥ 192 ng/mL). Final diagnosis was based on identifiable mucinous pancreatic cystic epithelium on cytology, microforceps histology and/or surgical histology when available. Results Forty-seven patients with PCs (mean size 30.7 mm) were included. TTNB was successfully performed in 46 of 47 (97.9 %). Technical success was significantly lower with FNA (48.9 %) compared to TTNB (85.1 %) ( P < .001). For cysts with insufficient amount of fluid for CEA (n = 19) or CEA < 192 ng/mL, the cumulative incremental diagnostic yield of a mucinous PC was significantly higher with TTNB vs. FNA (52.6 % vs 18.4 %; P = .004). TTNB alone (34.4 %) diagnosed more mucinous PCs than either CEA ≥ 192 ng/mL alone (6.3 %) or when combined with FNA cytology (9.4 %). One episode of self-limited bleeding (2.1 %) and one of pancreatitis (2.1 %) occurred. Conclusions EUS-TTNB is safe and effective for evaluating PCs. TTNB may help increase the diagnostic yield of mucinous PCs.

Productivity of a Selection of Spindle-grown Plum Varieties During the Full-yield Stage

In the conditions of the Czech Republic, a trial was conducted in 2012–2016 to evaluate the growth and yield of 16 spindle-grown plum varieties grafted on rootstocks St. Julien A, Wangenheim, Wavit and WaxWa. The trial was established in autumn 2005. As to the yield, ‘Tophit’ seems to be an interesting variety. This semi-prune reached high and regular fruit yields (44.1 kg/tree on average) on all rootstocks with the mean fruit weight of 60–70 g. The vigour of ‘Valjevka’ and ‘Cacanska Rana’ trees was significantly weakened by the Wangenheim rootstock compared to St. Julien A. At evaluating the mean fruit weight of ‘Elena’ and ‘Tophit’ varieties, a negative influence of the Wangenheim rootstock on this parameter was observed compared to St. Julien A. The mean fruit weight of the evaluated prunes and semi-prunes varieties ranged from 24.8 g at ‘Top 2000’ (Wavit) to 76.14 g at ‘Cacanska Rana’ (St. Julien A). A positive correlation was proved between trunk increment and fruit yield in the following year at all studied combinations of varieties and rootstocks; the strongest dependence was observed in plum trees on the Wavit rootstock.

Interest of chromosomal microarray analysis in the prenatal diagnosis of fetal intrauterine growth restriction.

The aim of this study is to evaluate the diagnostic utility of prenatal diagnosis using the chromosomal microarray analysis (CMA) for fetuses presenting with isolated or associated intrauterine growth restriction (IUGR). We retrospectively included all fetuses with IUGR referred for prenatal testing and studied by rapid fluorescence in situ hybridization (FISH), karyotype, and CMA. Among the 162 IUGR fetuses (78 associated and 84 isolated IUGR) included, 15 had an abnormal FISH result: 10 associated and five isolated fetal IUGRs. Among the 143 fetuses studied by CMA, 10 (7%) presented pathogenic copy number variations (CNVs). All 10 were in the associated fetal IUGR group (10/65 or 15.4%; 95% confidence interval [CI]: 8.4%-26.2%) versus 0/78 in the isolated fetal IUGR group (95% CI: 0%-5.6%). Six fetuses (4.2%) carried variants of unknown significance (VOUS) (three associated and three isolated fetal IUGRs). Our study highlights the added value of CMA in the case of associated fetal IUGR with an incremental yield of 6.1% (4/65) over karyotyping. No pathogenic CNVs were reported in the isolated fetal IUGR group. More studies must be conducted to determine when and whether CMA would be wisely indicated in this population.

A Survey of Expert Practice and Attitudes Regarding Advanced Imaging Modalities in Surveillance of Barrett's Esophagus.

