Screen-positive Cases Research Articles

Epilepsy surveillance in normocephalic children with and without prenatal Zika virus exposure

Children with Congenital Zika Syndrome and microcephaly are at high risk for epilepsy; however, the risk is unclear in normocephalic children with prenatal Zika virus (ZIKV) exposure [Exposed Children (EC)]. In this prospective cohort study, we performed epilepsy screening in normocephalic EC alongside a parallel group of normocephalic unexposed children [Unexposed Children (UC)]. We compared the incidence rate of epilepsy among EC and UC at one year of life to global incidence rates. Pregnant women were recruited from public health centers during the ZIKV outbreak in Grenada, West Indies and assessed for prior ZIKV infection using a plasmonic-gold platform that measures IgG antibodies in serum. Normocephalic children born to mothers with positive ZIKV results during pregnancy were classified as EC and those born to mothers with negative ZIKV results during and after pregnancy were classified as UC. Epilepsy screening procedures included a pediatric epilepsy screening questionnaire and video electroencephalography (vEEG). vEEG was collected using a multi-channel microEEG® system for a minimum of 20 minutes along with video recording of participant behavior time-locked to the EEG. vEEGs were interpreted independently by two pediatric epileptologists, who were blinded to ZIKV status, via telemedicine platform. Positive screening cases were referred to a local pediatrician for an epilepsy diagnostic evaluation. Epilepsy screens were positive in 2/71 EC (IR: 0.028; 95% CI: 0.003–0.098) and 0/71 UC. In both epilepsy-positive cases, questionnaire responses and interictal vEEGs were consistent with focal, rather than generalized, seizures. Both children met criteria for a clinical diagnosis of epilepsy and good seizure control was achieved with carbamazepine. Our results indicate that epilepsy rates are modestly elevated in EC. Given our small sample size, results should be considered preliminary. They support the use of epilepsy screening procedures in larger epidemiological studies of children with congenital ZIKV exposure, even in the absence of microcephaly, and provide guidance for conducting epilepsy surveillance in resource limited settings.

A retrospective analysis of the care cascades for non-communicable disease and mental health among people living with HIV at a tertiary-care centre in Malaysia: opportunities to identify gaps and optimize care.

IntroductionThe rapidly growing epidemic of non‐communicable diseases (NCDs) including mental health among aging people living with HIV (PLWH) has put a significant strain on the provision of health services in many HIV clinics globally. We constructed care cascades for specific NCDs and mental health among PLWH attending our centre to identify potential areas for programmatic improvement.MethodsThis was a follow‐up study of participants recruited in the Malaysian HIV & Aging study (MHIVA) from 2014 to 2016 at the University Malaya Medical Centre (n = 336). PLWH on suppressive antiretroviral therapy (ART) for a minimum of 12 months were invited to participate. At study entry, all participants underwent screening for diabetes (DM), hypertension (HTN) and dyslipidaemia; and completed assessments using the depression, anxiety and stress scale (DASS‐21). Screening results were recorded in medical charts and clinical management provided as per standard of care. A subsequent review of medical records was performed at 24 months following study completion among participants who remained on active follow‐up. Treatment pathways for NCD treatment and psychiatric referrals were assessed based on local practice guidelines to construct the care cascade.ResultsA total of 329 participants (median age = 43 years, 83% male, 100% on ART) completed follow‐up at 24 months. The prevalence of diabetes was 13%, dyslipidaemia 88% and hypertension 44%, whereas 23% presented with severe/extremely severe symptoms of depression, anxiety and/or stress. More than 50% of participants with dyslipidaemia and hypertension were not diagnosed until study screening, whereas over 80% with prevalent psychiatric symptoms were not previously recognized clinically. Suboptimal control of fasting lipids, sugar and blood pressure were found in the majority of participants despite optimal HIV treatment outcomes maintained over this same period. Only 32% of participants with severe/extremely severe mental health symptoms received psychiatric referrals and 83% of these attended their psychiatry clinic appointments.ConclusionsSystematic screening must be introduced to identify NCDs and mental health issues among PLWH followed by proper linkage and referrals for management of screen‐positive cases. Assessment of factors associated with attrition at each step of the care cascade is critically needed to improve health outcomes in our aging patients.

