False-negative Screening Results Research Articles

Evaluation of the analytical performance of four different manufacturer's reagent red blood cells in antibody detection and identification.

The detection/identification of clinically significant antibodies to red cell antigens form the foundation for safe transfusion practices. This study aimed to evaluate the diagnostic performance of commercially available 0.8% reagent red blood cells (RRBCs) in Australia. 166 patient-derived plasma samples with a positive indirect antiglobulin test (IAT) were tested using column agglutination technology (CAT) with Immulab, Bio-Rad, Grifols and QuidelOrtho screening and identification RRBCs with the respective manufacturer's proprietary CAT system. False-negative antibody screening and identification results were obtained with Bio-Rad (3/61), Grifols (14/68) and Quidel-Ortho (3/59) RRBCs when tested with the respective manufacturer's proprietary CAT system. Zero false-negative results were observed with Immulab RRBCs when tested with samples across all platforms. The sensitivity of the RRBCs used in this study were calculated to be 95.83% (95%CI 88.30-99.13%) for Bio-Rad RRBCs, 82.50% (95%CI 72.38-90.09%) for Grifols RRBCs and 95.65% (95%CI 87.82-99.09%) for QuidelOrtho RRBCs. The sensitivity of Immulab RRBCs were stratified based on performance in the 3 CAT platforms: Bio-Rad CAT (100%, 95%CI 95.01-100%), Grifols CAT (100%, 95%CI 95.49-100%) and QuidelOrtho CAT (100%, 95%CI 94.79-100%). RRBCs used in antibody detection and identification vary in diagnostic performance and should therefore be carefully considered before being implemented in routine patient testing.

Severe lung disease in children with cystic fibrosis missed in newborn screening.

Cystic fibrosis (CF) is now routinely diagnosed through newborn screening (NBS), but the tests employed in the USA have been evolving for two decades as missed cases become recognized and lab methods improve in association with more knowledge about CF genetics. New Jersey was among the first states to implement CF NBS in 2001 when it introduced the original two-tiered method that combined measurements of immunoreactive trypsinogen (IRT) with detection of the principal pathogenic variant (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. With continuation of the IRT/DNA (F508del) algorithm for two decades and identification of screening false negative children, we decided to examine the condition of some missed cases with special attention to their respiratory status. To strengthen the arguments for quality improvement in New Jersey's CF NBS program, we reviewed and evaluated false negative cases to determine the potential extent of preventable patient suffering as a consequence of delayed diagnoses. Five children with CF who had false negative screening results were studied in detail. In each case there was a different cause of the negative screening results. They all had clinically significant/severe lung disease, ranging from chronic cough with CF pathogens on respiratory culture at a young age to respiratory failure. This case series highlights the consequences of false negative screening results, which served as the impetus to upgrade New Jersey's CF NBS algorithm. Implemented changes include lowering the IRT cutoff to 70 ng/mL and expanding to a 139 variant CFTR panel. In 2023, a floating IRT cutoff is anticipated to be implemented.

Vergleich von Diagnosedaten nach der Einführung des Mukoviszidosescreenings bei Neugeborenen in Deutschland

ZusammenfassungHintergrundZum 01.09.2016 wurde das Neugeborenenscreening (NGS) auf Mukoviszidose (Cystic Fibrosis – CF) in Deutschland eingeführt. Bisher gibt es keinen epidemiologischen Goldstandard für die Erfassung der Diagnosezahlen. Daher werden Daten der in der Konfirmationsdiagnostik bestätigten Fälle der Deutschen Gesellschaft für Neugeborenenscreening (DGNS) und die Diagnosehäufigkeiten des Deutschen Mukoviszidoseregisters (DMR) gegenübergestellt. Dies kann auch die Evaluation des CF-Screenings unterstützen. Ziel der Arbeit ist es, die Daten der DGNS und des DMR zu vergleichen und Limitationen sowie Stärken dieser Datenquellen darzustellen.MethodenAnalysiert werden die Mukoviszidose-Diagnosedaten der DGNS (Datenstand 14.04.2023) und des DMR (Datenstand 12.04.2023) für 2017–2021 geborene Kinder im Hinblick auf Häufigkeiten, Anzahl falsch-negativ Gescreenter und Verhältnis CF zu „Fällen mit positivem Mukoviszidosescreening und unklarer Konfirmationsdiagnostik“ (CFSPID).ErgebnisseDer DGNS liegen 767 Datensätze von Neugeborenen mit CF/CFSPID vor, dem DMR 910 bestätigte Diagnosefälle CF/CFSPID. Ein falsch-negatives Screening wird von der DGNS für 37/767 (4,8 %) und vom DMR für 49/910 (5,4 %) berichtet. Das Verhältnis von CF zu CFSPID beträgt 17,4:1 (DGNS, 2017–2020) bzw. 28,1:1 (DMR).DiskussionDie DGNS und das DMR liefern bei unterschiedlichen Stärken in der Dokumentation der Screening-(DGNS) und Diagnosedaten (DMR) wichtige Anhaltspunkte für die Anzahl neu diagnostizierter Mukoviszidosepatienten nach Einführung des NGS. Gesetzliche Vorgaben zur Nachverfolgung der Gescreenten und Erfassung aller Kinder mit Mukoviszidose sowie der Datenaustausch zwischen DGNS und DMR könnten zukünftig die Evaluation verbessern.

