False-positive Test Research Articles

Rethinking False Positive Exercise Electrocardiographic Stress Tests by Assessing Coronary Microvascular Function

BackgroundExercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial ischemia can occur because of coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease. ObjectivesThe aim of this study was to assess the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in patients with angina with nonobstructive coronary arteries (ANOCA). MethodsPatients with ANOCA underwent invasive coronary physiological assessment using adenosine and acetylcholine. CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. EST was performed using a standard Bruce treadmill protocol, with ischemia defined as the appearance of ≥0.1-mV ST-segment depression 80 ms from the J-point on electrocardiography. The study was powered to detect specificity of ≥91%. ResultsA total of 102 patients were enrolled (65% women, mean age 60 ± 8 years). Thirty-two patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (nonischemic group); both groups were phenotypically similar. Ischemia during EST was 100% specific for CMD. Acetylcholine flow reserve was the strongest predictor of ischemia during exercise. Using endothelium-independent and endothelium-dependent microvascular dysfunction as the reference standard, the false positive rate of EST dropped to 0%. ConclusionsIn patients with ANOCA, ischemia on EST was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false positive rate.

False-Positive Human Immunodeficiency Virus Nucleic Acid Amplification Test After Chimeric Antigen Receptor T-Cell Therapy With Ciltacabtagene Autoleucel.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel therapeutic option for hematologic malignancies. Human immunodeficiency virus (HIV) nucleic acid amplification tests (NAATs) amplifying 5' long terminal repeat and gag genes cross-react with lentiviral vector-based CAR T-cell products. Cross-reactivity between CAR T-cell products and HIV NAATs may lead to false-positive test results.

Sample Loading - The Critical Step of Biopsy

Failed or poor sample loading following trophectoderm cells sampling can ruin all efforts made before by causing DNA amplification failure, false positive or false negative genetic testing results, and false mosaic reports. In this lecture, all steps involved in the sample loading procedure will be addressed and discussed in detail, including solutions needed, identification, PCR tube setup, washing, and loading.

Health benefits and harms of mammography screening in older women (75+ years)—a systematic review

BackgroundThere is little evidence on the balance between potential benefits and harms of mammography screening in women 75 years and older. The aim of this systematic review was to synthesise the evidence on the outcomes of mammography screening in women aged 75 years and older.MethodsA systematic review of mammography screening studies in women aged 75 years and over.ResultsThirty-six studies were included in this review: 27 observational studies and 9 modelling studies. Many of the included studies used no or uninformative comparison groups resulting in a potential bias towards the benefits of screening. Despite this, there was mixed evidence about the benefits and harms of continuing mammography screening beyond the age of 75 years. Some studies showed a beneficial effect on breast cancer mortality, and other studies showed no effect on mortality. Some studies showed some harms (false positive tests and recalls) being comparable to those in younger age-groups, with other studies showing increase in false positive screens and biopsies in older age-group. Although reported in fewer studies, there was consistent evidence of increased overdiagnosis in older age-groups.ConclusionThere is limited evidence available to make a recommendation for/against continuing breast screening beyond the age of 75 years. Future studies should use more informative comparisons and should estimate overdiagnosis given potentially substantial harm in this age-group due to competing causes of death.This review was prospectively registered with PROSPERO (CRD42020203131).

When HIT Testing Hurts- the Financial and Clinical Repercussions of Heparin Induced Thrombocytopenia Testing: A Single Center Analysis

