Screen-positive Cases Research Articles

Outcome of early detection approach in control of breast, cervical, and oral cancer: Experience from a rural cancer center in India.

In low- and middle-income countries most of the cancer patients attend the hospital at a late stage and treatment completion of these cases is challenging. The early detection program (EDP), in rural areas of Punjab state, India was initiated to identify breast, cervical, and oral cancer at an early stage by raising awareness and providing easy access to diagnosis and treatment. A total of 361 health education programs and 99 early detection clinics were organized. The symptomatic and self-interested (non-symptomatic individuals who opted for screening) cases visited the detection clinic. They were screened for breast, cervical, and/or oral cancer. Further diagnosis and treatment of screen-positive cases were carried out at Homi Bhabha Cancer Hospital (HBCH), Sangrur. Community leaders and healthcare workers were involved in all the activities. The EDP, Sangrur removed barriers between cancer diagnosis and treatment with the help of project staff. From 2019 to 2023, a total of 221,317 populations were covered. Symptomatic and self-interested individuals attended the breast (1627), cervical (1601), and oral (1111) examinations. 46 breast (in situ-4.3%; localized-52.2%), 9 cervical (localized-77.8%), and 12 oral (localized-66.7%) cancer cases were detected, and treatment completion was 82.6%, 77.8%, and 50.0%, respectively. We compared cancer staging and treatment completion of cases detected through EDP with the cases attended HBCH from Sangrur district in 2018; the difference between two groups is statistically significant. Due to the early detection approach, there is disease down-staging and improvement in treatment completion. This approach is feasible and can be implemented to control these cancers in low- and middle-income countries.

Autism screening and diagnostic outcomes among toddlers bornpreterm.

To examine the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up (M-CHAT-R/F), with follow-up screening and diagnostic outcomes for children born preterm. A secondary aim was to examine diagnostic evaluation attendance after screening to inform clinical practice. Using a cross-sectional design, 9725 toddlers (4951 males; 4774 females) whose gestational age was reported were screened at 15-month, 18-month, or 24-month well-child visits; screen-positive children were invited for an autism evaluation. Screening measure performance and diagnostic outcomes were evaluated according to preterm classification (Screening: nExtPreterm = 111; nVeryPreterm = 186; nModPreterm = 1122; nFullTerm = 8306; Evaluation: nExtPreterm = 27; nVeryPreterm = 21; nModPreterm = 86; nFullTerm = 301). Screen-positive rates were highest for children born extremely preterm (51.35%) and lowest for children born at term (6.95%). Evaluation attendance for screen-positive cases did not differ according to preterm classification. Rates of autism diagnoses differed depending on preterm birth status: for children born extremely preterm, it was 16.05%; for children born very preterm, it was 2.00%; for children born moderately preterm, it was 2.89%; and for children born at term, it was 1.49%. M-CHAT-R/F sensitivity decreased with increasing gestational age, whereas specificity improved with increasing gestational age. Positive predictive value was highest for children born extremely preterm and children born at term. Negative predictive value was consistently strong across all groups. The likelihood ratio for positive screening increased with gestational age. The sensitivity and specificity of the M-CHAT-R/F are acceptable in toddlers born preterm. Autism screening-positive rates and prevalence increased with earlier preterm birth. Those born extremely preterm showed the greatest likelihood of an autism diagnosis; screening should not be delayed based on adjusted age.

Systematic Review of Newborn Screening Programmes for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder causing the degeneration of motor neurons in the spinal cord. Recent studies suggest greater effectiveness of treatment in the presymptomatic stage. This systematic review synthesises findings from 37 studies (and 3 overviews) of newborn screening for SMA published up to November 2023 across 17 countries to understand the methodologies used; test accuracy performance; and timing, logistics and feasibility of screening. All studies screened for the homozygous deletion of SMN1 exon 7. Most (28 studies) used RT-PCR as the initial test on dried blood spots (DBSs), while nine studies also reported second-tier tests on DBSs for screen-positive cases. Babies testing positive on DBSs were referred for confirmatory testing via a range of methods. Observed SMA birth prevalence ranged from 1 in 4000 to 1 in 20,000. Most studies reported no false-negative or false-positive cases (therefore had a sensitivity and specificity of 100%). Five studies reported either one or two false-negative cases each (total of six cases; three compound heterozygotes and three due to system errors), although some false-negatives may have been missed due to lack of follow-up of negative results. Eleven studies reported false-positive cases, some being heterozygous carriers or potentially related to heparin use. Time to testing and treatment varied between studies. In conclusion, several countries have implemented newborn screening for SMA in the last 5 years using a variety of methods. Implementation considerations include processes for timely initial and confirmatory testing, partnerships between screening and neuromuscular centres, and timely treatment initiation.