S Estimation of HbA2 Alone Sufficient for Screening Beta Thalassaemia Carriers: A Case in Perspective

Beta thalassaemia is one of the most common inherited haemoglobinopathies, characterised by reduced or absent production of the beta globin chain. In India, the carrier frequency of thalassaemia is estimated to be 3-4%. The prevention of Beta thalassaemia is the best strategy, and this can be achieved through carrier screening and prenatal diagnosis. Carriers of beta thalassaemia can be easily identified using haematological parameters such as complete blood count and High Performance Liquid Chromatography (HPLC) for haemoglobin analysis. The characteristic findings observed in thalassaemia carriers include microcytosis, hypochromia, with a Mean Corpuscular Volume (MCV) of less than 80 fL and Mean Corpuscular Haemoglobin (MCH) of less than 28 pg. They also present with elevated levels of HBA2 (α2δ2) ≥3.5%. Carrier screening for beta thalassaemia primarily relies on the observation of elevated HbA2 levels. However, in rare cases, some carriers can have normal HbA2 levels, leading to false-negative screening results. In a case involving a married couple who underwent routine preconceptional screening by complete blood count and HPLC for thalassaemia screening, the male partner had elevated HbA2 levels (5.2%), while the female partner had normal HbA2 levels (1.6%). Molecular testing revealed that the male partner was heterozygous for the Intervening Sequence (IVS) 1-5 (G>C) mutation, while the female partner was found to be heterozygous for the CD41-42 (-CTTT) mutation. It is important to consider molecular testing of the HBB gene in couples, even if one partner is a carrier and the other partner has normal or borderline HbA2 levels.

Online information about mammography screening in Italy from 2014 to 2021

BackgroundMany studies have reported that the information women receive about the risk-to-benefit ratio of breast cancer screening is still scarce and biased toward benefit. In a study we conducted in 2014, we analysed online documents about breast cancer screening that were addressed to the general female public. In the present study, we used the same methodology to verify if the information provided to women was improved.MethodsWe evaluated documents addressed to the general female public and posted on the Internet by the Italian national and regional public health services. False-positive and false-negative screening results, biopsy-proven false-positive results, interval cancer, overdiagnosis, radiation exposure, and decrease in risk of mortality were analysed. In addition, quantitative data were searched.ResultsIn 2021, the most frequently reported information was reduction in breast cancer mortality (58.2%). The most frequently reported risk was a false-positive mammogram (42.5%). Similar frequency rates were reported for interval cancer, false-negative result, and radiation exposure (35.8%, 31.3%, and 28.3%, respectively). Overdiagnosis and biopsy-proven false-positive result were the less reported risks (20.1% and 10.4%). Thirteen documents provided quantitative data about reduction of mortality risk (16.7%), and only 19 provided quantitative data about risks or harms (8.4%). Almost all organisations sent letters of invitation to women (92.5%) and provided screening free of charge (92.5%). The most recommended was biennial screening for women aged between 50 and 69 years (48.5%). Compared with the information in 2014, that in 2021 showed some improvements. The most marked improvements were in the numbers of reports on overdiagnosis, which increased from 8.0 to 20.1%, and biopsy-proven false-positive result, which increased from 1.4 to 10.4%. Regarding the benefits of breast cancer screening, reduced mortality risk became increasingly reported from 2014 (34.5%) to 2021 (58.2%). Conversely, quantitative data remained scarce in 2021.ConclusionsModerate improvements in information were observed from 2014 to 2021. However, the information on breast cancer screening in documents intended for women published on Italian websites remain scarce.