Introduction: Thrombocytopenia is a common inpatient hematologic concern. Most often, thrombocytopenia is a multifactorial phenomenon, without one clear cause. Heparin Induced Thrombocytopenia (HIT) is a rare but serious hematologic consequence of exposure to heparin. In many hospitalized patients, heparin is routinely used as venous thromboembolism (VTE) prophylaxis or for therapeutic anticoagulation. The incidence of HIT is approximately 0.5-1.0% in patients exposed to unfractionated heparin (UFH). Though rare, there seems to be over-testing of HIT antibody in the inpatient setting. As such, there is potential for high cost with low yield and false positives that alter patient management, resulting in prolonged hospital stays and further complications in patient care. Methods: This was a retrospective, observational study reviewing the indications, results, and patient characteristics of cases in which HIT testing was ordered. Indications for testing and influence of results on management were determined based on clinical documentation. The tests of interest included HIT antibody testing and Seratonin Release Assay (SRA). We analyzed how many times a HIT antibody was positive with a negative result in the SRA. We also determined whether there was an increased length of stay in patients who had HIT testing ordered. The study population included patients who were admitted to University of Florida Shands Medical Center, an academic institution in Jacksonville, FL in 2022. All patients were >18 years of age. Results: 190 patients were identified, for whom 190 HIT antibody tests were ordered and 75 SRAs. All patients who had a SRA performed had exposure to low dose heparin or therapeutic high dose heparin. Out of 190 patients, HIT testing was positive in 30 patients (15.8%). SRA testing was performed on 75 patients despite only 30 positive HIT tests. The true positives were 10 patients who had positive SRA confirmatory testing out of 190 patients with suspected HIT. Based on the results of confirmatory testing, the false positive fraction of HIT testing was 66%. When analyzing the 190 patients who underwent HIT testing, the average length of stay was 14 days. On average, a hospital stay in the US is 5.5 days and evaluation of HIT results in 8.5 additional days of hospital admission at our institution. The prolonged length of stay for HIT testing is likely impacted by awaiting SRA results along with other factors. Conclusion: This analysis examines the relative over-testing for HIT at a single institution. Compared with the known incidence of positive HIT tests, there is a significant number of positive HIT antibody tests at our hospital. The data further reveals a high probability of a false positive HIT antibody test results in the hospitalized patient, possibly due to immune reactivity. Of 190 patients suspected with HIT, only 10 patients had a positive confirmatory SRA, indicating that only 5% of suspected patients truly had HIT. This demonstrates that 95% of the time HIT assays ordered did not provide clinically useful information. From the time work up was initiated to the time of discharge, the average stay length was 14 days in a patient suspected with HIT. Cost burden of HIT testing was evaluated. Each HIT panel is $153.83 and each confirmatory SRA test is approximately $250, at a commercial laboratory. Taken together, the total average cost per patient with suspected HIT is $413.83 in diagnostic testing. Prolonged hospital stay contributes to approximately $25,000 increase in hospital stay per patient being evaluated for HIT. This does not include the cost of further work up or interventions. Changing to an alternate anticoagulant such as Argatroban increased costs by nearly $1,500 per case and this number increased further when adding the daily coagulation panel required while on this drug. In other studies, this cost has been estimated to add $90,000 to the hospital stay. Prolonged hospital stays are also associated with unintended incidents such as GI bleeding leading to blood transfusions, invasive testing (such as endoscopy/colonoscopy) and increased morbidity to the patient. We will use this information to implement a tool in our Electronic Medical Record (EMR) that will require answering the 4T score in order to establish high pre-test probability, prior to ordering HIT antibody testing at the University of Florida in Jacksonville.

Wait Time Advantage for Transplant Candidates With HIV Who Accept Kidneys From Donors With HIV Under the HOPE Act.

Kidney transplant (KT) candidates with HIV face higher mortality on the waitlist compared with candidates without HIV. Because the HIV Organ Policy Equity (HOPE) Act has expanded the donor pool to allow donors with HIV (D + ), it is crucial to understand whether this has impacted transplant rates for this population. Using a linkage between the HOPE in Action trial (NCT03500315) and Scientific Registry of Transplant Recipients, we identified 324 candidates listed for D + kidneys (HOPE) compared with 46 025 candidates not listed for D + kidneys (non-HOPE) at the same centers between April 26, 2018, and May 24, 2022. We characterized KT rate, KT type (D + , false-positive [FP; donor with false-positive HIV testing], D - [donor without HIV], living donor [LD]) and quantified the association between HOPE enrollment and KT rate using multivariable Cox regression with center-level clustering; HOPE was a time-varying exposure. HOPE candidates were more likely male individuals (79% versus 62%), Black (73% versus 35%), and publicly insured (71% versus 52%; P < 0.001). Within 4.5 y, 70% of HOPE candidates received a KT (41% D + , 34% D - , 20% FP, 4% LD) versus 43% of non-HOPE candidates (74% D - , 26% LD). Conversely, 22% of HOPE candidates versus 39% of non-HOPE candidates died or were removed from the waitlist. Median KT wait time was 10.3 mo for HOPE versus 60.8 mo for non-HOPE candidates ( P < 0.001). After adjustment, HOPE candidates had a 3.30-fold higher KT rate (adjusted hazard ratio = 3.30, 95% confidence interval, 2.14-5.10; P < 0.001). Listing for D + kidneys within HOPE trials was associated with a higher KT rate and shorter wait time, supporting the expansion of this practice for candidates with HIV.