Clinical outcomes of screen-positive genome-wide cfDNA cases for trisomy 20: results from the global expanded NIPT Consortium.

Trisomy 20 has been shown to be one of the most frequent rare autosomal trisomies in patients that undergo genome-wide noninvasive prenatal testing. Here, we describe the clinical outcomes of cases that screened positive for trisomy 20 following prenatal genome-wide cell-free (cf.) DNA screening. These cases are part of a larger cohort of previously published cases. Members of the Global Expanded NIPT Consortium were invited to submit details on their cases with a single rare autosomal aneuploidy following genome-wide cfDNA screening for retrospective analysis. Clinical details including patient demographics, test indications, diagnostic testing, and obstetric pregnancy outcomes were collected. Genome-wide cfDNA screening was conducted following site-specific laboratory procedures. Cases which screened positive for trisomy 20 (n = 10) were reviewed. Clinical outcome information was available for 90% (9/10) of our screen-positive trisomy 20 cases; the case without diagnostic testing ended in a fetal demise. Of the nine cases with outcome information, one was found to have a mosaic partial duplication (duplication at 20p13), rather than a full trisomy 20. Only one case in the study cohort had placental testing; therefore, confined placental mosaicism could not be ruled out in most cases. Adverse pregnancy outcomes were seen in half of the cases, which could suggest the presence of underlying confined placental mosaicism or mosaic/full fetal trisomy 20. Based on our limited series, the likelihood of true fetal aneuploidy is low but pregnancies may be at increased risk for adverse obstetric outcomes and may benefit from additional surveillance.

Digital recruitment and compliance to treatment recommendations in the Norwegian Atrial Fibrillation self-screening pilot study.

Atrial fibrillation (AF) is prevalent, undiagnosed in approximately one-third of cases, and is associated with severe complications. Guidelines recommend screening individuals at increased risk of stroke. This report evaluated the digital recruitment procedure and compliance with the follow-up recommendations in participants with screen-detected AF in the Norwegian Atrial Fibrillation self-screening pilot study. Norwegians ≥65 years were invited through Facebooks posts, web pages, and newspapers to participate in the study. Targeted Facebook posts promoted over 11 days reached 84 208 users and 10 582 visitors to the study homepage. This accounted for 51% of the total homepage visitors (n = 20 704). A total of 2118 (10%) of the homepage visitors provided digital consent to participate after they met the inclusion criteria. The mean (standard deviation) age of the participants was 70 (4) years, and the majority [n = 1569 (74%)] were women. A total of 1849 (87%) participants completed the electrocardiogram self-screening test, identifying AF in 41 (2.2%) individuals. Of these, 39 (95%) participants consulted a general practitioner, and 34 (83%) participants initiated anticoagulation therapy. Digital recruitment and inclusion in digital AF screening with a high rate of initiation of anticoagulation therapy in AF positive screening cases are feasible. However, digital recruitment and inclusion may introduce selection bias with regard to age and gender. Larger studies are needed to determine the efficacy and cost-effectiveness of a fully digital AF screening. Clinical trials: NCT04700865.

Validation of ICD-10 Codes for Severe Maternal Morbidity at Delivery in a Public Hospital.

Severe maternal morbidity is a composite measure of serious obstetric complications that is often identified in administrative data using the International Classification of Diseases (ICD) diagnosis and procedure codes for a set of 21 indicators. Prior studies of screen-positive cases have demonstrated low predictive value for ICD codes relative to the medical record. To our knowledge, the validity of ICD-10 codes for identifying severe maternal morbidity has not been fully described. We estimated the sensitivity, specificity, positive predictive value, and negative predictive value of ICD-10 codes for severe maternal morbidity occurring at delivery, compared with medical record abstraction (gold standard), for 1,000 deliveries that took place during 2016-2018 at a large, public hospital. We identified a total of 67 cases of severe maternal morbidity using the ICD-10 definition and 74 cases in the medical record. The sensitivity was 26% (95% confidence interval [CI] = 16%, 37%), the positive predictive value was 28% (95% CI = 18%, 41%), the specificity was 95% (95% CI = 93%, 96%), and the negative predictive value was 94% (95% CI = 92%, 96%). The validity of ICD-10 codes for severe maternal morbidity in our high-burden population was poor, suggesting considerable potential for bias.