S3122 Factors Associated With Inadequate Colonoscopy Bowel Prep: Not the Patient but the Endoscopist, and the Role of Volume of Colonic Irrigation (VOCI)

INTRODUCTION: Colonoscopies with inadequate bowel preparation (BP) decrease the detection of adenomas and lead to earlier repeat follow up exams. There is no data on the impact of the endoscopists’ effort to achieve an adequate exam through water lavage and the endoscopists’ adequate BP rate. METHODS: This is a single center institutionally approved prospective study of eight endoscopists performing colonoscopy from 07/2017-03/2020. All endoscopists trained in the use of the Boston Bowel Prep Score (BBPS). We measured the volume of colonic irrigation (VOCI), defined as water infused in and fluid suctioned out for each colonoscopy. Data collection included patient demographics, factors associated with inadequate BP (BMI, constipation, tricyclic antidepressant and opiate medication use, diabetes), and colonoscopy findings (BBPS, VOCI in and out, polyp number, pathology). Only screening, surveillance and FIT positive cases were included. Inadequate BP was defined as a BBPS score of < 2 in any segment. We calculated the modified adenoma detection rate (mADR) defined as the proportion of screening or surveillance exams for which one adenoma was identified, as well as the modified adenomas per colonoscopy (mAPC) for each endoscopist. Comparisons between means were made using T-tests and ANOVA, with comparisons between proportions were made using Chi square. Coefficients of determination were calculated for linear correlations. RESULTS: Eight endoscopists performed 1223 colonoscopies (Table 1). Rates of adequate BP varied from 71.3% to 96.3%. There was no difference in VOCI in or out between high vs low adequate BP rate endoscopists (Table 2). There was no difference in VOCI in between high vs low mAPC endoscopists, but there was a statistically significant higher mean VOCI out (P = 0.035), although the volume was small (42 mL). mADR significantly differed among endoscopists but correlated with mAPC (R2 = 0.915). Rates of adequate BP did not correlate with mADR (R2 = 0.283). CONCLUSION: Despite standardized BP and prep scoring as well as equal distribution of inadequate BP patient factors, the rates of adequate BP still varied by 25% among endoscopists and was not affected by VOCI. These findings require further study but suggest that differences in rates of BP adequacy may have more to do with endoscopist factors than previously recognized, and may not correlate with other markers of endoscopist performance like mADR.Table 1.: Patient Demographics and Risk Factors for Inadequate Colon BP by EndoscopistTable 2.: VOCI, BBPS, mAPC, and mADR Rates by EndoscopistFigure 1.: Scatter Plot of Adequate Bowel Prep Percent by modified ADR.

Should vanishing twin pregnancies be systematically excluded from cell-free fetal DNA testing?

To demonstrate the feasibility of cell-free DNA (cfDNA) testing in vanishing twin (VT) pregnancies in routine clinical practice. Our study included 24 874 singleton and 206 VT consecutive pregnancies. Cell-free DNA was analyzed by massively parallel sequencing. Both aneuploidy analysis (chromosomes 13,18, 21, X, and Y) and fetal fraction estimation were performed according to an Illumina algorithm. Contaminant DNA contribution from the demised co-twin was studied in detail. VT pregnancies exhibited a higher prevalence of screen-positive cases (5.8% vs 2.5%), sex discrepancies (10.2% vs 0.05%), and false positive rates (FPR) (2.6% vs 0.3%) than singleton pregnancies. However, their incidence was significantly lower in tests performed after the 14th week (screen-positive cases: 3.1%; sex discrepancies: 7.8%; and FPR: 0.8%). Among the 12 cases in which cfDNA was performed at two time points, fading of contaminating cfDNA was observed in four cases with a sex discrepancy and in one false positive for trisomy 18, resulting in a final correct result. Our data suggest VT pregnancies could be included in cfDNA testing as long as it is applied after the 14th week of pregnancy. However, future studies to validate our findings are needed before including VT cases in routine clinical practice. Once established, unnecessary invasive procedures could be avoided, mitigating negative emotional impact on future mothers.