Benefits and Harms of Mammography Screening in 75 + Women to Inform Shared Decision-making: a Simulation Modeling Study.

Guidelines recommend shared decision-making (SDM) around mammography screening for women ≥ 75years old. To use microsimulation modeling to estimate the lifetime benefits and harms of screening women aged 75, 80, and 85years based on their individual risk factors (family history, breast density, prior biopsy) and comorbidity level to support SDM in clinical practice. We adapted two established Cancer Intervention and Surveillance Modeling Network (CISNET) models to evaluate the remaining lifetime benefits and harms of screening U.S. women born in 1940, at decision ages 75, 80, and 85years considering their individual risk factors and comorbidity levels. Results were summarized for average- and higher-risk women (defined as having breast cancer family history, heterogeneously dense breasts, and no prior biopsy, 5% of the population). Remaining lifetime breast cancers detected, deaths (breast cancer/other causes), false positives, and overdiagnoses for average- and higher-risk women by age and comorbidity level for screening (one or five screens) vs. no screening per 1000 women. Compared to stopping, one additional screen at 75years old resulted in six and eight more breast cancers detected (10% overdiagnoses), one and two fewer breast cancer deaths, and 52 and 59 false positives per 1000 average- and higher-risk women without comorbidities, respectively. Five additional screens over 10years led to 23 and 31 additional breast cancer cases (29-31% overdiagnoses), four and 15 breast cancer deaths avoided, and 238 and 268 false positives per 1000 average- and higher-risk screened women without comorbidities, respectively. Screening women at older ages (80 and 85years old) and high comorbidity levels led to fewer breast cancer deaths and a higher percentage of overdiagnoses. Simulation models show that continuing screening in women ≥ 75 years old results in fewer breast cancer deaths but more false positive tests and overdiagnoses. Together, clinicians and 75 + women may use model output to weigh the benefits and harms of continued screening.

1621. "False-Positive" Cytomegalovirus (CMV) Screening Tests in Neonates: A Real Dilemma!

Abstract Background PCR testing of clinical specimens has been associated with false-positive test results. Detection of CMV DNA by PCR in saliva and urine has been used to identify neonates with congenital CMV infection, but the frequency of false-positive PCR results is not fully known. Our objective is to describe the frequency of "false-positive" saliva and urine CMV PCR tests when performed as screening for congenital CMV infection. Methods From 2018 to 2023, neonates were screened for CMV infection if they had abnormal clinical, laboratory, or radiographic findings, referred on the newborn hearing screen, and since 2019, on admission to the 9 neonatal intensive care units (NICU) of the Nationwide Children’s Hospital neonatal network, Columbus, OH. Pertinent demographic, clinical, audiologic, laboratory, and radiographic data were obtained and managed using REDCap. Infants who had an initial positive PCR screening test for CMV but subsequent negative PCR tests were identified. Results During the 6 year study period, 139 infants were diagnosed with congenital CMV infection. An additional 28 (17%) neonates tested positive for CMV DNA in saliva (n=26) or urine (n=2) but subsequent tests of urine specimens were negative for CMV. Most of the infants were tested as part of universal NICU screening (n=22), 5 had symptomatic disease, 3 referred on the newborn hearing screen, and 1 had thrombocytopenia. The infants were tested at a median (IQR) age of 3 (2-6) days. Their median (IQR) birth weight and gestational age were 2458 (1865-3360) grams and 37 (33-39) weeks, respectively. Four infants had their dried blood spot tested for CMV by PCR and were negative. 17 (77%) of 22 infants had known maternal milk exposure in the neonatal period. Conclusion Neonatal saliva and/or urine screening for congenital CMV infection was associated with a “false-positive” test result in 17% of neonates who tested positive for CMV DNA by PCR. These results suggest that confirmation of a diagnosis of congenital CMV infection by PCR requires testing of multiple specimens with one of them being urine. Disclosures Asuncion Mejias, MD, PhD, MsCS, Astra-Zeneca: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Sanofi-Pasteur: Advisor/Consultant Alexandra Katherine Medoro, MD, Merck: Grant/Research Support Amy Leber, PhD, Biomeriux: Grant/Research Support|BioRad: Advisor/Consultant|Cephied: Grant/Research Support|Diasorin: Grant/Research Support

