Comparative Diagnostic Accuracy Studies Research Articles

Comparison of targeted next-generation sequencing and metagenomic next-generation sequencing in the identification of pathogens in pneumonia after congenital heart surgery: a comparative diagnostic accuracy study

BackgroundThis study aimed to compare targeted next-generation sequencing (tNGS) with metagenomic next-generation sequencing (mNGS) for pathogen detection in infants with severe postoperative pneumonia after congenital heart surgery.MethodsWe conducted a retrospective observational study using data from the electronic medical record system of infants who developed severe pneumonia after surgery for congenital heart disease from August 2021 to August 2022. Infants were divided into tNGS and mNGS groups based on the pathogen detection methods. The primary outcome was the efficiency of pathogen detection, and the secondary outcomes were the timeliness and cost of each method.ResultsIn the study, 91 infants were included, with tNGS detecting pathogens in 84.6% (77/91) and mNGS in 81.3% (74/91) of cases (P = 0.55). No significant differences were found in sensitivity, specificity, PPA, and NPA between the two methods (P > 0.05). tNGS identified five strains with resistance genes, while mNGS detected one strain. Furthermore, tNGS had a faster detection time (12 vs. 24 h) and lower cost ($150 vs. $500) compared to mNGS.ConclusiontNGS offers similar sensitivity to mNGS but with greater efficiency and cost-effectiveness, making it a promising approach for respiratory pathogen detection.

P-528 Establishing sequencing coverage depth for preimplantation genetic testing for monogenic disorders (PGT-M) using a specific targeted next generation sequencing (tNGS)

Abstract Study question What is the sufficient sequencing coverage read depth (RD) for direct variant analysis for PGT-M using a specific tNGS assay? Summary answer Downsampling modelling experiments identified a minimum sequencing depth of 50X that is recommended for PGT-M with this specific tNGS assay. What is known already Properly developed and validated multiplex PCR amplification and NGS-based analysis reliably produces PGT-M diagnoses with low allele and amplification failure at RD of hundreds of reads when analyzing a 3-10 cell trophectoderm (TE) biopsy. However, the RD can be affected by amplification efficiency in a specific genomic region and therefore affect the reproducibility of variant detection: the higher the number of aligned reads, the higher the confidence of base calling at a particular position. Downsampling is a powerful bioinformatics tool for modelling comparisons between samples or between replicates, identifying analytical sequencing depth limits for accurate clinical diagnosis. Study design, size, duration This is a retrospective comparative diagnostic test accuracy (DTA) and verification study. Twenty-three embryos from 8 patients that had undergone PGT-M with clinically established Taqman qPCR genotyping were used as positive controls. The primary outcome was to establish the lowest RD point of down sampling where allelic frequency is reliably detected at heterozygosity between 20-80% in known positive controls. A further 30 PGT-M clinical cases were used to verify analytical performances under clinical conditions. Participants/materials, setting, methods Embryo biopsies were pre-amplified with a multiplex primer pool for PGT-M and PGT-A, using a two-step PCR strategy. Sequencing was performed on Illumina NextSeq550. Reads were aligned to a human reference genome (GRCh37/hg19) and processed with an in house bioinformatic pipeline. The RD and alternative allele frequencies (AAF) for PGT-M was calculated. The reads for the heterozygous variants were downsampled to 10X, 20X, 30X, 50X, 100X, 200X, 300X, 500X, and 1000X to establish the cutoff. Main results and the role of chance One or two TE biopsies (N = 44) of 23 embryos that were 100% concordant with previous PGT-M results were tested for 1 to 3 of the 12 variants (MLH1 c.199G>A, RB1 c.1589A>G, SLC16A2 c.604G>A, GNPTAB c.1123C>T, GNPTAB c.3314A>G, WFS1 c.1391C>G, USH2A c.10073G>A, USH2A del exons 5-11, F5 c.1601G>A, GAA c.693-1G>C, GAA c.875A>G, and HEXA c.1274_1277dupTATC). PGT-A analysis of multiple biopsies from the same embryo demonstrated consistent karyotypes (N = 44). The 19 heterozygous variants from 17 biopsies exhibited average RD of 763X (238X -1980X) with average AAF of 50% (44%- 56%). The reads for the heterozygous variants were downsampled to different levels (100,000 replicates). The distribution of the AAF were compared among the different depth levels. At a RD of 50X, the AAF displayed an interquartile range (IQR) of 8% (46%-54%) between the maximum and minimum values from 20% to 78%. Compared to 30X (IQR: 43%-57%, with minimum 13% and maximum 90%), and 100X (IQR: 47%-54%, with minimum 30% and maximum 71%), the RD at 50X generated reliable heterozygous calls with minimum depth requirement. 245 biopsies from 30 clinic cases were analyzed by tNGS-based PGT-M. 90 samples with heterozygous variant calls showed average RD of 979X (57X-5803X) with average AAF of 47% (29%-585). Limitations, reasons for caution The 50X cutoff is based on the heterozygous variants with theoretical 50% AFF and is specific for this PGT-A assay. This evaluation should be corroborated for complicated variants with homologous genes, which might require different thresholds. The aneuploidy at specific chromosome can cause the deviation of AFF from 50%. Wider implications of the findings This specific tNGS-based PGT-M can provide direct variant analysis at a 50X read depth with a high level of consistency compared to established methodologies while allowing for simultaneous aneuploidy screening using the same biopsy and procedural optimization. Trial registration number not applicable