The low excretor phenotype of glutaric acidemia type I is a source of false negative newborn screening results and challenging diagnoses.

BackgroundGlutaric acidemia type I (GA1) is an organic acidemia that is often unrecognized in the newborn period until patients suffer an acute encephalopathic crisis, which can be mistaken for nonaccidental trauma. Presymptomatic identification of GA1 patients is possible by newborn screening (NBS). However, the biochemical “low‐excretor” (LE) phenotype with nearly normal levels of disease metabolites can be overlooked, which may result in untreated disease and irreversible neurological sequelae. The LE phenotype is also a potential source of false negative (FN) NBS results that merits further investigation.MethodsSamples from six LE GA1 patients were analyzed by biochemical and molecular methods and newborn screen outcomes were retrospectively investigated.ResultsFive LE GA1 patients were identified that had normal NBS results and three of these presented clinically with GA1 symptoms. One additional symptomatic patient was identified who did not undergo screening. Semiquantitative urine organic acid analysis was consistent with a GA1 diagnosis in two (33%) of the six patients, while plasma glutarylcarnitine was elevated in four (67%) of the six and urine glutarylcarnitine was elevated in four (80%) of five patients. Five GCDH variants were identified in these patients; three of which have not been previously linked to the biochemical LE phenotype.ConclusionsThe data presented here raise awareness of potential FN NBS results for LE GA1 patients. The LE phenotype is not protective against adverse clinical outcomes, and the possibility of FN NBS results calls for high vigilance amongst clinicians, even in the setting of a normal NBS result.

THE EFFECT OF RAMIPRIL ON THE ALDOSTERONE/RENIN RATIO AND THE ALDOSTERONE/ANGIOTENSIN II RATIO IN PATIENTS WITH PRIMARY ALDOSTERONISM

Objective: The aldosterone/renin ratio (ARR) is recommended for case detection of PA. However, many anti-hypertensive medications [such as angiotensin-converting enzyme (ACE) inhibitors] and physiological factors have been reported to affect renin and aldosterone, thereby causing false-negative ARR screening results. We sought to investigate the diagnostic performance of the ARR and aldosterone/AngII ratio (AA2R) among PA patients receiving ramipril treatment. Design and method: Blood samples from 60 PA and 40 non-PA patients were collected, aiming to predict optimal PA screening cut-offs for the ARR and AA2R (using ROC analysis). Another 26 PA patients were recruited and were administered ramipril (5 mg tablet, once daily) for 2 weeks. Blood was collected in the morning of day 0 (basal), day 14 (2 h after taking ramipril) and day 15 (26 h after last dose ramipril). Plasma aldosterone (PAC), equilibrium AngI and AngII (eqAngI and eqAngII) were measured by LC-MS/MS, while renin concentration (DRC) and activity (PRA) were measured by immunoassays. Results: When PAC was measured by LC-MS/MS, the predicted PA screening cut-offs for the ARR_DRC, ARR_PRA and AA2R were 53.9 (pmol/mU), 495.9 (pmol/L)/(ng/ml/h) and 8.3 (pmol/pmol), respectively. Compared to the basal levels, eqAngII and ACE activity (ACE-S, eqAngII/eqAngI) both decreased (P < 0.01) after ramipril treatment, whereas DRC, PRA and eqAngI all increased (P < 0.01 or P < 0.05). Although median PAC tended to fall from 504.9 (day 0) to 458.3 (day 14) and to 488.0 (day 15) pmol/L, the changes were not statistically significant. On day 14, five patients displayed false-negative results in both ARR_DRC and ARR_PRA, whereas no false-negative AA2R result was observed. On day 15, three patients still demonstrated false-negative screening results, including one with both false-negative ARR_DRC and ARR_PRA, one with both false-negative ARR_DRC and AA2R, and one with false-negative ARR_PRA only. Conclusions: Although PAC did not change significantly, the changes of renin, eqAngI, eqAngII and ACE-S were consistent with ramipril's effect on ACE. Unlike the ARR which can be affected by ACE inhibitors causing false-negative screening results, the AA2R seems to be superior in PA screening among subjects who are receiving ACE inhibitors.