Cervical Cancer Screening Program in Bangladesh

Background: Cervical cancer (CC) is the fourth most common cancer in women worldwidewith an estimated 569,847 new cases and 311,365 deaths in the year 2018. In Bangladesh,the incidence of CC was 8068 and 5214 women died from CC in the year 2018.1CC constitutesabout 12% of the female cancer in this country.1&#x0D; Methods: The present situation of cervical cancer screening program is reviewed.&#x0D; Results: The Government of Bangladesh (GOB) adopted visual inspection of cervix withacetic acid (VIA) method for cervical cancer screening. The major strengths of VIA is itssimplicity, low cost, potential for immediate linkage with investigations/treatment, feasible inlow resource settings and the possibility of rapid training to the providers. The GOB hasextended the program to all districts and selected upazilas.The screening programme hasbeen implemented through capacity building of service providers of Medical College Hospitals(MCHs), District Hospitals (DHs), Mother and Child care Welfare Centers (MCWCs) andselected Upazila Health Compleses(UHCs) and several institutes.Serviceprovidersareperforming VIA for the women of 30 years and above at about 417 VIA centres at primary,secondary and tertiary level health care facilities of 64 districts of Bangladesh. Screen positivecases are being referred to the colposcopy clinics of 14 government MCHs and BSMMU,where evaluation and management are carried out. From January 2005 to June 2017,1647380VIA tests were performed at different facilities with 4.6%positivity.Among the VIA+ve women attending women at the colposcopy clinic of Bangabandhu Sheikh Mujib MedicalUniversity (BSMMU), 51% had precancerous or cancerous condition of the cervix, 3312(14.10%) were treated by local excision, 2428 (10.30%)by local ablative method and1413(6%) women with cervical cancer were referred to oncology. In Bangladesh, LEEPand thermalablation has acquired acceptability as a commonly used treatment method for selected CINand ‘see-and-treat’ approach for high grade diseases combining colposcopy and LEEP/thermal ablation has been adopted since the year 2010 to improve compliance to treatment.&#x0D; Conclusion: Bangladesh has established VIA as screening test for prevention of cervicalcancer in quiet a good number of facilities with wide coverage. But the program has to beexpanded readily to prevent cancer and reduce sufferings &amp; untimely death of women dueto this devastating disease.&#x0D; Bangladesh J Obstet Gynaecol, 2018; Vol. 33(1) : 63-73

Clinical Performance of Cell-Free Fetal DNA Testing for Fetal Aneuploidies and Subchromosomal Deletions/Duplications in a Cohort of 19,531 Pregnancies

Objective: We aim to assess the clinical performance of cell-free fetal DNA (cffDNA) testing for detecting common fetal aneuploidies as well as subchromosomal deletions/duplications and explore the pregnancy decisions in screen-positive cases. Methods: A cohort of 19,531 pregnant women was offered cffDNA testing for detection of trisomies 21, 18, and 13 (T21, T18, and T13); sex chromosome aneuploidies (SCAs); and subchromosomal deletions/duplications. Screen-positive cases were confirmed by karyotyping and single-nucleotide polymorphism array analysis. Results: A total of 47 cases failed the test. The overall screen-positive rate of chromosomal abnormalities was 1.07% (208/19,484), including 57 cases with T21, 18 cases with T18, 7 cases with T13, 106 cases with SCAs, and 20 cases of subchromosomal deletions/duplications. Positive predictive values were 91.30% (42/46), 38.46% (5/13), 33.33% (2/6), 41.33% (31/75), and 27.78% (5/18), respectively. There was no significant difference in the screening of fetal chromosomal aneuploidies in the high-risk group compared with the low-risk group (P > 0.05). All of the pregnant women who had confirmed fetal T21, T18, or T13 terminated their pregnancies, except for a case of T13 mosaic, whereas 45.16% (14/31) of women with fetal SCAs continued their pregnancies. Furthermore, 17 pregnant women with positive screens for T21, T18, or T13 without a subsequent diagnosis chose to terminate their pregnancy, whereas 29 of 31 women with SCAs chose to continue their pregnancies. Conclusions: CffDNA testing exhibited good screening accuracy for T21, T18, and T13 and also contributed to detecting fetal SCAs and subchromosomal deletions/duplications. Pregnant women with fetal 47, XXX or 47, XYY were more willing to terminate their pregnancy than those with fetal 45, X or 47, XXY.