False-positive HIV screening tests during the COVID-19 pandemic, a passing trend?

False-positive fourth-generation HIV screening tests are rare and are usually associated with various infections and autoimmune diseases. SARS-CoV-2 infection and vaccination were recently linked with false-positive HIV screening test results. However, little is known about false-positives in people who performed HIV screening tests after outbreaks of different SARS-CoV-2 strains and vaccination campaigns. Here, we examined the false-positive rates in samples collected by the Israeli AIDS Task Force in 2018--2022, with respect to such factors.

Content and specificity of the Anti-SARS-CoV-2 antibodies in solutions for immunoglobulin replacement therapy

BackgroundSpecific antibodies are important for post-vaccination and post-infection immune responses against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The role of antibodies in preventing and treating Coronavirus disease 2019 (COVID-19) in high-risk populations has been highlighted through the use of virus-specific monoclonal antibodies, which has raised the question of immunoglobulin replacement therapy (IRT) used in immunocompromised patients. MethodsVirus-specific anti-receptor-binding domain (RBD) and anti-nucleocapsid protein (NCAP) antibodies (assessed using a chemiluminescence assay and virus-neutralizing antibodies (virus neutralization test against Delta and Omicron variants)) were analyzed in 20 batches of 10 % (100 mg/mL) immunoglobulin solutions for intravenous IRT from two commercially available producers between January 2022 and March 2023 for clinical use. ResultsAnti-RBD and anti-NCAP antibodies were detected in all 20 batches of assessed IRT solutions (mean concentrations of 2817 IU/mL and 2380 IU/mL, respectively). Notably, the concentration of the virus-specific antibodies increased continuously during the follow-up period (from 822.5 IU/mL to 4066.4 IU/mL and 102 IU/mL to 3455.9 IU/mL). These antibodies demonstrated high virus-neutralizing activity against the Delta variant (mean titers of 436 and 325) but were limited to the Omicron variant (mean titers 78 and 70). The differences observed between the two brands were not statistically significant. ConclusionIRT solutions contain high concentrations of anti-SARS-CoV-2 specific antibodies, which may prevent COVID-19; however, the efficacy can be influenced by variable virus-neutralizing activities against different viral strains. Therefore, appropriate IRT should be combined with other approaches, such as vaccination or pre- and post-exposure prophylaxis. Passively transmitted specific antibodies may also lead to false-positive serological test results.

Rethinking the false positive exercise stress test in the context of coronary microvascular dysfunction