Imaging-based detection of anterior chamber inflammation: a comparative diagnostic accuracy study

PurposeWe investigated the impact of operator parameters on the diagnostic performance of danterior segment optical coherence tomography (AS-OCT) in anterior uveitis. DesignProspective comparative diagnostic analysis. MethodsSetting: Single site.Study Population: Children aged under 18 years with anterior uveitis, recruited consecutively.Observation Procedures: Index testing: Optovue RTVue80 AS-OCT using ‘low-volume’ (LV, horizontal and vertical cross-sections) and ‘high-volume’ (HV, 68 horizontal cross-sections) protocols. Reference testing: slit lamp examination with anterior chamber inflammation graded using standardisation of uveitis nomenclature (SUN).Main Outcome Measure: Index test performance metrics (sensitivity, specificity, likelihood ratios), utility for ‘ruling-in’ and ‘ruling-out’ disease (positive / negative predictive values, PPV/NPV), receiver operating characteristic (ROC) curves to explore the impact of different imaging derived metrics, multivariable multilevel regression analyses to quantify correlation of index to reference testing, and repeatability indices across protocols. Results40 children (77 eyes: 51 eyes at SUN grade 0, 10 at SUN0.5+, 8 at SUN1+, 8 SUN≥2+ or higher) were included. There was high repeatability across protocols (0.98, p<0.001, 95% CI 0.75-1.0). OCT resulted in strong predictive values for ‘ruling-out’ (LV-scan NPV 82.9%, 95% CI 71.5 - 90.4%; HV-scan NPV 100%, 95% CI 3% to 100%), and but less predictive value for ‘ruling-in’ SUN≥0.5+ (LV-scan PPV 52.8% 95% CI 41.5 - 63.7%; HV-scan PPV 34.2%, 95% CI 33.3 to 35.1%). Detection of more than 1 cell within a cross sectional scan was strongly suggestive of clinical activity, with area under the curve of 0.76 (95% CI 0.62 - 0.89) for SUN≥0.5+, and 0.85 (95% CI 0.73- 0.98), for the detection of SUN≥1+. Cell count correlated with SUN grades at higher levels of inflammation (SUN≥2+ both protocols, SUN≥1+ HV-scans). There was an independent positive association between age and AS-OCT cell (adjusted correlation coefficient 0.2 cells for each additional year of age). ConclusionsOperator dependent factors impact the diagnostic and quantification performance of AS-OCT for anterior chamber inflammation. However, the strong, ‘dose-respondent’ correlation of low-volume protocols with SUN grading promises clinical utility without the storage and analysis burden of high-volume approaches. Further work will involve exploration of the need for age-specific image metric interpretation.

Urine high-risk human papillomavirus testing as an alternative to routine cervical screening: A comparative diagnostic accuracy study of two urine collection devices using a randomised study design trial.

To evaluate the sensitivity of human papillomavirus (HPV) tested urine to detect high-grade cervical precancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) using two urine collection devices. Randomised controlled trial. St Mary's Hospital, Manchester, UK. Colposcopy attendees with abnormal cervical screening; a total of 480 participants were randomised. Matched urine and cervical samples were available for 235 and 230 participants using a first-void urine (FVU)-collection device and standard pot, respectively. Urine was self-collected and mixed with preservative - randomised 1:1 to FVU-collection device (Novosanis Colli-pee® 10 mL with urine conservation medium [UCM]) or standard pot. Matched clinician-collected cervical samples were taken before colposcopy. HPV testing used Roche cobas® 8800. A questionnaire evaluated urine self-sampling acceptability. The primary outcome measured sensitivity of HPV-tested urine (FVU-collection device and standard pot) for CIN2+ detection. Secondary outcomes compared HPV-tested cervical and urine samples for CIN2+ and evaluated the acceptability of urine self-sampling. Urine HPV test sensitivity for CIN2+ was higher with the FVU-collection device (90.3%, 95% CI 83.7%-94.9%, 112/124) than the standard pot (73.4%, 95% CI 64.7%-80.9%, 91/124, p = 0.0005). The relative sensitivity of FVU-device-collected urine was 0.92 (95% CI 0.87-0.97, pMcN = 0.004) compared with cervical, considering that all women were referred after a positive cervical HPV test. Urine-based sampling was acceptable to colposcopy attendees. Testing of FVU-device-collected urine for HPV was superior to standard-pot-collected urine in colposcopy attendees and has promising sensitivity for CIN2+ detection. General population HPV testing of FVU-device-collected urine will establish its clinical performance and acceptability as an alternative to routine cervical screening.