False Negative Critical Congenital Heart Disease Screening Result Arising from a Complex Cardiac Disease with Duct Dependent Systemic Circulation

Background: Critical congenital heart disease (CCHD) encompasses congenital structural heart defects that cause significant morbidity and mortality in the first few weeks of life unless treated and/or require surgery or catheter intervention within the 1st year of life. Since these deteriorate acutely due to their cardiac condition, they may be misdiagnosed as septicemia or perinatal asphyxia, especially in resource-poor settings. The American Academy of Pediatrics recommends universal screening with pulse oximetry after 24 h of life by a simple screening protocol. Although specificity is high, CCHD may be missed. We present a case who screened negative became symptomatic on day 10 of life and was finally diagnosed with a CCHD. Clinical Description: A full-term baby with uneventful postnatal course and negative CCHD screening was discharged on day 2 of life. He returned on day 10 with cardiogenic shock. Echocardiography confirmed interrupted aortic arch with large ventricular septal defect (VSD), moderate-sized atrial septal defect (ASD), and a small, restrictive patent ductus arteriosus (PDA). The initial false-negative result was attributed to the presence of large VSD that leads to equalization of preductal and postductal oxygen saturations. Management: The baby was stabilized with prostaglandin infusion and ventilatory support. He underwent staged repair with end-to-end anastomosis of interrupted segment and PDA ligation in the first sitting. The postoperative course was uneventful, and the patient was discharged home at day 25 of life. He is planned for VSD and ASD repair in follow-up. Conclusion: Complex heart diseases may behave unusually due to complicated inter-related hemodynamics arising from the various lesions. Primary health-care personnel should recognize the limitations of CCHD screening protocol and learn to counsel parents accordingly.

The cytological component of cervical cancer screening: causes of false negative and false positive results, and ways to avoid them

Cervical cancer (CC) screening is a major component of secondary prevention of CC and involves screening all women at risk of developing this disease, most of whom are asymptomatic. Cytology remains an important component of CC screening in the era of primary screening by genotyping the human papillomavirus. Papanikolaou staining is the method of choice for CC screening. This review highlights the causes of false negative results for various methods of Pap tests and how they can be prevented. A detailed analysis of conditions accompanied by a high probability of false positive abnormal results of the Pap test, an explanation of the pathophysiological basis of this phenomenon, clinical and cytological criteria for differential diagnosis is also presented.Pap test is a screening test. The aim of the cytological examination in CC screening is to assign the patient to a group with absent neoplastic changes in the cervical epithelium, a group with neoplastic changes in the cervical epithelium present, or a group when it is impossible to make an accurate differential diagnosis between benign reactive changes and neoplasia. The Bethesda Cytology Reporting System is used to unify and standardize these categories in most countries of the world. Benign conditions are a common cause of false positive reports of cellular atypia on cervical screening, as evidenced by a large number of studies. This fact should be taken into account both in the interpretation of the results and, if possible, in the planning of cervical screening. The most common conditions that are accompanied by reactive changes in the cervical epithelium, which can be incorrectly assessed as atypia, are: reactive and reparative inflammatory changes, atrophy, metaplasia, reactive changes caused by intrauterine devices. In this regard, when working with the cytological component of cervical screening, it is important for the clinician to understand the basic principles of assessing the cervical epithelium, which will allow using the descriptive part of the report to determine tactics if a false negative or false positive screening result is suspected.Thus, understanding the impact of common benign conditions on the cervical epithelium makes it possible to rationally plan cytological cervical screening and correctly interpret its results in order to achieve the best clinical results that are not limited to the detection of precancerous conditions.

Hypertension Editors' Picks: Hyperaldosteronism.

Hypertension Editors' Picks: Hyperaldosteronism.

Congenital Hypothyroidism: A Review of 2020 European Society for Pediatric Endocrinology and the European Society for Endocrinology Consensus Guidelines

Congenital Hypothyroidism: A Review of 2020 European Society for Pediatric Endocrinology and the European Society for Endocrinology Consensus Guidelines

Extension of platelet shelf life with an improved bacterial testing algorithm.