Abstract Background Exercise stress testing (EST) was the traditional tool to detect myocardial ischaemia, but its use has declined due to its perceived high false positive rate. However, EST was historically validated against the reference standard of obstructive coronary artery disease (CAD). It is now well recognised that myocardial ischaemia can occur in the absence of CAD and this cohort, termed angina with non-obstructive coronary arteries (ANOCA), comprises nearly 50% of all patients presenting with stable angina. Purpose Our study assesses the accuracy of EST in detecting a substrate for myocardial ischaemia, with the reference standard being comprehensive coronary physiology assessment in patients with ANOCA. Methods Patients with typical angina and non-obstructive coronary arteries underwent physiological characterisation of the coronary circulation using a dual sensor-tipped intracoronary guidewire in the left anterior descending artery. The epicardial vessel was assessed by Fractional Flow Reserve (FFR) and the microcirculation by both endothelium-independent function (coronary flow reserve, CFR, using intravenous adenosine) and endothelium-dependent function (acetylcholine flow reserve, AChFR, using intracoronary acetylcholine infusion). Those with FFR≤0.80 were excluded per protocol. Coronary microvascular dysfunction was defined a priori as impaired CFR (&amp;lt;2.5) or impaired AChFR (≤1.5). All patients underwent a treadmill EST, using a standard Bruce protocol, with ischaemic electrocardiographic (ECG) changes defined as the appearance of 0.1mV ST-segment depression 80 milliseconds from the J-point. Patients, physiologists, and researchers were all blinded to the coronary physiology data. All data are presented as mean±SD or median (IQR). Results Ninety-one patients [67% female, 62±9 years, CCS 3 (2 to 3)] were recruited into this study. EST was performed 27 (15 to 139) days after angiography. Twenty-seven patients (30%) developed ischaemic ECG changes during their EST (Ischaemic group), whereas 64 patients (70%) did not (Control group). Both groups were phenotypically similar for demographics, risk factors, exercise time and FFR (Figure 1). 100% of the Ischaemic group and 69% of the control group had CMD. Conversely, 38% of patients with CMD developed ischaemic ECG changes on exercise but none (0%) of those with normal microvascular function did (p=0.001) (Figure 2A). The false positive rates with progressively granular reference standards are depicted in Figure 2B; there were no false positive ESTs using a comprehensive physiological reference standard. Angina reported during EST was less specific for CMD than induced ECG changes (70% vs 100%, p&amp;lt;0.001). Conclusions In patients with ANOCA a positive EST is always indicative of CMD. The potential utility of EST as a rule-in test for CMD makes it an attractive non-invasive widely available test that could be re-integrated into clinical pathways for assessing new onset angina.Patient characteristicsEST versus coronary physiology

Facile synthesis of 14 C-nitrofurazone from 14 C-urea.

The veterinary drug nitrofurazone (5-nitro-2-furaldehyde semicarbazone) exhibits excellent antimicrobial properties but its application in food-producing animals is prohibited. The illegal use of nitrofurazone is regularly monitored by food regulatory agencies. Currently, semicarbazide (SEM) is used as a marker of nitrofurazone exposure. However, the use of SEM as a marker of nitrofurazone is under scrutiny after evidence of a high incidence of false positive tests. To overcome the current dilemma, it is necessary to identify a nitrofurazone-specific marker analyte which requires conducting nitrofurazone metabolism studies in food-producing animals. The use of carbon-14 labeled nitrofurazone would facilitate metabolism studies and structural elucidation of nitrofurazone metabolites of possible utility as a marker compound. In the present work, a synthetic method is described to procure radiolabeled nitrofurazone that incorporates 14 C- carbon at the semicarbazide moiety. The method incorporates 14 C-carbon via employing readily available and more economically affordable [14 C]-urea compared with [14 C]-semicarbazide. To the best of our knowledge, there is no report on the synthesis of 5-nitro-2-furaldehyde [14 C]-semicarbazone from 14 C-urea. The developed method involves monoamination of [14 C]-urea followed by a condensation reaction with 5-nitro-2-furaldehyde to produce 5-nitro-2-furaldehyde [14 C]-semicarbazone in 85% yield with greater than 98% radiochemical purity.

'Pitfalls for differentiating basal cell carcinoma from non-basal cell carcinoma on optical coherence tomography: A clinical series'.

Optical coherence tomography (OCT), a non-invasive diagnostic modality, may replace biopsy for diagnosing basal cell carcinoma (BCC) if a high-confidence BCC diagnosis can be established. In other cases, biopsy remains necessary to establish a histopathological diagnosis and treatment regimen. It is, therefore, essential that OCT assessors have a high specificity for differentiating BCC from non-BCC lesions. To establish high-confidence BCC diagnoses, specific morphological BCC characteristics on OCT are used. This study aimed to review several cases of non-BCC lesions that were misclassified as BCC by experienced OCT assessors, thereby providing insight into the causes of these misclassifications and how they may be prevented. The study population consisted of patients who had a histopathologically-verified non-BCC lesion. Patients from Maastricht University Medical Center+ from February 2021 to April 2021 were included in the study. Two independent OCT assessors assessed OCT scans. One OCT assessor recorded the presence or absence of validated morphological BCC characteristics. A false-positive OCT test result was defined as certainty of BCC presence in a non-BCC lesion. The frequency of misclassifications and the presence or absence of morphological BCC features are discussed. A total of 124 patients with non-BCC lesions were included. Six patients were misclassified by both OCT assessors and are discussed in more detail. Histopathological diagnoses were squamous cell carcinoma (n = 2/21), actinic keratosis (n = 2/29), squamous cell carcinoma insitu/Bowen's disease (n = 1/16), or interphase dermatitis (n = 1/4). In all misclassified cases, multiple, apparent morphological BCC characteristics on OCT were present. Most non-BCC lesions are recognized as such by OCT assessors. However, there remains a small risk that a high-confidence BCC diagnosis is established in non-BCC lesions wherein features mimicking validated BCC characteristics are present. Misclassification may be prevented by careful delineation of epidermal layers and good differentiation between dermal ovoid structures typical of BCC versus squamous cell carcinoma.