GeneXpert MTB/RIF Ultra vs Unstimulated Interferon γ (IRISA-TB) for the Diagnosis of Tuberculous Pericarditis in a Tuberculosis-Endemic Setting.

Tuberculous pericarditis (TBP) is a paucibacillary disease, where host biomarkers such as unstimulated interferon γ (IRISA-TB) have high diagnostic accuracy. However, DNA-based diagnostic tests (GeneXpert Ultra), more sensitive than an earlier versions, have recently become available. Given that the diagnosis of TBP is challenging, we performed a comparative diagnostic accuracy study comparing both assays. We recruited 99 consecutive patients with suspected TBP in Cape Town, South Africa. Definite TBP was defined by microbiological confirmation of tuberculosis (TB) on pericardial fluid culture or an alternative polymerase chain reaction-based test (GeneXpert MTB/RIF) or by use of sputum (polymerase chain reaction or culture). Probable TBP was defined as a high clinical suspicion of TB accompanied by anti-TB treatment, while non-TBP was defined as negative microbiological test results for TB without initiation of TB treatment and/or the presence of an alternative diagnosis. There were 39 patients with definite TBP, 35 with probable TBP, and 23 with non-TBP. Approximately 70% of participants who received TB treatment were HIV coinfected. Overall, IRISA-TB was more sensitive than Xpert Ultra (88.6% [95% CI, 74.1%-95.5%] vs 71.5% [55.0%-83.7%], n = 53) and significantly more sensitive in participants who were HIV uninfected (100% [95% CI, 72.3%-100.0%] vs 60% [31.3%-83.2%], P = .03). In patients with definite and probable TBP combined (n = 84), sensitivity was significantly higher with IRISA-TB (77.3% [95% CI, 65.9%-85.8%] vs 37.9 [27.2%-50.0%], P < .0001). A similar pattern was seen in persons who were HIV uninfected (88.3% vs 35.3%, P = .002). Specificity was high for both assays (>95%). Unstimulated interferon γ (IRISA-TB) was significantly more sensitive than Xpert Ultra for the diagnosis of TB pericarditis in a TB-endemic resource-poor setting.

Comparative Study of Diagnostic Accuracy of Pelviabdominal Computed Tomography with Contrast versus Appendicitis Inflammatory Response Score in the Diagnosis of Acute Appendicitis

Comparative Study of Diagnostic Accuracy of Pelviabdominal Computed Tomography with Contrast versus Appendicitis Inflammatory Response Score in the Diagnosis of Acute Appendicitis

Comparison of the diagnostic utility of CHOKAI, STONE and STONE PLUS scores in predicting ureteral stones larger than 5 mm

Objective: The objective of this study is to assess the diagnostic accuracy of CHOKAI, STONE, and STONE plus scores in detecting ureteral stones larger than 5 mm. Methods: This comparative diagnostic accuracy study was performed in a tertiary care emergency department (ED) and included consecutive patients who presented to the ED with flank pain over a 1-year period. The performance of these scoring scales in detecting ureteral stones measuring &gt;5 mm was determined by area under the receiver operating characteristics (AUROC) comparison. Results: Ureteral stones were detected in 270 (70.3%) of 384 patients included in the study. While 146 patients (54.1%) had ureteral stones measuring &lt;5 mm, 124 patients (54.1%) had stones measuring 5 mm or more in size. The performance of the CHOKAI score in predicting ureteral stones was superior to that of the STONE PLUS score; STONE PLUS score was also superior to STONE score ( p &lt; 0.001). Analysis of the diagnostic value of CHOKAI score and STONE PLUS scores in predicting &gt;5-mm stones showed no statistically significant difference ( p = 0.59). Conclusion: CHOKAI and STONE PLUS scores are useful in predicting &gt;5-mm ureteral stones and have similar diagnostic utility to each other. STONE score does not provide accurate diagnostic information about ureteral stones larger than 5 mm. Level of evidence: Level 2b

Role of creatine phosphokinase as a diagnostic marker in tubal ectopic pregnancy.