A164 OPTIMIZING A PROVINCIAL SCREENING PROGRAM FOR DETECTION OF LYNCH SYNDROME

Abstract Background Up to 30% of those with colorectal cancer (CRC) have an affected family member. Lynch syndrome (LS) is the most common inherited condition predisposing patients to CRC. LS is an autosomal dominant condition associated with microsatellite instability (MSI) and mutations in DNA mismatch repair (MMR) genes, and screening CRC cases ≤ age 70 can identify LS in a cost-effective manner. Manitoba launched Canada's first provincial reflex screening program for all CRC cases diagnosed ≤ age 70 using MMR immunohistochemistry (MMR-IHC) in 2017. Our prior 2022 study evaluating the program showed compliance rates of 89.4% for MMR-IHC reflex testing and a 75.8% overall referral rate of screen-positive cases to genetics. However, only 50% were referred directly by pathologists. Several modifications have since been implemented to enhance the program. These included providing feedback to pathologists, creating an “additional testing comment section” on synoptic pathology reports, and regular review of the pathology reports by a pathology assistant. Information materials were developed to encourage genetic testing among relatives. Aims Assess whether modifications to Manitoba’s universal screening protocol improved LS patient outcomes and determine any remaining factors to optimize. We specifically aimed to identify current compliance rates for MMR-IHC testing, the overall referral rate of screen-positive cases to genetics, uptake of genetic referrals and genetic testing as well as rate of cascade testing among relatives. Methods Data has been obtained by searching the provincial pathology database for “adenocarcinoma” in the colorectal specimen pathology reports. All specimens from 2022 and Q1/Q2 of 2023 were reviewed, meeting the criteria of: a) specimen from colon biopsy/excision containing the term “adenocarcinoma”, b) patient age ≤70 years, and c) missing MMR centralized by the IT/Pathology department. Additionally, a random sample of cases categorized as “MMR performed” will be audited. We are in the process of reviewing genetic referrals, genetic uptake and the frequency of reminders triggered to each pathologist. Results Currently, a total of 1,308 colonic adenocarcinoma specimens (811 from 2022, 497 for 2023) have been reviewed. Appropriate MMR testing was missed in only 1.5% of cases (13/811 =1.6% missed in 2022, 7/497= 1.4% missed in 2023). Conclusions Current MMR testing rates for colonic adenocarcinoma specimens within the Manitoba LS screening program have reached a current compliance rate of 98.5%, a substantial improvement from the prior audit (89.4% previously). Further data collection and analysis is ongoing and will also be presented. The reported rates of compliance are the highest that have been reported from any jurisdiction. This study highlights the sustained efforts required to improve detection of LS. Funding Agencies None

Basic new born and antenatal screening for aspirational districts: unique methods of management and treatment of inherited disorders

Background: Early screening, diagnosis and management program can contribute in reducing the burden of genetic disorders which can lead to early neonatal death or long-term disability in the vulnerable areas. UMMID (Unique Methods of Management and treatment of Inherited Disorders) and NIDAN (National Inherited Diseases Administration), aimed at developing a community level program for need assessment and to evaluate the feasibility of basic screening for some genetic/endocrine disorders in high-risk population. Methods: UMMID was carried out at the aspirational district Ranchi, Jharkhand for 3 years (2019-2022) to perform newborn screening (NBS) in <7 days old newborn babies for 5 metabolic disorders and to screen antenatal mothers for prevention of thalassemia and other hemoglobinopathies. Results: G6PD deficiency being more prevalent in Ranchi district out of five metabolic disorders screened. 13.6% of screen positive cases were confirmed positive for hemoglobinopathies. c.20 A>T is the most common mutation found among carriers. Conclusions: This initiative underscores the need of such screening programs in aspirational districts to manage and prevent these disorders effectively.