Telomere Length Testing of Lymphocytes Alone By Flow-FISH Is a Highly Sensitive and Specific Test to Screen for a Telomere Biology Disorder in a Cohort of Children and Very Young Adults with Bone Marrow Failure

Background Uncovering an underlying telomere biology disorder (TBD) in patients with bone marrow failure (BMF) has crucial implications for treatment and outcomes, including hematopoietic cell transplantation and malignancy risk. Telomere length (TL) testing of peripheral blood leukocytes by clinical Flow-FISH has become an important test in diagnosing TBDs. In seminal studies, Alter et al. compared age-adjusted TL lengths (&amp;lt; or ≥1 st percentile) in lymphocytes (lymphs), granulocytes (grans), and four lymph subsets in individuals with a known TBD and their unaffected relatives. They found that very low (VL) TL (&amp;lt;1 st percentile) in lymphs had a sensitivity (Sens) of 97%, specificity (Spec) of 91%, and positive predictive value (PPV) of 85% for a TBD diagnosis. VL TL in 3 or 4 lymph subsets had slightly better test performance with a Sens of 98%, Spec of 94%, and PPV of 89%. We hypothesized that test performance characteristics of flow FISH would be different if applied to a ‘real-world’ cohort, which could inform the use of TL in lymphs alone versus in the four lymph subsets for different clinical indications. Methods We performed a search of the electronic medical record to identify all individuals who had Flow-FISH performed at Texas Children's Hospital from 2007 - 2022 (Figure 1). We excluded those who had the 2-panel test (lymphs and grans) or family TL cascade testing. We collected the indication for and results of Flow-FISH, demographic and clinical characteristics, and genetic testing information via chart review. A composite score (Comp Score) was created to define TBD (Comp Score of 1 or 2) vs. Not TBD (Comp Score &amp;lt;1). Performance of lymph TL alone and TL in 3 or 4 lymph subsets in predicting TBD was evaluated using Sens, Spec, PPV, NPV, area under ROC curve (AUC), and Cohen's Kappa statistic (k). Results Our final cohort included 433 individuals who received the 6-panel test (lymphs, grans, and four lymph subsets) with a median age of 9.7 years, range 0.06-22.6. Top indications for Flow-FISH were severe aplastic anemia (SAA) (n=106), mild aplastic anemia (AA) (i.e., not fulfilling criteria for MAA or SAA) (103), cytopenias without known or documented bone marrow hypoplasia or dysplasia (70), moderate aplastic anemia (MAA) (37), non-therapy-related myelodysplastic syndrome (26), and an incidental TBD gene variant identified through comprehensive sequencing (17). Twenty-two subjects (5.1%) had a TBD, 17 (3.9%) of which had a pathogenic/likely pathogenic variant (P/LPV) in a known TBD gene (Figure 1). Seven of those with SAA (6.6%) had VL TL in lymphs, 5 (4.7%) of which also had VL TL in 3 or 4 of the lymph subsets, and only 1 (0.9%) had a TBD based on Comp Score. Importantly, none had VL TL in 3 or 4 of the lymph subsets without VL TL in lymphs. Five of those with MAA (13.5%) had VL TL in lymphs, all of which had VL TL in 3 or 4 lymph subsets. Three had a TBD based on Comp Score, and each had a PV in a TBD gene; a TBD variant was not identified in two despite exome sequencing and chromosomal microarray testing. Eighteen of those with mild AA (17.5%) had VL TL in lymphs, 15 (14.6%) also had VL TL in 3 or 4 lymph subsets, 9 (8.7%) had a TBD based on Comp Score, and 7 (6.8%) had a P/LPV in a TBD gene. The Sens of TL in lymphs &amp;lt; vs. ≥ 1 st percentile and TL &amp;lt; 1 st percentile in 3 or 4 vs. &amp;lt; 3 lymph subsets against TBD based on Comp Score in those with AA regardless of severity was 100%, and the Spec ranged from 90.4% (lymph TL testing alone in mild AA) to 96.2% (lymph subsets testing in SAA) (Table 1). The PPV for both test approaches was low (≤20%) in SAA due to the low prevalence of TBD in this population. PPV was between 50-60% in the other AA groups. The AUC for detecting a TBD in the various AA groups was comparably high for both test approaches (0.95-0.98). The two tests had a substantial to almost perfect agreement (k=0.82, p&amp;lt;0.001). Conclusions This single institutional cohort demonstrates that the prevalence of TBD in young patients presenting with SAA is remarkably low, and the Sens and Spec of TL testing in lymphs alone are sufficiently high to detect the rare TBD patient and prompt additional testing (e.g., genetics) in few patients due to false positive testing. The prevalence of TBD is higher in those with MAA or mild AA, yet both test approaches detect all TBD patients. Spec level in mild AA is marginally higher with lymph subset TL testing but, at ~94%, underscores the need for other clinical parameters (e.g., genetics) to establish a TBD diagnosis in a small percentage of patients.