Exploratory study of a screening measure for polycystic ovarian syndrome, quality of life assessment, and neuropsychological evaluation

BackgroundThe universally adopted 2018 PCOS medical diagnostic and treatment guidelines for Polycystic Ovarian Syndrome (PCOS) cites the need for a brief screening measure that can be easily administered in the clinical care setting. We evaluate a 12-item questionnaire emphasizing the medical symptoms of PCOS with a group of women with PCOS as well as comparison samples of college women not diagnosed with PCOS.MethodOf 120 undergraduate psychology women 18 to 41 years of age, 86 screened negative on a 12-item PCOS symptoms inventory. They were compared to a group of PCOS patients diagnosed medically in a manner consistent with the Teede et al. (2018) evidence-based diagnostic guidelines. The screen-positive, screen-negative, and PCOS-confirmed groups were compared on the PCOS Quality-of-Life (QoL) questionnaire, Zung Self-Rating Depression Scale (ZDS), Spielberg State-Trait Anxiety Inventory (STAI), Fatigue Symptom Inventory (FSI), Spiritual well-being and Spiritual Beliefs Inventories, the computerized Automated Neuropsychological Assessment Metric (ANAM) battery, and an experimental tachistoscopic Bilateral Perceptual Asymmetries Letter and Dots Matching Bilateral Field Advantage (BFA) test (to evaluate the effects of early brain androgenization possible from PCOS). For each questionnaire and neuropsychological performance principal outcome, the Linear Mixed Effects (LME) model was employed to evaluate the predictive significance of demographic characteristics and group membership (confirmed cases, screen negative and screen positive cases) for these outcomes.ResultsThe PCOS-confirmed women scored more poorly than the screen-negative (reference) and screen-positive groups on all the measures of physical, emotional, social, and spiritual well-being measures. On the ANAM neuropsychological battery, PCOS-confirmed women did more poorly on Sternberg Memory and Stimulus Response throughput measures. They also had slower correct response speed for both the unilateral and bilateral dot- and letter-matching tachistoscopic stimulus presentations. However, the bilateral field advantage throughput performance ratio did not differ among groups, which is a global measure of bilateral versus unilateral brain/behavior asymmetries.ConclusionPCOS screening can be a feasible and important part of women’s healthcare. PCOS-confirmed women should receive not only the medical standard of care from the 2018 guidelines, but also comprehensive psychosocial and neurocognitive support to enhance their quality of life.

Newborn screening for primary carnitine deficiency and variant spectrum of SLC22A5 gene in Guangzhou

Objective: To evaluate and improve the performance of the newborn screening program for primary carnitine deficiency (PCD) based on tandem mass spectrometry and to investigate the incidence of PCD and molecular characteristics of SLC22A5 gene in Guangzhou. Methods: A total of 200 180 neonates born in Guangzhou from 2015 to 2019 were enrolled into the newborn screening program for PCD by tandem mass spectrometry at Guangzhou Newborn Screening Center. The positive results of screening for PCD was defined as free carnitine (C0) less than 10 μmol/L with decreased acylcarnitine species in dried blood spots of three to seven days after birth. Screen-positive newborns and their mothers were recalled for another blood spot sample. The diagnosis was confirmed based on decreased levels of C0 and acylcarnitine species in recalled blood spots and genetic analysis in SLC22A5 gene sequencing. The utility of using the sum of propionylcarnitine and palmitoylcarnitine (C3+C16) as a biomarker for acylcarnitine species in newborn screening was retrospectively evaluated. The levels of C0 and (C3+C16) at first screening were compared between newborns with PCD and newborns born to mothers with PCD by independent t test. The variant spectrum and known pathogenic variants carrier rate of SLC22A5 in 2 395 healthy children in Guangzhou Women and Children's Medical Center through whole exon sequencing were analyzed. Results: Among 200 180 neonates, 239 (0.12%) cases were screen-positive for PCD. A total of 37 patients including 15 newborns and 22 mothers had confirmed PCD. The incidence of PCD was 1/13 345 in newborns and 1/9 099 in mothers, respectively. The positive predictive value of this program was 15.5%. Taking cutoff values of C0<8.5 μmol/L or C0 8.5~9.9 μmol/L with (C3+C16)<2 μmol/L, the number of screen-positive cases would be reduced from 810 to 224 without additional false negative case, when compared with cutoff value C0<10 μmol/L only. Both levels of C0 and (C3+C16) at first screening were not significant difference between newborns with PCD and newborns born to mothers with PCD ((6.2±2.4) vs. (5.0±1.8) μmol/L, (1.4±0.4) vs. (1.2±0.5) μmol/L, t=3.826, 0.326; P=0.058, 0.572). Seven PCD mothers experienced moderate fatigue and dizziness in the morning. One of them presented with cardiomyopathy in pregnancy. Genetic analysis of the SLC22A5 gene showed that p.S467C, p.F17L, p.R254X were the three most common variants in newborns with PCD. In PCD mothers and healthy children, the p.S467C, p.F17L and R399W were the three most common whereas the severe variant p.R254X was rare. The population carrier rate for pathogenic variants was 1 in 65 and the estimated incidence of PCD was about 1/16 500. Conclusions: Newborn screening can detect PCD both in newborns and mothers. Adding a quantitative biomarker (C3+C16) <2 μmol/L into the newborn screening program can improve the PCD screen performance. The severe variant p.R253X was common in PCD newborns but rare in PCD mothers and healthy children, indicating that the current screening program maybe failed to detect all PCD newborns and under-estimated the incidence rate of PCD in Guangzhou.