Clinical Acceptability of Artificial Intelligence-Screened Interstitial Lung Disease (AI-ILD) in Lung Cancer Patients Treated with Radiotherapy

Patients with interstitial lung disease (ILD) treated with thoracic radiotherapy (RT) are at greater risk of pulmonary toxicity. Automatic universal screening for ILD allows radiation oncologists (ROs) to risk stratify patients and implement necessary modifications to their respiratory monitoring or treatment. Automatic screening however may affect RO workload and so it is imperative to assess the clinical acceptability of this tool. We have developed a machine learning algorithm to identify patients who are at high risk of having ILD based on RT planning computed tomography (CT) images. A quality improvement (QI) project was initiated to test feasibility and acceptability of the machine learning algorithm. If positive, the results of the machine learning algorithm were made available to ROs via structured electronic reporting. ROs were prompted to review the patient and consider expert radiologist consultation if thought appropriate. All electronic surveys and qualitative comments were summarized to describe clinical acceptability. Expert radiologist established gold standard ILD status of all patients on the study. A formal review of RO feedback was collected for all screen-positive, true-positive cases. Two hundred forty cases were screened of which 45 were flagged as AI-ILD positive and the responsible RO notified. Of these 45 screen-positive cases, all continued on to RT except for 3 patients with tumor progression. From these 45, 24 surveys were completed, 21 had no prior suspicion of ILD. There were 7 true-positives, of which 1 had a survey response. Based on the survey responses, 88% of cases underwent review by the responsible RO. In 16 cases this automatic notification prompted case consultation with an expert radiologist. Expert review was performed from 10 minutes up to 53 hours after the email prompt to the radiologist, with median response time of 1.5 hours. In the 7 screen-positive, true-positive cases, only 2 were not previously known to the responsible RO. In the two cases where true-positive ILD status was previously unknown, one was a mild case of ILD and the other had previously received thoracic RT at this institution without ILD being identified, in both cases the ROs were grateful that this diagnosis was identified prior to treatment. RO confidence in the machine learning prediction was moderate due to the high proportion of false positives. Based on available survey results, more than 75% of the screen-positive cases were reviewed by the responsible RO and two-thirds of these involved expert radiology input. RO feedback was generally positive and this tool was rated as a net benefit despite the high rate of false-positives and the need for clarification.

The Positive Predictive Value of Hospital Discharge Data for Identifying Severe Maternal Morbidity With and Without Blood Transfusion.

Blood transfusion is 1 of the 21 indicators for severe maternal morbidity (SMM) as defined by the Centers for Disease Control and Prevention (CDC) using administrative data. The CDC SMM definition is being prepared to measure hospital quality of care; however, transfusion coding reliability has been questioned. The authors assessed the positive predictive value (PPV) of administrative data for identifying gold standard SMM using the CDC SMM definition, with and without the transfusion indicator. A retrospective cohort study of one hospital's childbirth admissions (2016-2019) was performed. Data were screened for CDC SMM, and subgroups were created for those with transfusion as the sole indicator for SMM (transfusion-only SMM) versus those with at least one other SMM indicator (other SMM). Medical chart review classified CDC SMM cases based on gold standard SMM criteria. Gold standard SMM was defined by validated indicators identified by internal hospital quality reviews and confirmed by expert consensus. The PPV was calculated for all CDC SMM cases and the subgroups. Of 4,212 eligible people, 278 (6.6%) had CDC SMM. Chart review identified 110 gold standard SMM cases among screen-positive cases, yielding an overall PPV of the CDC SMM definition for gold standard SMM of 39.6%. CDC SMM cases identified solely by administrative coding for transfusion were half as likely to meet gold standard criteria, compared to cases identified by other SMM administrative codes (25.9% vs. 49.4%). Blood transfusion, coded as an independent risk factor, had a poor PPV for gold standard SMM. Given efforts to use CDC SMM for quality comparisons, more research is needed to reliably identify cases of SMM without relying on blood transfusion codes.

Neonatal Screening for Cystic Fibrosis in Hungary-First-Year Experiences.

The aim of this study is to evaluate the strategy of the cystic fibrosis newborn screening (CFNBS) programme in Hungary based on the results of the first year of screening. A combined immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) CFNBS protocol (IRT/IRT×PAP/IRT) was applied with an IRT-dependent safety net (SN). Out of 88,400 newborns, 256 were tested screen-positive. Fourteen cystic fibrosis (CF) and two cystic fibrosis-positive inconclusive diagnosis (CFSPID) cases were confirmed from the screen-positive cases, and two false-negative cases were diagnosed later. Based on the obtained results, a sensitivity of 88% and a positive predictive value (PPV) of 5.9% were calculated. Following the recognition of false-negative cases, the calculation method of the age-dependent cut-off was changed. In purely biochemical CFNBS protocols, a small protocol change, even after a short period, can have a significant positive impact on the performance. CFNBS should be monitored continuously in order to fine-tune the screening strategy and define the best local practices.