At Canadian Blood Services, platelet concentrate (PC) shelf life was extended to 7 days with a large-volume, delayed-sampling bacterial screening algorithm. We present the development study and postimplementation results. In the development study, PCs inoculated with five bacteria (various concentrations) were incubated for 7 days with daily sampling for BacT/ALERT cultures and bacterial quantification. After implementation, from August 2017 to December 2019, a total of 223 156 pools and 39 725 apheresis units and 5310 outdated PCs were screened. Since March 2018, cocomponents associated to false-positive results have been released to inventory. In the development study, Klebsiella pneumoniae, Serratia marcescens, and Staphylococcus aureus were detected at concentrations of at least 0.01 colony-forming units (CFUs)/mL at 24 hours postinoculation. However, Staphylococcus epidermidis was detected at concentrations of less than 0.16 CFUs/mL only more than 48 hours postinoculation. After implementation, 776 (0.35%) and 303 (0.77%) initial-positive results and 201 (0.09%) and 16 (0.04%) confirmed-positive results were obtained for pools and apheresis units, respectively, predominantly with Cutibacterium acnes. Other organisms included staphylococci, streptococci, Klebsiella oxytoca and Pseudomonas aeruginosa. One nonfatal reaction involving a 7-day pool contaminated with S. epidermidis occurred. Approximately, 1-in-1000 false-negative screening results were obtained during testing of outdated PCs. Approximately 1000 cocomponents associated with false-positive results were released into inventory. Combined PC outdating at Canadian Blood Services and hospitals was reduced from 18.9% to 13.1%. Screening of 7-day PCs increased bacterial detection mainly of anaerobes and reduced outdating. The incidence of septic transfusion events has decreased approximately threefold. A longer surveillance period is needed to evaluate the value of anaerobic cultures and residual safety risk.

Challenges for cocaine detection in smuggling samples

Screening of seized cocaine powders is routinely performed by means of colour tests. An alternative fast screening technique is Mid-InfraRed (MIR) spectroscopy. In the context of smuggling cases, however, drugs are often processed to circumvent detection. In this study, the current screening techniques (cocaine colour test and MIR spectroscopy using libraries and chemometrics) were applied to five smuggling cases. For each case, all samples were first screened with a cocaine colour test and MIR analysis, followed by confirmation analyses with GC–MS and GC-FID to identify and quantify cocaine and cutting agents. Finally, Scanning Electron Microscopy-Energy Dispersive X-ray spectroscopy (SEM-EDX) analyses were performed for additional characterization. All smuggling samples tested negative, both on-site as in the laboratory, for cocaine with the cocaine colour test. Four smuggling cases consisted of coloured samples. Consequently the colour test result was influenced because discolouration of the test showed almost the same colour as the colour of the powders (brown, green, red or black). In contrast, the (coloured) powders could be measured with MIR, but the MIR spectra showed no hit for cocaine using a reference library search. Moreover, cocaine was not detected in four out of the five cases after application of a chemometric classification model. GC–MS analysis, the golden standard for identification, resulted in a positive identification of cocaine in all cases. These samples contained cocaine ranging between 0.8w% and 35w%. Taking into account the results of the screening, the chromatographic and the SEM-EDX analyses, it could be presumed that cocaine was masked. False negative screening results were caused by chemically modified cocaine and/or cocaine mixed with coloured powders. In additional experiments, a sample extraction step prior to the screening techniques was performed. Two sample preparation methods (acetone and ethyl acetate) were tested and resulted in a positive screening of cocaine with the colour test and/or MIR spectroscopy. It can be concluded that the outcome of screening techniques such as colour tests and MIR spectroscopy is only presumptive and should always be confirmed.

State-wide utilization and performance of traditional and cell-free DNA-based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study.

To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and < 0.1% (n = 35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95% CI, 82.64-93.93%) for a screen-positive rate (SPR) of 2.94%. There were 12 false-negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95% CI, 95.00-100%) for a SPR of 1.21%. When high-risk cfDNA results for any chromosome (including the sex chromosomes) and failed cfDNA tests were treated as screen positives, the SPR for cfDNA increased to 2.42%. The risk of any major chromosomal abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low-risk screening result was 1 in 1188 for CFTS (n = 37) and 1 in 762 for cfDNA (n = 16) (P = 0.13). The range of chromosomal abnormalities detected after a low-risk cfDNA result included pathogenic copy-number variants (n = 6), triploidy (n = 3), rare autosomal trisomies (n = 3) and monosomy X (n = 2). Our state-wide record-linkage analysis delineated the utilization and clinical performance of the multitude of prenatal screening pathways available to pregnant women. The sensitivity of cfDNA for T21, T18 and T13 was clearly superior to that of CFTS. While there was no statistically significant difference in the residual risk of any major chromosomal abnormality after a low-risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosomal abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