Assessing the impact of increasing lung screening eligibility by relaxing the maximum years-since-quit threshold: Asimulation modeling study.

In 2021, the US Preventive Services Task Force expanded its lung screening recommendation to include persons aged 50-80 years who had ever smoked and had at least 20 pack-years of exposure and less than 15 years since quitting (YSQ). However, studies have suggested that screening persons who formerly smoked with longer YSQ could be beneficial. The authors used two validated lung cancer models to assess the benefits and harms of screening using various YSQ thresholds (10, 15, 20, 25, 30, and no YSQ) and the age at which screening was stopped. The impact of enforcing the YSQ criterion only at entry, but not at exit, also was evaluated. Outcomes included the number of screens, the percentage ever screened, screening benefits (lung cancer deaths averted, life-years gained), and harms (false-positive tests, overdiagnosed cases, radiation-induced lung cancer deaths). Sensitivity analyses were conducted to evaluate the effect of restricting screening to those who had at least 5 years of life expectancy. As the YSQ criterion was relaxed, the number of screens and the benefits and harms of screening increased. Raising the age at which to stop screening age resulted in additional benefits but with more overdiagnosis, as expected, because screening among those older than 80 years increased. Limiting screening to those who had at least 5 years of life expectancy would maintain most of the benefits while considerably reducing the harms. Expanding screening to persons who formerly smoked and have greater than 15 YSQ would result in considerable increases in deaths averted and life-years gained. Although additional harms would occur, these could be moderated by ensuring that screening is restricted to only those with reasonable life expectancy.

False positive non-invasive prenatal testing (NIPT) for trisomy 21 in vanishing twin syndrome pregnancy: A comparison of the NIPT results performed in different gestations

False positive non-invasive prenatal testing (NIPT) for trisomy 21 in vanishing twin syndrome pregnancy: A comparison of the NIPT results performed in different gestations

Non-Asymptotic Guarantees for Reliable Identification of Granger Causality via the LASSO.

Granger causality is among the widely used data-driven approaches for causal analysis of time series data with applications in various areas including economics, molecular biology, and neuroscience. Two of the main challenges of this methodology are: 1) over-fitting as a result of limited data duration, and 2) correlated process noise as a confounding factor, both leading to errors in identifying the causal influences. Sparse estimation via the LASSO has successfully addressed these challenges for parameter estimation. However, the classical statistical tests for Granger causality resort to asymptotic analysis of ordinary least squares, which require long data duration to be useful and are not immune to confounding effects. In this work, we address this disconnect by introducing a LASSO-based statistic and studying its non-asymptotic properties under the assumption that the true models admit sparse autoregressive representations. We establish fundamental limits for reliable identification of Granger causal influences using the proposed LASSO-based statistic. We further characterize the false positive error probability and test power of a simple thresholding rule for identifying Granger causal effects and provide two methods to set the threshold in a data-driven fashion. We present simulation studies and application to real data to compare the performance of our proposed method to ordinary least squares and existing LASSO-based methods in detecting Granger causal influences, which corroborate our theoretical results.