A Rare Case of Microduplication on Chromosome 13 Detected as High Risk for Trisomy 13 on NIPT Screening

AbstractNoninvasive prenatal testing (NIPT) has revolutionized the screening methods for fetal chromosomal aneuploidies with high utility for aneuploidies for common chromosomes 13,18, 21, X and Y. Trisomy 13 is often associated with major and minor fetal malformations and can be screened by antenatal fetal scan and first- and second-trimester biochemical screening. We describe a case with high risk for trisomy 13 on NIPT, but without any fetal abnormalities on fetal scan. As recommended, follow-up invasive testing of amniotic fluid by chromosomal microarray detected a microduplication on chromosome 13, which has been associated with congenital microcoria. This case demonstrates the high sensitivity and clinical utility of NIPT in detecting rare copy number variations, which can assist families in making informed reproductive decisions. This also emphasizes that all screen positive NIPT cases should be confirmed with an appropriate diagnostic test by an invasive method.

Validation of a targeted metabolomics panel for improved second-tier newborn screening.

Improved second-tier assays are needed to reduce the number of false positives in newborn screening (NBS) for inherited metabolic disorders including those on the Recommended Uniform Screening Panel (RUSP). We developed an expanded metabolite panel for second-tier testing of dried blood spot (DBS) samples from screen-positive cases reported by the California NBS program, consisting of true- and false-positives from four disorders: glutaric acidemia type I (GA1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). This panel was assembled from known disease markers and new features discovered by untargeted metabolomics and applied to second-tier analysis of single DBS punches using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a 3-min run. Additionally, we trained a Random Forest (RF) machine learning classifier to improve separation of true- and false positive cases. Targeted metabolomic analysis of 121 analytes from DBS extracts in combination with RF classification at a sensitivity of 100% reduced false positives for GA1 by 83%, MMA by 84%, OTCD by 100%, and VLCADD by 51%. This performance was driven by a combination of known disease markers (3-hydroxyglutaric acid, methylmalonic acid, citrulline, and C14:1), other amino acids and acylcarnitines, and novel metabolites identified to be isobaric to several long-chain acylcarnitine and hydroxy-acylcarnitine species. These findings establish the effectiveness of this second-tier test to improve screening for these four conditions and demonstrate the utility of supervised machine learning in reducing false-positives for conditions lacking clearly discriminating markers, with future studies aimed at optimizing and expanding the panel to additional disease targets.

Improving Lyme disease testing with data driven test design in pediatrics

Diagnostic advances have not kept pace with the expansion of Lyme disease caused by Borrelia burgdorferi and transmitted by ticks. Lyme disease clinical manifestations can overlap with many other diagnoses making Lyme disease a critical part of many differential diagnoses in endemic areas. Current diagnostic blood tests rely on a 2-tiered algorithm for which the second step is either a time-consuming western blot or a whole cell lysate immunoassay. Neither of these second step tests allow for rapid results of this critical rule out test. We hypothesized that using western blot confirmation information, we could create computational models to propose recombinant second-tier tests that would allow for more rapid, automated, and specific testing algorithms. We propose here a framework for assessing retrospective data to determine putative recombinant assay components. A retrospective pediatric cohort of 2755 samples submitted for Lyme disease screening was assessed using support vector machine learning algorithms to optimize tier 1 diagnostic thresholds for the Vidas IgG II assay and determine optimal tier 2 components for both a positive and negative confirmation test. In cases where the tier 1 screen was negative, but clinical suspicion was high, we found that 1 protein (L58) could be used to reduce false-negative results. For second-tier testing of screen positive cases, we found that 6 proteins could be used to reduce false-positive results (L18, L39M, L39, L41, L45, and L58) with a final machine learning classifier or 2 proteins using a final rules-based approach (L41, L18). This led to an overall accuracy of 92.36% for the proposed algorithm without a final machine learning classifier and 92.12% with integration of the machine learning classifier in the final algorithm when compared to the IgG western blot as the gold-standard. Use of this framework across multiple assays and institutions will allow for a data-driven approach to assay development to provide laboratories and patients with the improvements in turnaround time needed for this testing.