Epidemiology of psychiatric disorders among pregnant women attending antenatal care in rural areas of Bangladesh

Background: Pregnancy brings about an enormous change in women on physical, social and psychological aspects. To adopt these changes, women become vulnerable to different psychiatric disorders, particularly depression and anxiety. The prevalence of psychiatric disorders among pregnant women is ranged from 10% to 32% that has a negative impact on general health of women as well as development of children. This study was aimed to find out the prevalence of possible psychiatric disorders among pregnant women and to delineate its relationship with socio-demographic variables, physical health, and pregnancy-related factors. Methods: This cross-sectional, descriptive, quantitative, one-staged survey-type study was conducted from January to March 2018. Through consecutive sampling, confirmed pregnant women attending antenatal care in rural area aged between 18 and above were supplied a structured questionnaire containing sociodemographic and related variables and Self-Reporting Questionnaire (SRQ)-20 for screening psychopathology of the cases. Subjects were divided into screen-positive and screen-negative cases, and a comparison was made. Results: The mean age of the cases was 24.76 ± 5.2 years. Using SRQ-20 cutoff, the prevalence of possible psychiatric disorders among the respondents was 27.5% and that was found to be 20.19%, 24.07%, and 23.28% in first, second, and third trimesters, respectively. Anxiety and depressive symptom category were significantly higher followed by somatic symptom and reduced vital energy categories among screen-positive cases than screen-negative cases. A good number of pregnancy-related variables both the social and physical were found to be significantly associated with possible psychiatric disorders. Conclusions: This study explores and supports the wide magnitude of the possibility of mental health disorders during pregnancy, predominantly depression and anxiety. There should have a provision of the routine screening of psychopathology for all pregnant women with the aim toward early identification and treatment.

High risk screening for Gaucher disease in patients with splenomegaly and/or thrombocytopenia in China: 55 cases identified

Gaucher disease (GD) is a common lysosomal storage disorder caused by deficiency of glucocerebrosidase (GCase) due to the pathogenic variants in the GBA gene. The aim of this study was to evaluate the performance of high risk screening program for GD by measuring the enzyme activities of GCase and chitotriosidease in dried blood spots of patients with splenomegaly and/or thrombocytopenia. A total of 787 subjects (364 females and 423 males) with unexplained splenomegaly and/or thrombocytopenia were enrolled in this study from May 2016 to Aug 2019. The cutoff value of GCase activity was set as less than 3.0 pmol/punch/h for screening positive. The diagnosis of GD was confirmed by Sanger sequencing of the GBA gene. Among 131 screening positive cases, 49 patients were confirmed GD. The positive predictive value was 37.4%.Three patients with boundary values (GCase 3–4 pmol/punch/h) and other three splenectomic patients with normal GCase activity were confirmed GD by GBA genetic analysis because of increased chitotriosidase or Gaucher cells in bone marrow. A total of 55 GD cases were identified. The sensitivity and specificity of the high risk screening were 98.2% and 89.5%, respectively. These 55 GD patients presented splenomegaly (100%), hepatomegaly (70.9%), thrombocytopenia (83.6%). The level of GCase in GD patients was (1.7 ± 1.6) pmol/punch/h. The increased chitotriosidase (383.8 ± 130.2 pmol/punch/h) was found in 42 (76.4%) patients with GD. Molecular genetic analysis identified 44 variants in the GBA gene, including 11 novel variants. The results showed the high risk screening for GD is accurate, rapid and cost-effective.