Published guidelines do not address what the minimum incremental diagnostic yield (IDY) for detection of dysplasia/cancer is required over the standard Seattle protocol for an advanced imaging modality (AIM) to be implemented in routine surveillance of Barrett's esophagus (BE) patients. We aimed to report expert practice patterns and attitudes, specifically addressing the minimum IDY in the use of AIMs in BE surveillance. An international group of BE experts completed an anonymous electronic survey of domains relevant to surveillance practice patterns and use of AIMs. The evaluated AIMs were conventional chromoendoscopy (CC), virtual chromoendoscopy (VC), volumetric laser endomicroscopy (VLE), confocal laser endomicroscopy (CLE), and wide-area transepithelial sampling (WATS3D). Responses were recorded using five-point balanced Likert items and analyzed as continuous variables. The survey response rate was 84% (61/73)-41 US and 20 non-US. Experts were most comfortable with and routinely use VC and CC, and least comfortable with and rarely use VLE, CLE, and WATS3D. Experts rated data from randomized controlled trials (1.4 ± 0.9) and guidelines (2.6 ± 1.2) as the two most influential factors for implementing AIMs in clinical practice. The minimum IDY of AIMs over standard biopsies to be considered of clinical benefit was lowest for VC (15%, IQR 10-29%) and highest for VLE (30%, IQR 20-50%). Compared to US experts, non-US experts reported higher use of CC for BE surveillance (p < 0.001). These results should inform benchmarks that need to be met for guidelines to recommend the routine use of AIMs in the surveillance of BE patients.

Cost-effectiveness of surveillance schedules in older adults with non-muscle-invasive bladder cancer.

ObjectiveTo estimate the cost‐effectiveness of surveillance schedules for non‐muscle‐invasive bladder cancer (NMIBC) amongst older adults.Patients and MethodsWe developed a MIcrosimulation SCreening ANalysis (MISCAN) microsimulation model to compare the cost‐effectiveness of various surveillance schedules (every 3 months to every 24 months, for 2, 5 or 10 years or lifetime) for older adults (aged 65–85 years) with NMIBC. For each surveillance schedule we calculated total costs per patient and the number of quality adjusted life‐years (QALYs) gained. Incremental cost‐effectiveness ratios (ICERs), as incremental costs per QALY gained, were calculated using a 3% discount.ResultsAs age increased, the number of QALYs gained per patient decreased substantially. Surveillance of patients aged 65 years resulted in 2–7 QALYs gained, whereas surveillance at age 85 years led to <1 QALY gained. The total costs of the surveillance schedules also decreased as age increased. The ICER of 6‐monthly surveillance at age 65 years for lifetime was $4999 (American dollars)/QALY gained. Amongst patients aged >75 years, the incremental yield of QALY gains for any increase in surveillance frequency and/or duration was quite modest (<2 QALYs gained).ConclusionWith increasing age, surveillance for recurrences leads to substantially fewer QALYs gained. These data support age‐specific surveillance recommendations for patients treated for NMIBC.

Incremental yield and cost of urine Determine TB-LAM and sputum induction in seriously ill adults with HIV

BackgroundTuberculosis is a major cause of mortality among HIV-infected inpatients, and the World Health Organization (WHO) recommends an algorithm to improve diagnosis. The urine lateral flow lipoarabinomannan (LAM) and sputum Xpert MTB/RIF tests are promising tools, but the optimal diagnostic algorithm is unclear. MethodsThis prospective cohort study enrolled HIV-positive inpatients with cough and WHO danger signs. The Xpert MTB/RIF test and mycobacterial culture were performed on sputum using sputum induction when necessary, and the LAM test was performed on stored urine. Tuberculosis was diagnosed by culture from any site. The diagnostic accuracy and costs of testing were determined for single and combined tests. ResultsTuberculosis was confirmed in 169 of 332 patients (50.9%). The yield of LAM, Xpert MTB/RIF on spontaneous sputum (Xpert Spot), and Xpert MTB/RIF on spontaneous or induced sputum (Xpert SI) was 35.5%, 23.1%, and 90.5%, respectively. When LAM was placed before Xpert Spot and Xpert SI in an algorithm, the yield was 50.9% and 92.3%, respectively. Adding culture to Xpert MTB/RIF only increased the yield by 1.2% and 2.7%, respectively. Use of the LAM test reduced costs. ConclusionsSputum induction is important to increase the yield of Xpert MTB/RIF for seriously ill patients with HIV and cough. LAM testing has little effect on yield when sputum induction is available, but reduces costs and may have other benefits.