The dexamethasone assay as a useful tool to identify false positive dexamethasone screening test results

The dexamethasone assay as a useful tool to identify false positive dexamethasone screening test results

Hepatocellular carcinoma surveillance in cirrhotic patients: Beyond guidelines

Hepatocellular carcinoma (HCC) surveillance of individuals with cirrhosis or other conditions that confer a high risk of HCC development is essential for early detection and improved overall survival. HCC surveillance is a complex process, with failure at any step in the process contributing to a gap between its efficacy and effectiveness. Biannual ultrasonography with or without alpha-fetoprotein is widely recommended as the standard method for HCC surveillance, but it has limited sensitivity in early disease and may be inadequate in certain individuals. HCC surveillance implementation can be affected by either provider or patient-related factors. Proper screening for HCC is a continuum of services, extending from initial patient screening, diagnosis, treatment and ultimately surveillance. As one may expect, there are numerous chances for failure in the delivery of cancer screening care. When considering the risk versus benefits of HCC surveillance, we must consider the possible harm to the patient. Such concerns include false-positive testing resulting in unnecessary and risk-associated procedures such as liver biopsy, overdiagnosis of HCC among patients with cirrhosis, as well as false-negative investigations resulting in delayed diagnosis of HCC. The development of tools to enhance our ability in optimizing available surveillance is likely to improve the prognosis of patients with HCC. This review article will provide a comprehensive overview of the rationale behind current HCC surveillance guidelines, their utilisation, effectiveness, limitations, benefits, and harms as well as methods to improve the outcome of HCC surveillance.

False-positive Aspergillus galactomannan immunoassay in the glucose component of total parenteral nutrition products.

In October 2022, we experienced a significant increase in samples showing high galactomannan (GM) indexes ranging from 6.22 to 10.58, as determined by the Platelia Aspergillus antigen immunoassay, also known as the GM test. After reviewing the medical records of nine GM antigenemia cases that did not show evidence of invasive aspergillosis, we found that these patients had received total parenteral nutrition (TPN) products from the same manufacturer, whose supplier of the glucose component had recently changed. The TPN products supplied by the specific manufacturer in October were subjected to a GM assay. The glucose component of the products from three different lot numbers exhibited strong positive results in the GM assay. Microbiological investigations through fungal culture and PCR on the TPN products were negative. The present study demonstrated that the glucose component of the TPN products contained a high level of GM antigen, which caused false-positive GM test results. The source of GM in the glucose component was glucoamylase, which was produced from Aspergillus niger to obtain glucose monohydrate from starch. Investigation of three commercially available glucoamylase products exhibited positive GM and 1,3-β-D-glucan tests with various titers positive up to 1:1,000 dilutions, while fungal cultures were all negative. Quality assurance measures of TPN products to prevent GM contamination should be emphasized during the manufacturing process to avoid unnecessary additional diagnostic procedures and overtreatment of invasive aspergillosis due to false-positive GM tests.IMPORTANCEThis manuscript describes an occurrence of false-positive GM tests in patients receiving TPN products from a manufacturer who had recently changed the supplier of the glucose component. We describe the clinical presentation of nine false-positive cases and the results of serologic and microbiological investigations of the TPN products suspected of contamination with GM. Attempts to detect GM in parenteral nutrition products were made since the detection of GM in sodium gluconate-containing solutions in 2007, but none of them identified the source of elevated GM indexes in TPN products. However, the present study demonstrated that the glucose component of the TPN products contained a high level of GM antigen, which caused false-positive GM assay results. The source of GM was glucoamylase, which was derived from A. niger in the manufacturing process. Physicians and clinical microbiology laboratories should be aware of this issue to improve interpretation and patient care.