Primary HPV screening for cervical cancer.

Cytology-based cervical screening had unequivocal success in reducing the incidence and mortality of cervical cancer in the last century. The recognition of the role of human papillomavirus (HPV) as a necessary cause of cervical cancer led to the development of HPV testing. Gradually, there has been a shift from reflex HPV testing for mild cytological abnormalities, to co-testing with cytology and HPV, and lately to primary HPV screening, based on evidence from well-designed large randomized controlled trials and meta-analyses. Advantages of primary HPV screening include higher sensitivity to detect pre-neoplastic lesions, better re-assurance with a negative test, and safe prolongation of screening intervals. However, clinicians and policy makers must ensure the availability of clinically validated HPV assays and triage protocols of screen positive cases prior to implementation of primary HPV screening. This is likely to reduce potential harm from over-treatment as well as extra burden on the health care system.

Early Screening of Autism among 18 to 24 months Old Toddlers Using the Quantitative Checklist for Autism in Toddlers (Q-CHAT).

The aim of the present study was to screen the toddlers who are suspected to be autistic in their well-child visits at age 18 to 24 months via the Quantitative-Checklist for Autism in Toddlers (Q-CHAT). After the screening, the screen-positive cases were clinically assessed by a child psychiatrist and a child developmental psychologist. The total sample included 2467 toddlers; the mean total score of Q-CHAT was 30.64 (SD: 9.133). According to the clinical examinations, 6 cases met the criteria for autism (equal to 5.8% of screen-positive cases and 0.25% of the total sample), and 18 cases had a high probability of autism or other neurodevelopmental disorders. This study showed that the toddlers who were at risk of autism could be screened in PHC. Also, Q-CHAT could be used as a screening tool in Iran.

Newborn screening program and blood amino acid profiling in early neonates with citrin deficiency

Objective: To investigate the profiles of blood amino acid and acylcarnitine in early neonates with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and the sensitivity of newborn screening, and to explore potential biochemical metabolic markers for newborn screening program. Methods: Amino acid and acylcarnitine profiles in dried blood spots of newborn screening program were analyzed by tandem mass spectrometry (MS/MS). A total of 158 651 neonates born in Guangzhou from January 1, 2015 to June 30, 2019 were enrolled in this newborn screening program, and additionally 55 patients with NICCD confirmed by SLC25A13 gene analysis in Guangzhou Women and Children Medical Center were included in this study. NICCD screen-positive was defined as the cutoff value of citrulline (Cit) ≥ 30 μmol/L. The values of blood sampling time of the true positive group and those of the false negative group were compared by t-test. The levels of amino acid and acylcarnitine among different groups, including true positive group (Cit≥30 μmol/L), false negative group (Cit 21-<30 μmol/L and Cit<21 μmol/L) and the normal control group, were analyzed by F test, respectively. Results: Among 158 651 neonates, 39 neonates were positive for NICCD screening. Three of them were confirmed NICCD and 4 cases were found to be false negatives. The positive predictive value was 7.7% and the sensitivity was about 43.0%. Among 55 patients with NICCD, 18 cases (18/55, 32.7%) were true positives and 37 cases (37/55, 67.3%) were false negatives based on the cutoff value of citrulline in the dried blood spots for newborn screening. The blood sampling time was significantly different between true positive group and false negative group ((4.28±1.6) vs. (2.98±0.74) d, t=4.06, P<0.01). The increased levels of tyrosine((176.0±98.4) μmol/L), methionine ((37.0±26.9) μmol/L) and phenylalanine ((133.0±80.9)μmol/L) in Cit≥30 μmol/L group (n=18) were significantly different as compared with those in the other three groups, respectively (F=117.0, 58.5, 135.0, P<0.01). The levels of arginine ( (10.0±9.2) , (11.0±9.3) , (9.0±17.8) μmol/L), valine ( (119.0±29.8) , (107.6±14.1) , (102±68) μmol/L) and leucine ( (167.0±37.1) , (161.0±37.7) , (163.5±180.6) μmol/L) were not statistically significant among groups of Cit≥30 μmol/L(n=18), Cit21-<30 μmol/L(n=7) and Cit<21μmol/L(n=30,P>0.05), but they were significantly higher than those of the normal control group ((4±3), (78±21), (114.0±31.5) μmol/L, n=1 000), respectively(F=30.1, 23.0, 29.8, P<0.01). Alanine (Ala) ( (150±50) , (156.0±30.2), (168±105), (152±52) μmol/L) levels showed no significant difference (F=0.86, P>0.05) but the ratios of Ala/Cit (1.52±1.44, 6.82±1.56, 12.06±7.71, 19.42±6.27) decreased significantly among the four groups (F=69.0, P<0.05). The acylcarnitine levels showed no statistically significant results among the different groups (P>0.05). With Cit≥30 μmol/L and Ala/Cit<7.5 as cutoff values, the number of screen-positive cases reduced from 39 to 22 cases with no additional false negative case. With Cit≥21 μmol/L and Ala/Cit<7.5 as cutoff values the number of screen-positive cases increased to 117 cases with 1 additional true positive. Conclusions: The profiles of blood amino acid in early neonates with NICCD present the increased levels of multiple amino acids including citrulline, tyrosine, methionine and phenylalanine, and decreased ratio of Ala/Cit. Taking citrulline and ratio of Ala/Cit as screening markers can improve the positive predictive value appropriately. The limited sensitivity of NICCD newborn screening may be related to early blood sampling time.