The Yield Curve’s Search for the Natural Rate of Interest

Two novel models specify interest rates from factors other than time to demonstrate bond market expectations of riskless rates converge to the natural rate of interest. The first yield curve model is based upon risk rather than time. The riskless rate is the incremental yield for an infinitesimal amount of risk and is computed directly from bond yields. Resulting expected riskless rates are comparable to survey measures of expected short-term rates. Conversely, expected riskless rates for specific periods produce expected bond yields for those periods that also are comparable to survey expectations measures. The model produces a typical concave yield curve shape. The second model aligns with Wicksell’s original conception of a natural rate of interest as determined by productivity of real capital rather than time. The natural rate is the capital factor share of incremental growth from capital investment. The savings/consumption function is determined by equivalence between incremental capital product and forgone consumption, replacing the problematic IS equation. This proxy provides a real rate of interest consistent with short-term yields in the U.S. and other advanced economies, especially when adjusted for central bank intervention. The measure is more stable and easier to estimate than other natural rate measures. This natural rate of interest proxy provides better forecasts of riskless rates over multi-year horizons than do expectations measures. Future yield curves are expected to be flatter and future real rates lower than historical averages.

Comparison of one versus two sputum specimens in the diagnosis of pulmonary tuberculosis

Background: In 2007, the number of sputum smears required for diagnosis of pulmonary tuberculosis was reduced from three to two. In high burden settings such as India, this practice continues to be the referenced standard whilst using smear microscopy. The objective of the study was to assess the plausibility of relying on one sputum smear rather than two serial sputum smears for tuberculosis diagnosis while also examining inter-specimen grading discrepancies.Methods: A retrospective review of tuberculosis specimen registers (2012–2016) to compare sputum positivity and grading for incremental yield. Inter-specimen grading proportions were compared using McNemar’s test.Results: Incremental yield of the second specimen was 9.9% [95% CI 7.3%, 12.6%]. Differences in inter-specimen grading were not significant: nil (p=0.08), scanty (p=0.75), 1+ (p=0.66), 2+ (p=0.39), 3+ (p=0.15). Less than 25% of specimens showed a change in inter-specimen grading when classified as negative, low-grade, or high-grade results.Conclusions: Two serial sputum specimens for the diagnosis of pulmonary tuberculosis remains a valid practice while continuing to rely on conventional smear microscopy. Inter-specimen grading congruencies support further exploration into same-day two-specimen collections to expedite diagnosis.

The clinical utility of cycle of threshold value of GeneXpert MTB/RIF (CBNAAT) and its diagnostic accuracy in pulmonary and extra-pulmonary samples at a tertiary care center in India

BackgroundThere are knowledge gaps in the in-depth analysis of the most promising and robust diagnostic tool, GeneXpert MTB/RIF (CBNAAT). The cycle of threshold (CT) value of the CBNAAT test and its clinical implications has not been explored much. Aims and objectivesThe study aimed at (a) estimating the diagnostic accuracy and incremental yield of Xpert MTB/RIF in various specimens (b) establishing the association between CT value category (high, medium, low, very low) and culture time-to-positivity (TTP). MethodsA total of 1000 samples, both pulmonary and extra-pulmonary were collected from presumptive TB cases in a large tertiary care hospital. Sensitivity and specificity of CBNAAT was calculated with culture as the gold standard. The association of CT value with culture TTP was also studied. ResultsThe overall sensitivity of CBNAAT was 88.5%, with bronchial washing specimen being the most sensitive (92.3%) and pleural fluid being the least (66.7%). In smear negative individuals, the sensitivity of CBNAAT was 80.9%. The additional yield of CBNAAT over smear microscopy was 10.9%. It was observed that as we move from high to very low CT category, culture positivity decreases significantly (p<0.001), whereas time taken for culture growth increases (p<0.001). ConclusionCBNAAT is a robust test for accurate diagnosis of tuberculosis both pulmonary and extra-pulmonary, smear negative as well, especially in resource-limited settings. The correlation between CT value and culture TTP has potential in predicting bacillary load, though further studies are required.