False-Positive Results in Pregnancy Screening for Aneuploidy

Objectives: The screening of chromosomal aberrations is one of the most common methods during pregnancy although this test is occasionally false-positive. Materials and Methods: In this case-control study, 252 mothers with false-positive (n=126) and -negative (n=126) tests were evaluated respectively. Demographic data during pregnancy and postpartum included maternal and neonatal complications, and finally, perinatal variables were compared between the two groups. Results: The mean age of the case group was significantly higher than that of the control group (P &lt; 0.001). In addition, lower smoking history in the spouse (P = 0.01), higher prevalence of preeclampsia (P = 0.33) and proteinuria (P = 0.03), preterm infant (P = 0.01), and low birth weight (P = 0.04) were observed in this group as well. Eventually, the shorter height P = 0.004) and lower 5-minute Apgar score (P = 0.03) were found in infants. Conclusions: In general, mothers with positive screening results showed a higher risk of preeclampsia and preterm labor in comparison with those with false-negative screening results.

Effects of Ramipril on the Aldosterone/Renin Ratio and the Aldosterone/Angiotensin II Ratio in Patients With Primary Aldosteronism.

The aldosterone/renin ratio (ARR) is currently considered the most reliable approach for case detection of primary aldosteronism (PA). ACE (Angiotensin-converting enzyme) inhibitors are known to raise renin and lower aldosterone levels, thereby causing false-negative ARR results. Because ACE inhibitors lower angiotensin II levels, we hypothesized that the aldosterone/equilibrium angiotensin II (eqAngII) ratio (AA2R) would remain elevated in PA. Receiver operating characteristic curve analysis involving 60 patients with PA and 40 patients without PA revealed that the AA2R was not inferior to the ARR in screening for PA. When using liquid chromatography-tandem mass spectrometry to measure plasma aldosterone concentration, the predicted optimal AA2R cutoff for PA screening was 8.3 (pmol/L)/(pmol/L). We then compared the diagnostic performance of the AA2R with the ARR among 25 patients with PA administered ramipril (5 mg/day) for 2 weeks. Compared with basally, plasma levels of equilibrium angiotensin I (eqAngI) and direct renin concentration increased significantly (P<0.01 or P<0.05) after ramipril treatment, whereas eqAngII and ACE activity (eqAngII/eqAngI) decreased significantly (P<0.01). The changes of plasma renin activity and plasma aldosterone concentration in the current study were not significant. On day 14, 4 patients displayed false-negative results using ARR_direct renin concentration (plasma aldosterone concentration/direct renin concentration), 3 of whom also showed false-negative ARR_plasma renin activity (plasma aldosterone concentration/plasma renin activity). On day 15, 2 patients still demonstrated false-negative ARR_plasma renin activity, one of whom also showed a false-negative ARR_direct renin concentration. No false-negative AA2R results were observed on either day 14 or 15. In conclusion, compared with ARR which can be affected by ACE inhibitors causing false-negative screening results, the AA2R seems to be superior in detecting PA among subjects receiving ACE inhibitors.

OC01.03: State‐wide performance of traditional and cell‐free DNA‐based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study

OBJECTIVES: Women's choices of prenatal screening and diagnostic pathways have increased in complexity since the introduction of cell-free DNA (cfDNA) screening and chromosomal microarrays. We performed individual record-linkage of women undergoing screening with cfDNA, combined first trimester screening (CFTS), second trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing to (i) obtain population-based estimates on women's utilization of screening and diagnosis, (ii) analyse the performance of different screening strategies, and (iii) report the residual risks of any major chromosome abnormality following a low risk aneuploidy screen. METHODS: Retrospective study of women resident in Victoria, Australia, undergoing screening or prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false negative screening results and atypical chromosome abnormalities. Individual record-linkage was performed with LinkageWizTM and statistical analyses with STATA v14.0. RESULTS: There were 79,140 births during the study period; 66,166 women (83.4%) underwent at least one form of aneuploidy screening. Linkage data were complete for 92.4% of women undergoing screening (n=61,911) and of these, 73.1% (n=45,275) used CFTS alone, 20.2% (n=12,520) used cfDNA alone; 5.3% (n=3268) used STSS alone, 1.3% (n=813) used both CFTS and cfDNA, and < 0.1% (n=35) used both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21, 13 and 18 of 89.57% (95%CI 82.64-93.93) for a screen positive rate (SPR) of 2.94%. There were 12 false negative results in the CFTS pathway (10 trisomy 21, 1 trisomy 18 and 1 trisomy 13). CfDNA had a combined sensitivity of 100% (95% CI 95.0-100.0) for trisomies 21, 13 and 18 for a 1.21% screen positive rate. When high risk cfDNA results for any chromosome, including the sex chromosomes, and failed cfDNA tests were treated as screen positives, the cfDNA SPR increased to 2.42%. The risk of any major chromosome abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low risk screening result was 1 in 1188 for CFTS (n=37) and 1 in 762 for cfDNA (n=16) (p= 0.13). The range of chromosome abnormalities detected after low risk cfDNA included pathogenic CNVs (n=6), triploidy (n=3), rare autosomal trisomies (n=3) and monosomy X (n=2). CONCLUSIONS: Our state-wide linkage analysis delineated the utilization and clinical performance of the multitude of screening pathways available to pregnant women. The sensitivity of cfDNA for trisomies 21, 13 and 18 was clearly superior to CFTS. While there was no statistically significant difference in the residual risk of any major chromosome abnormality after low risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosome abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policy. This article is protected by copyright. All rights reserved.