Severe Maternal Morbidity in Twins.

While twin gestations are at increased risk of severe maternal morbidity (SMM), there is limited information about timing and causes of SMM in twins. Furthermore, existing data rely on screening definitions of SMM because a gold standard approach requires chart review. We sought to determine the timing and cause of SMM in twins using a gold standard definition outlined by the American College of Obstetricians and Gynecologists (ACOG). We used a perinatal database to identify all twin deliveries from 1998 to 2013 at a single academic medical center (n = 2,367). Deliveries were classified as screen positive for SMM if they met any of the following criteria: (1) one of the Centers for Disease Control and Prevention (CDC) International Classification of Diseases Ninth Revision diagnosis and procedure codes for SMM; (2) a prolonged postpartum length of stay (>3 standard deviations beyond mean length of stay by mode of delivery); or (3) maternal intensive care unit admission. We identified true cases of SMM through medical record review of all screen-positive deliveries using the definition of SMM outlined in the ACOG Obstetric Care Consensus. We also determined cause and timing of SMM. A total of 165 (7%) of twin deliveries screened positive for SMM. After chart review of all screen-positive cases, 2.4% (n = 56) were classified as a true case of SMM using the ACOG definition for a positive predictive value of 34%. The majority of SMM occurred postpartum (65%). Hemorrhage was the most common cause of SMM, followed by hypertensive and pulmonary etiologies. Commonly used approaches to screen for SMM perform poorly in twins. This has important implications for quality initiatives and epidemiologic studies that rely on screening definitions of maternal morbidity. Our study demonstrates that the immediate postpartum period is a critical time for maternal health among women with twin pregnancies. · Screening approaches for SMM have low positive predictive value in twins.. · Hemorrhage, hypertensive, and pulmonary complications were the most common morbidities.. · SMM was most common postpartum..

Is the first-trimester combined screening result associated with the phenotype of Down syndrome? A population-based cohort study.

To investigate if the Down syndrome phenotype differs according to the result of first-trimester combined screening (FTS). We included all Down syndrome cases diagnosed by karyotype in pregnancy or after birth in Denmark during 2005-2018. We compared screen positive (odds ≥1:300) and screen negative (odds <1:300) cases as well as screen result subgroups with respect to anthropometrics, congenital malformations, childhood diseases, and hospitalization. Absolute measures of fetal and birth anthropometrics were comparable between groups. A prenatal malformation diagnosis was more prevalent among screen positive than screen negative cases. Analyses suggested that this could reflect a detection bias. Cases with a screen result of 1:2-1:10 had a higher probability of being diagnosed with a malformation prenatally and with severe congenital heart disease (CHD) postnatally compared with a result of 1:11-1:300. Screen positive cases more often had non-severe CHD but less often a non-heart malformation compared with screen negative cases, while proportions of severe CHD were similar in these groups. Data on hospitalizations showed inconsistent results. The 1:300 screening threshold had limited or no value in predicting Down syndrome phenotype severity. In contrast, cases with a screen result between 1:2 and 1:10 may represent a more severe phenotype.

Combination of PLGF and PAPPA as a biochemical markers to the first trimester maternal screening

Screening of fetal chromosomal abnormalities is an essential part of antenatal care. Effective first trimester screening involves PAPP-A (pregnancy associated plasma protein A) and free HCG (human chorionic gonadotropin) levels in the maternal serum along with ultrasound examination. The objective of this study is to investigate whether the measurement of PLGF (Placental Growth Factor) can improve the performance of first trimester combined screening for Trisomy 21, 18 and 13. A total of 350 samples were collected from pregnant women during the first trimester between 10 to 14 weeks of gestation. The ultrasound (US) data were collected from all cases which include US gestational age, NT value, CRL, and fetus number, if any. Blood samples were collected and tested for PAPP-A and free HCG tests. The combined risk of trisomy 21, 18 and 13 were calculated using PRISCA software. The screen positive cases (more than a defined cutoff rate) were stored at -20oC for PLGF testing. A total of 97 cases, including low and high risk patients were analyzed for PLGF. A significant reduction was observed among the risk group p ≤ 0.005 when compared to the negative control group. A positive correlation between PLGF and PAPPA was identified (r=0.69) p ≤0.001. In conclusion the study provide data indicating that inclusion of serum PLGF improve the performance of first trimester combined test for screening of Trisomy 21, 18 and 13 risk

PCR-Based Screening of Spinal Muscular Atrophy for Newborn Infants in Hyogo Prefecture, Japan.