Ectopic pregnancy (EP) is still one of the leading preventable causes of maternal morbidity and mortality in the first trimester. Amidst the use of sensitive assays for β-HCG and high-definition ultrasonography for the identification of EP, the search for a more reliable and sensitive marker remains a challenge till date. Our aim was to determine the validity of creatine phosphokinase (CPK) and its isoenzyme (CPK-MB) in the prediction of tubal EP. A prospective and comparative diagnostic accuracy study was conducted among 105 pregnant women in the first trimester who met the eligibility criteria in the Department of Obstetrics and Gynecology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS). The study included 35 patients each with tubal EP (EP), abortive intrauterine pregnancy (AP), and normal intrauterine pregnancy (NP). CPK, CPK-MB, and β-HCG were measured among all the participants, and the participants were followed up longitudinally. A total of 105 pregnant women were included. The mean CPK and CPK-MB levels were significantly higher among the women with EP when compared to NP (P < 0.05) and AP (P < 0.05) women; however, there was no significant difference between the NP and AP groups (P > 0.05). Moreover, the receiver operating characteristic (ROC) curve showed that both CPK and CPK-MB were good predictors of EP, with CPK (area under the curve [AUC] = 0.764) being a better predictor than CPK-MB (AUC: 0.650) in the diagnosis of EP. Early diagnosis of EP allows appropriate and timely management, which would not only reduce mortality and morbidity associated with the condition but also enable preservation of fertility and improve future pregnancy outcome. Hence, the need of the hour is a reliable biochemical diagnostic marker for EP, such as CPK.

C3d immunohistochemistry in the diagnosis of bullous pemphigoid: A comparative diagnostic test accuracy and cost analysis study

C3d immunohistochemistry in the diagnosis of bullous pemphigoid: A comparative diagnostic test accuracy and cost analysis study

Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study

The reference standard for detecting non-alcoholic steatohepatitis (NASH) and staging fibrosis-liver biopsy-is invasive and resource intensive. Non-invasive biomarkers are urgently needed, but few studies have compared these biomarkers in a single cohort. As part of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) project, we aimed to evaluate the diagnostic accuracy of 17 biomarkers and multimarker scores in detecting NASH and clinically significant fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) and identify their optimal cutoffs as screening tests in clinical trial recruitment. This was a comparative diagnostic accuracy study in people with biopsy-confirmed NAFLD from 13 countries across Europe, recruited between Jan 6, 2010, and Dec 29, 2017, from the LITMUS metacohort of the prospective European NAFLD Registry. Adults (aged ≥18 years) with paired liver biopsy and serum samples were eligible; those with excessive alcohol consumption or evidence of other chronic liver diseases were excluded. The diagnostic accuracy of the biomarkers was expressed as the area under the receiver operating characteristic curve (AUC) with liver histology as the reference standard and compared with the Fibrosis-4 index for liver fibrosis (FIB-4) in the same subgroup. Target conditions were the presence of NASH with clinically significant fibrosis (ie, at-risk NASH; NAFLD Activity Score ≥4 and F≥2) or the presence of advanced fibrosis (F≥3), analysed in all participants with complete data. We identified thres holds for each biomarker for reducing the number of biopsy-based screen failures when recruiting people with both NASH and clinically significant fibrosis for future trials. Of 1430 participants with NAFLD in the LITMUS metacohort with serum samples, 966 (403 women and 563 men) were included after all exclusion criteria had been applied. 335 (35%) of 966 participants had biopsy-confirmed NASH and clinically significant fibrosis and 271 (28%) had advanced fibrosis. For people with NASH and clinically significant fibrosis, no single biomarker or multimarker score significantly reached the predefined AUC 0·80 acceptability threshold (AUCs ranging from 0·61 [95% CI 0·54-0·67] for FibroScan controlled attenuation parameter to 0·81 [0·75-0·86] for SomaSignal), with accuracy mostly similar to FIB-4. Regarding detection of advanced fibrosis, SomaSignal (AUC 0·90 [95% CI 0·86-0·94]), ADAPT (0·85 [0·81-0·89]), and FibroScan liver stiffness measurement (0·83 [0·80-0·86]) reached acceptable accuracy. With 11 of 17 markers, histological screen failure rates could be reduced to 33% in trials if only people who were marker positive had a biopsy for evaluating eligibility. The best screening performance for NASH and clinically significant fibrosis was observed for SomaSignal (number needed to test [NNT] to find one true positive was four [95% CI 4-5]), then ADAPT (six [5-7]), MACK-3 (seven [6-8]), and PRO-C3 (nine [7-11]). None of the single markers or multimarker scores achieved the predefined acceptable AUC for replacing biopsy in detecting people with both NASH and clinically significant fibrosis. However, several biomarkers could be applied in a prescreening strategy in clinical trial recruitment. The performance of promising markers will be further evaluated in the ongoing prospective LITMUS study cohort. The Innovative Medicines Initiative 2 Joint Undertaking.