Characteristics of Cystic Fibrosis Patients Diagnosed After False Negative Cystic Fibrosis Newborn Screening Results

Characteristics of Cystic Fibrosis Patients Diagnosed After False Negative Cystic Fibrosis Newborn Screening Results

Infections and associated behaviors among deceased organ donors: Informing the assessment of risk.

For infectious disease risk assessment among deceased organ donors, pre-donation clinical, microbiological, and behavioral information are reviewed; however, uncertainty may arise due to false negative screening results of recently acquired infections. The burden of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV), and residual risks (RR) of undetected virus was estimated, with the impact of more sensitive screening. For United Kingdom potential deceased organ donors between 2010 and 2014, prevalence of HBsAg was 0.1%, HIV 0.06% and HCV 0.9%, increasing to 25.7% in people who injected drugs (PWID). Incidence, derived from new blood donors, was multiplied by duration of screening assay window periods to give RR per 100000 donors as 0.43 (95% confidence interval [CI] 0.03-3.99) for HBV, 0.08 (95% CI 0.02-0.21) for HIV, and 5.96 (95% CI 0.82-37.89) for HCV. For PWID, HCV RR was 163.3 (95% CI 22.8-1107.8) compared to 2.76 (95% CI 0.35-17.36) for non-PWID. RR decreased significantly with nucleic acid testing (NAT), and, for HCV, antigen testing had a similar impact. While the burden of HCV risk lies within PWID, these are in small numbers therefore few HCV antigen or NAT tests would be needed to more accurately assess risk.

Thirty years of the newborn screening program in Central Serbia: the missed cases of congenital hypothyroidism.

Milenkovic T, Vukovic R, Radojicic B, Mitrovic K, Todorovic S, Zatezalo L. Thirty years of the newborn screening program in Central Serbia: the missed cases of congenital hypothyroidism. Turk J Pediatr 2019; 61: 319- 324. Newborn Screening (NS) program for congenital hypothyroidism (CH) has completely changed the natural history of this devastating disorder for the vast majority of children with CH. However, cases of missed CH do happen, and it is important to keep this possibility in mind during every day clinical practice. The objective of this study was to analyze the recognized cases of undiagnosed CH by the NS program in Central Serbia in order to evaluate the reasons for such omissions. Data regarding the recognized missed cases of CH between the years of 1983 and 2013 were collected and analyzed. During 30 years of the NS program for CH on the territory of Central Serbia, 1,547,122 newborns were screened, and during this period, 14 children with CH were missed by the NS. Five missed cases were children with athyreosis (35.8%), 8 had ectopic thyroid gland (57.1%) and one child had dyshormonogenesis (7.1%). The median age at diagnosis of CH in these missed cases was 1.12 years (range 0.08-13.5 years). In the group of children with missed diagnosis of CH, 71.4% were missed due to errors during sample collection, and 28.6% of patients were missed due to false negative screening results. Continuous education of neonatologists as well as nurses in neonatal units of maternity hospital are necessary to avoid errors in sample collection. It is of high importance to notice in a discharge list if a child is referred to the hospital before the sample is taken in a maternity hospital. On the other hand, the maternity hospital has to inform the screening laboratory about any child who was referred to another hospital if the blood samples for screening are not taken. Parents should be better informed that each child has to be included in the NS which is obligatory in Serbia. In addition, awareness amongst pediatricians in primary care should be raised regarding the possibility of missed cases of CH.