Complementary Longitudinal Serum Biomarkers to CA125 for Early Detection of Ovarian Cancer.

Early detection of ovarian cancer has the potential to impact mortality. A multimodal screening strategy where rising CA125 values over time, analyzed with the risk of ovarian cancer algorithm (ROCA), triggers transvaginal sonography and possible surgery has high sensitivity and specificity, but still fails to detect the 20% of early-stage cases that do not express CA125. Use of multiple biomarkers could detect cases missed by CA125. We have studied the sensitivity and lead time of a multi-marker panel (CA125, HE4, MMP-7, and CA 72-4) compared with CA125 alone. We used PRoBE design principles to select preclinical longitudinal specimens from 75 women (50 screen-positive, 25 screen-negative) who developed invasive epithelial ovarian cancer (3-5 serial specimens each) and 547 corresponding healthy controls (1-10 serial specimens each) from the ovarian cancer screening trial, UKCTOCS, in a blinded fashion. We measured the multi-marker concentrations in ultra-low serum volumes (16 μL) utilizing multiplexed bead-based immunoassays with low detection limits, high inter- and intra-assay precision, negligible cross-reactivity, and good correlation with standard immunoassays. While, at least one of the complementary biomarkers rose with CA125 in 44% (22/50) of screen-positive cases, there was no advantage in lead time over CA125. Therefore, we developed single-marker longitudinal algorithms (ROCA-like) to determine the presence of a change point to distinguish between the cases and controls. Using these algorithms, at 98% specificity, HE4 and CA72-4 identified 16% (4/25) of screen-negative cases, while MMP-7 identified none. Taken together, HE4 and CA72-4 show promise as complementary biomarkers to CA125 for longitudinal screening.

Age-Specific Cut-off Values of Amino Acids and Acylcarnitines for Diagnosis of Inborn Errors of Metabolism Using Liquid Chromatography Tandem Mass Spectrometry.