Artificial intelligence for assistance of radiology residents in chest CT evaluation for COVID-19 pneumonia: a comparative diagnostic accuracy study.

In hospitals, it is crucial to rule out coronavirus disease 2019 (COVID-19) timely and reliably. Artificial intelligence (AI) provides sufficient accuracy to identify chest computed tomography (CT) scans with signs of COVID-19. To compare the diagnostic accuracy of radiologists with different levels of experience with and without assistance of AI in CT evaluation for COVID-19 pneumonia and to develop an optimized diagnostic pathway. The retrospective, single-center, comparative case-control study included 160 consecutive participants who had undergone chest CT scan between March 2020 and May 2021 without or with confirmed diagnosis of COVID-19 pneumonia in a ratio of 1:3. Index tests were chest CT evaluation by five radiological senior residents, five junior residents, and an AI software. Based on the diagnostic accuracy in every group and on comparison of groups, a sequential CT assessment pathway was developed. Areas under receiver operating curves were 0.95 (95% confidence interval [CI]=0.88-0.99), 0.96 (95% CI=0.92-1.0), 0.77 (95% CI=0.68-0.86), and 0.95 (95% CI=0.9-1.0) for junior residents, senior residents, AI, and sequential CT assessment, respectively. Proportions of false negatives were 9%, 3%, 17%, and 2%, respectively. With the developed diagnostic pathway, junior residents evaluated all CT scans with the support of AI. Senior residents were only required as second readers in 26% (41/160) of the CT scans. AI can support junior residents with chest CT evaluation for COVID-19 and reduce the workload of senior residents. A review of selected CT scans by senior residents is mandatory.

Accuracy of Modified Blue-Dye Testing in Predicting Dysphagia in Tracheotomized Critically Ill Patients.

(1) Background: Diagnosis of dysphagia in critically ill patients with a tracheostomy is important to avoid aspiration pneumonia. The objective of this study was to analyze the validity of the modified blue-dye test (MBDT) on the diagnosis of dysphagia in these patients; (2) Methods: Comparative diagnostic test accuracy study. Tracheostomized patients admitted to the Intensive Care Unit (ICU) were studied with two tests for dysphagia diagnosis: MBDT and fiberoptic endoscopic evaluation of swallowing (FEES) as the reference standard. Comparing the results of both methods, all diagnostic measures were calculated, including the area under the receiver-operating-characteristic curve (AUC); (3) Results: 41 patients, 30 males and 11 females, mean age 61 ± 13.9 years. The prevalence of dysphagia was 70.7% (29 patients) using FEES as the reference test. Using MBDT, 24 patients were diagnosed with dysphagia (80.7%). The sensitivity and specificity of the MBDT were 0.79 (CI95%: 0.60-0.92) and 0.91 (CI95%: 0.61-0.99), respectively. Positive and negative predictive values were 0.95 (CI95%: 0.77-0.99) and 0.64 (CI95%: 0.46-0.79). AUC was 0.85 (CI95%: 0.72-0.98); (4) Conclusions: MBDT should be considered for the diagnosis of dysphagia in critically ill tracheostomized patients. Caution should be taken when using it as a screening test, but its use could avoid the need for an invasive procedure.

Study protocol for a multicentre comparative diagnostic accuracy study of tools to establish the presence and severity of peripheral arterial disease in people with diabetes mellitus: the DM PAD study

IntroductionPeripheral arterial disease (PAD) is a key risk factor for cardiovascular disease, foot ulceration and lower limb amputation in people with diabetes. Early diagnosis of PAD can enable optimisation of...

A comparative study of diagnostic accuracy in 3026 pleural biopsies and matched pleural effusion cytology with clinical correlation.