Spinal muscular atrophy (SMA) is a common devastating neuromuscular disorder, usually involving homozygous deletion of the SMN1 gene. Newly developed drugs can improve the motor functions of infants with SMA when treated in the early stage. To ensure early diagnosis, newborn screening for SMA (SMA-NBS) via PCR-based genetic testing with dried blood spots (DBSs) has been spreading throughout Japan. In Hyogo Prefecture, we performed a pilot study of SMA-NBS to assess newborn infants who underwent routine newborn metabolic screening between February 2021 and August 2022. Hyogo Prefecture has ~40,000 live births per year and the estimated incidence of SMA is 1 in 20,000-25,000 based on genetic testing of symptomatic patients with SMA. Here, we screened 8336 newborns and 12 screen-positive cases were detected by real-time PCR assay. Multiplex ligation-dependent probe amplification assay excluded ten false positives and identified two patients. These false positives might be related to the use of heparinized and/or diluted blood in the DBS sample. Both patients carried two copies of SMN2, one was asymptomatic and the other was symptomatic at the time of diagnosis. SMA-NBS enables us to prevent delayed diagnosis of SMA, even if it does not always allow treatment in the pre-symptomatic stage.

Screening for fetal chromosomal anomalies using cell free DNA at a tertiary care centre

Aim of the study: To Evaluate the usefulness and reliability of cell free DNA as a screening method to identify the mothers at risk of fetus with trisomy 21, 18, 13, sex chromosomal anomalies and other chromosomal abnormalities.Method: This is a prospective observational study conducted at Chalmeda Anand Rao Institute of Medical Sciences, Karimnagar from a period of October 2020 to October 2022. Patients were included with at least one atypical biochemical marker of first trimester screening test or with abnormal NT scan. The cell free DNA was analysed by VeriSeq NIPT Solution v2 method. The accuracy of cell free DNA assay was evaluated by calculation of sensitivity and specificity. Screen positive cases were validated by comparing with karyotyping analysis.Results: Among the 250 patients with atypical biochemical markers who underwent a cell free DNA analysis, fourteen (5.6%) were excluded because of loss to follow-up, mis-carriage and affordability constraints. Out of 236, Cell free DNA was positive for Trisomy 21 in 3 pregnant women (n = 3), Trisomy 18 in 1 pregnant woman (n = 1) and Sex Chromosomal Aneuploidy in 1 pregnant woman (n = 1) and negative in 227 pregnant women. Test failure occurred for two pregnant women (0.8%).Conclusion: Cell free DNA assay is an effective and reliable tool in screening for fetal chromosomal anomalies.

Missed Cystic Fibrosis Newborn Screening Cases due to Immunoreactive Trypsinogen Levels below Program Cutoffs: A National Survey of Risk Factors.

Testing immunoreactive trypsinogen (IRT) is the first step in cystic fibrosis (CF) newborn screening. While high IRT is associated with CF, some cases are missed. This survey aimed to find factors associated with missed CF cases due to IRT levels below program cutoffs. Twenty-nine states responded to a U.S-wide survey and 13 supplied program-related data for low IRT false screen negative cases (CFFN) and CF true screen positive cases (CFTP) for analysis. Rates of missed CF cases and odds ratios were derived for each factor in CFFNs, and two CFFN subgroups, IRT above ("high") and below ("low") the CFFN median (39 ng/mL) compared to CFTPs for this entire sample set. Factors associated with "high" CFFN subgroup were Black race, higher IRT cutoff, fixed IRT cutoff, genotypes without two known CF-causing variants, and meconium ileus. Factors associated with "low" CFFN subgroup were older age at specimen collection, Saturday birth, hotter season of newborn dried blood spot collection, maximum ≥ 3 days laboratories could be closed, preterm birth, and formula feeding newborns. Lowering IRT cutoffs may reduce "high" IRT CFFNs. Addressing hospital and laboratory factors (like training staff in collection of blood spots, using insulated containers during transport and reducing consecutive days screening laboratories are closed) may reduce "low" IRT CFFNs.