Pleural effusion can be caused by a wide range of benign and malignant conditions. Pleural biopsy and effusion cytology represent two key methods of pathological diagnosis. To compare the performance these two methods, a large cohort of matched pleural biopsy and effusion cytology with clinical follow-up was reviewed. Pleural biopsies and effusion cytology specimens over a period of 18 years were retrieved. Cytology specimens collected within 7 days of pleural biopsy were matched. Reports were reviewed, and the cause for pleural effusion was determined by hospital disease coding and clinical data. Totally, 3026 cases were included. The leading cause of benign effusion was tuberculosis (n= 650). Malignant pleural effusion (MPE) was more common in older females (p< 0.001) and mostly due to lung cancer (n= 959), breast cancer (n= 64), and mesothelioma (n= 48). The inadequate/insufficient (B1/C1) rate of biopsy was higher than cytology (15.6% vs. 0.3%) but the rates for other diagnostic categories were similar. Biopsy and cytology showed a correlation coefficient of 0.315, improving to 0.449 when inadequate/insufficient (B1/C1) cases were excluded. The ROM for benign cytology (C2) was lower than biopsy (B2) (p< 0.001). Compared with biopsy, the diagnostic accuracy was higher in cytology overall and for metastatic carcinomas (p< 0.001) but lower for hematolymphoid malignancies (p= 0.014) and mesotheliomas (p= 0.002). These results suggest that effusion cytology may be better for confirming benignity and diagnosing carcinomatous MPE. In these cases, pleural biopsy may be withheld to reduce procedural risks. However, for suspected hematolymphoid malignancies and mesothelioma, biopsy should be considered.

Blinded sample size re-estimation in a comparative diagnostic accuracy study

BackgroundThe sample size calculation in a confirmatory diagnostic accuracy study is performed for co-primary endpoints because sensitivity and specificity are considered simultaneously. The initial sample size calculation in an unpaired and paired diagnostic study is based on assumptions about, among others, the prevalence of the disease and, in the paired design, the proportion of discordant test results between the experimental and the comparator test. The choice of the power for the individual endpoints impacts the sample size and overall power. Uncertain assumptions about the nuisance parameters can additionally affect the sample size.MethodsWe develop an optimal sample size calculation considering co-primary endpoints to avoid an overpowered study in the unpaired and paired design. To adjust assumptions about the nuisance parameters during the study period, we introduce a blinded adaptive design for sample size re-estimation for the unpaired and the paired study design. A simulation study compares the adaptive design to the fixed design. For the paired design, the new approach is compared to an existing approach using an example study.ResultsDue to blinding, the adaptive design does not inflate type I error rates. The adaptive design reaches the target power and re-estimates nuisance parameters without any relevant bias. Compared to the existing approach, the proposed methods lead to a smaller sample size.ConclusionsWe recommend the application of the optimal sample size calculation and a blinded adaptive design in a confirmatory diagnostic accuracy study. They compensate inefficiencies of the sample size calculation and support to reach the study aim.

Comparative Study of Diagnostic Accuracy of Ultrasonography Vs Histopathology in patients Undergoing Hysterectomy due to Uterine Pathologies

Background: Accurate diagnosis of uterine pathologies has become a core part when referring patients for hysterectomy. A variety of modalities can be used for the diagnosis of uterine abnormalities. Aims: To evaluate the accuracy of ultrasound in diagnosing various uterine pathologies and to compare histopathological findings with ultrasonographical findings. Methods: A cross-sectional study was conducted on 80 females who met the inclusion criteria at Department of Gynaecology, University of Lahore Teaching Hospitalover a period of 9 months from November 2020 to August 2021. The study was started after the approval of ethical committee at the University of Lahore. All the patients were enrolled in this study after signing the informed consent form. Patients preop ultra-sonographic findings and post-operative histopathology reports of the hysterectomy was analyzed and sensitivity, specificity and diagnostic accuracy of ultrasonography for uterine pathologies was calculated. Results: Majority of the patients were in 40’s age group. Most common sonographical indication for hysterectomy was fibroids, followed byadenomyosis and endometrial hyperplasia. The overall sensitivity, specificity and diagnostic accuracy values for ultrasonography in the diagnosis of uterine abnormality was satisfactory. The diagnostic accuracy of ultrasonography in detection of uterine fibroids and adenomyosis was 96.25% and 98.75%. Conclusion: Histo-pathological analysis correlates well with the pre-operative sonographical diagnosis. The diagnostic accuracy of ultrasound in detecting intrauterine pathology urges us to utilize ultrasonography as a first-line investigation in gynaecological patients. It is a valuable adjunctive to histopatholoogy with high accuracy for identification and characterization of uterine pathologies. Keywords: Ultrasound, Menorrhagia, Fibroids, Adenomyosis, Endometrial hyperplasia.

A comparative study of diagnostic accuracy in 3,026 cases of matched pleural effusion cytology and pleural biopsy with clinical correlation

Introduction: The aetiology of pleural effusion is diverse. Pleural biopsy and effusion cytology represent the two major methods of investigation and tissue diagnosis. A large cohort of matched pleural biopsy and effusion cytology with clinical follow-up was reviewed to report the clinical associations and cause of pleural effusion, and compare the performance these two methods.

Assessment of cervical spine CT scans by emergency physicians: A comparative diagnostic accuracy study in a non-clinical setting.

ObjectivesTo determine and compare the diagnostic accuracy of assessing injuries on cervical spine computed tomography (CT) scans by trained emergency physicians and radiologists, both in a non‐clinical setting.MethodsIn this comparative diagnostic accuracy study, 411 cervical spine CT scans, of which 120 contained injuries (fractures and/or dislocations), were divided into 8 subsets. Eight emergency physicians received focused training and assessed 1 subset each before and after training. Four radiologists assessed 2 subsets each. Diagnostic accuracy between both groups was compared. The reference standard used was a multiverified data set, assessed by radiologists, neurosurgeons, and emergency physicians. The neurosurgeons also classified whether an "injury in need of stabilizing therapy" (IST) was present.ResultsPosttraining, the emergency physicians demonstrated increased sensitivity and specificity for identifying cervical spine injuries compared to pretraining: sensitivity 88% (95% confidence interval [CI] 80% to 93%) versus 80% (95% CI 72% to 87%) and specificity 89% (95% CI 85% to 93%) versus 86% (95% CI 81% to 89%). When comparing the trained emergency physicians to the group of radiologists, no difference in sensitivity was found, 88% (95% CI 80% to 83%); however, the radiologists showed a significantly higher specificity (P < 0.01): 99% (95% CI 96% to 100%). In the 12% (15 scans) with missed injuries, emergency physicians missed more ISTs than radiologists, 6 versus 4 scans; however, this difference was not significant (P = 0.45).ConclusionAfter focused training and in a non‐clinical setting, no significant difference was found between emergency physicians and radiologists in ruling out cervical spine injuries; however, the radiologists achieved a significantly higher specificity.

Serological testing for SARS-CoV-2 antibodies in clinical practice: A comparative diagnostic accuracy study.

BackgroundSerological tests are a powerful tool in the monitoring of infectious diseases and the detection of host immunity. However, manufacturers often provide diagnostic accuracy data generated through biased studies, and the performance in clinical practice is essentially unclear.ObjectivesWe aimed to determine the diagnostic accuracy of various serological testing strategies for (a) identification of patients with previous coronavirus disease‐2019 (COVID‐19) and (b) prediction of neutralizing antibodies against SARS‐CoV‐2 in real‐life clinical settings.MethodsWe prospectively included 2573 consecutive health‐care workers and 1085 inpatients with suspected or possible previous COVID‐19 at a Swiss University Hospital. Various serological immunoassays based on different analytical techniques (enzyme‐linked immunosorbent assays, ELISA; chemiluminescence immunoassay, CLIA; electrochemiluminescence immunoassay, ECLIA; and lateral flow immunoassay, LFI), epitopes of SARS‐CoV‐2 (nucleocapsid, N; receptor‐binding domain, RBD; extended RBD, RBD+; S1 or S2 domain of the spike [S] protein, S1/S2), and antibody subtypes (IgG, pan‐Ig) were conducted. A positive real‐time PCR test from a nasopharyngeal swab was defined as previous COVID‐19. Neutralization assays with live SARS‐CoV‐2 were performed in a subgroup of patients to assess neutralization activity (n = 201).ResultsThe sensitivity to detect patients with previous COVID‐19 was ≥85% in anti‐N ECLIA (86.8%) and anti‐S1 ELISA (86.2%). Sensitivity was 84.7% in anti‐S1/S2 CLIA, 84.0% in anti‐RBD+LFI, 81.0% in anti‐N CLIA, 79.2% in anti‐RBD ELISA, and 65.6% in anti‐N ELISA. The specificity was 98.4% in anti‐N ECLIA, 98.3% in anti‐N CLIA, 98.2% in anti‐S1 ELISA, 97.7% in anti‐N ELISA, 97.6% in anti‐S1/S2 CLIA, 97.2% in anti‐RBD ELISA, and 96.1% in anti‐RBD+LFI.The sensitivity to detect neutralizing antibodies was ≥85% in anti‐S1 ELISA (92.7%), anti‐N ECLIA (91.7%), anti‐S1/S2 CLIA (90.3%), anti‐RBD+LFI (87.9%), and anti‐RBD ELISA (85.8%). Sensitivity was 84.1% in anti‐N CLIA and 66.2% in anti‐N ELISA. The specificity was ≥97% in anti‐N CLIA (100%), anti‐S1/S2 CLIA (97.7%), and anti‐RBD+LFI (97.9%). Specificity was 95.9% in anti‐RBD ELISA, 93.0% in anti‐N ECLIA, 92% in anti‐S1 ELISA, and 65.3% in anti‐N ELISA. Diagnostic accuracy measures were consistent among subgroups.ConclusionsThe diagnostic accuracy of serological tests for SARS‐CoV‐2 antibodies varied remarkably in clinical practice, and the sensitivity to identify patients with previous COVID‐19 deviated substantially from the manufacturer's specifications. The data presented here should be considered when using such tests to estimate the infection burden within a specific population and determine the likelihood of protection against re‐infection.

Non-invasive testing for early detection of neovascular macular degeneration in unaffected second eyes of older adults: EDNA diagnostic accuracy study.

Neovascular age-related macular degeneration is a leading cause of sight loss, and early detection and treatment is important. For patients with neovascular age-related macular degeneration in one eye, it is usual practice to monitor the unaffected eye. The test used to diagnose neovascular age-related macular degeneration, fundus fluorescein angiography, is an invasive test. Non-invasive tests are available, but their diagnostic accuracy is unclear. The primary objective was to determine the diagnostic monitoring performance of tests for neovascular age-related macular degeneration in the second eye of patients with unilateral neovascular age-related macular degeneration. The secondary objectives were the cost-effectiveness of tests and to identify predictive factors of developing neovascular age-related macular degeneration. This was a multicentre, prospective, cohort, comparative diagnostic accuracy study in a monitoring setting for up to 3 years. A Cox regression risk prediction model and a Markov microsimulation model comparing cost-effectiveness of the index tests over 25 years were used. This took place in hospital eye services. Participants were adults (aged 50-95 years) with newly diagnosed (within the previous 6 weeks) neovascular age-related macular degeneration in one eye and an unaffected second (study) eye who were attending for treatment injections in the first eye and who had a study eye baseline visual acuity of ≥ 68 Early Treatment Diabetic Retinopathy Study letters. The index tests were Amsler chart (completed by participants), fundus clinical examination, optical coherence tomography, self-reported vision assessment (completed by participants) and visual acuity. The reference standard was fundus fluorescein angiography. The main outcome measures were sensitivity and specificity; the performance of the risk predictor model; and costs and quality-adjusted life-years. In total, 552 out of 578 patients who consented from 24 NHS hospitals (n = 16 ineligible; n = 10 withdrew consent) took part. The mean age of the patients was 77.4 years (standard deviation 7.7 years) and 57.2% were female. For the primary analysis, 464 patients underwent follow-up fundus fluorescein angiography and 120 developed neovascular age-related macular degeneration on fundus fluorescein angiography. The diagnostic accuracy [sensitivity (%) (95% confidence interval); specificity (%) (95% confidence interval)] was as follows: optical coherence tomography 91.7 (85.2 to 95.6); 87.8 (83.8 to 90.9)], fundus clinical examination [53.8 (44.8 to 62.5); 97.6 (95.3 to 98.9)], Amsler [33.7 (25.1 to 43.5); 81.4 (76.4 to 85.5)], visual acuity [30.0 (22.5 to 38.7); 66.3 (61.0 to 71.1)] and self-reported vision [4.2 (1.6 to 9.8); 97.0 (94.6 to 98.5)]. Optical coherence tomography had the highest sensitivity across all secondary analyses. The final prediction model for neovascular age-related macular degeneration in the non-affected eye included smoking status, family history of neovascular age-related macular degeneration, the presence of nodular drusen with or without reticular pseudodrusen, and the presence of pigmentary abnormalities [c-statistic 0.66 (95% confidence interval 0.62 to 0.71)]. Optical coherence tomography monitoring generated the greatest quality-adjusted life-years gained per patient (optical coherence tomography, 5.830; fundus clinical examination, 5.787; Amsler chart, 5.736, self-reported vision, 5.630; and visual acuity, 5.600) for the lowest health-care and social care costs (optical coherence tomography, £19,406; fundus clinical examination, £19,649; Amsler chart, £19,751; self-reported vision, £20,198; and visual acuity, £20,444) over the lifetime of the simulated cohort. Optical coherence tomography dominated the other tests or had an incremental cost-effectiveness ratio below the accepted cost-effectiveness thresholds (£20,000) across the scenarios explored. The diagnostic performance may be different in an unselected population without any history of neovascular age-related macular degeneration; the prediction model did not include genetic profile data, which might have improved the discriminatory performance. Optical coherence tomography was the most accurate in diagnosing conversion to neovascular age-related macular degeneration in the fellow eye of patients with unilateral neovascular age-related macular degeneration. Economic modelling suggests that optical coherence tomography monitoring is cost-effective and leads to earlier diagnosis of and treatment for neovascular age-related macular degeneration in the second eye of patients being treated for neovascular age-related macular degeneration in their first eye. Future works should investigate the role of home monitoring, improved risk prediction models and impact on long-term visual outcomes. This study was registered as ISRCTN48855678. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 8. See the NIHR Journals Library website for further project information.