Liquid Chromatography tandem mass spectrometry (LC-MS/MS) is used for the diagnosis of more than 30 inborn errors of metabolisms (IEMs). Accurate and reliable diagnosis of IEMs by quantifying amino acids (AAs) and acylcarnitines (ACs) using LC-MS/MS systems depend on the establishment of age-specific cut-offs of the analytes. This study aimed to (1) determine the age-specific cut-off values of AAs and ACs in Bangladesh and (2) validate the LC-MS/MS method for diagnosis of the patients with IEMs. A total of 570 enrolled healthy participants were divided into 3 age groups, namely, (1) newborns (1-7 days), (2) 8 days–7 years, and (3) 8–17 years, to establish the age-specific cut-offs for AAs and ACs. Also, 273 suspected patients with IEMs were enrolled to evaluate the reliability of the established cut-off values. Quantitation of AAs and ACs was performed on an automated LC-MS/MS system using dried blood spot (DBS) cards. Then the specimens of the enrolled clinically suspected patients were analyzed by the established method. Nine patients came out as screening positive for different IEMs, including two borderline positive cases of medium-chain acyl-CoA dehydrogenase deficiency (MCAD). A second-tier test for confirmation of the screening positive cases was conducted by urinary metabolic profiling using gas chromatography- mass spectrometry (GC-MS). Out of 9 cases that came out as screening positive by LC-MS/MS, seven cases were confirmed by urinary GC-MS analysis including 3 cases with phenylketonuria, 1 with citrullinemia type II, 1 with methylmalonic acidemia, 1 with isovaleric acidemia and 1 with carnitine uptake defect. Two borderline positive cases with MCAD were found negative by urinary GC-MS analysis. In conclusion, along with establishment of a validated LC-MS/MS method for quantitation of AAs and ACs from the DBS cards, the study also demonstrates the presence of predominantly available IEMs in Bangladesh.

NEONATAL SCREENING FOR CONGENITAL HYPOTHYROIDISM IN ROMANIA: DATA FROM MEDILOG MEDICAL INFORMATION REGISTRY.

Congenital hypothyroidism (CH) is one of the common preventable causes of intellectual disability in neonates, by early detection through neonatal screening. We present the 8-year experience of the National Institute for Mother and Child Health (INSMC) in using MEDILOG national registry for the neonatal screening of CH. Neonatal screening for CH, done by TSH measurement in dried blood spot, is organized in 5 regional centers, each with a reference laboratory. In 2018 80% of all the newborns, from 80% of the maternity hospitals, were registered in MEDILOG. After re-testing of TSH and T4/FT4 from venous blood in positive cases, the incidence of confirmed CH in 2018 was 1/3576 - 1/ 4746. In INSMC center (which includes 26 counties and Bucharest, out of 41 counties), in 2018 the incidence of positive CH cases at screening was 1/2094 (TSH cut-off ≥17 mIU/L) and of confirmed CH cases 1/3576 newborns. For positive screening cases, the median duration from birth to the INSMC laboratory result was 19 days: median of 9 days between screening and laboratory registration and 6 days between registration and test result. MEDILOG registry is a practical instrument for monitoring the steps of neonatal CH screening, the incidence of CH, the evolution of the diagnosed cases, for evaluation of iodine deficiency (by neonatal TSH), and also for research, with the aim of improving early disease detection and treatment.

New Advances for Newborn Screening of Inborn Errors of Metabolism by Capillary Electrophoresis-Mass Spectrometry (CE-MS).

Expanded newborn screening of inborn errors of metabolism (IEM) based on tandem mass spectrometry (MS/MS) technology is one of the most successful preventative healthcare initiatives for presymptomatic diagnosis and treatment of rare yet treatable genetic diseases in the population. However, confirmatory testing of presumptive screen-positive cases is required using high efficiency separations for improved specificity in order to improve the positive predictive value (PPV) for certain classes of IEMs. Here, we describe recent advances using capillary electrophoresis-mass spectrometry (CE-MS) for reliable second-tier screening or confirmatory testing based on targeted analysis of amino acids, acylcarnitines, nucleosides, and other classes of polar metabolites associated with IEMs. Additionally, nontargeted metabolite profiling enables the identification of unknown biomarkers of clinical significance for other genetic diseases that are currently screened by bioassays and/or mutation panels, such as cystic fibrosis (CF). Noteworthy, CE-MS allows for resolution of isobaric/isomeric interferences without complicated sample handling that is ideal when analyzing volume-restricted biospecimens from neonates/infants, including dried blood spots and sweat specimens. New developments to improve concentration sensitivity, as well as enhance sample throughput and quality control for unambiguous confirmatory testing of IEMs will also be discussed when using multiplexed separations based on multisegment injection-CE-MS.

712: Validity of commonly used screening criteria for severe maternal morbidity

ACOG and SMFM recommend that institutions screen for severe maternal morbidity (SMM) and review cases to determine which “screen” positive cases represent true morbidity. Previous validation studies have evaluated screen positive, but not screen negative cases. This limits our understanding of the performance of the screening criteria. Our objective was to validate four common screening criteria, and apply our false-negative rate to a previous validation study. From an administrative delivery database of deliveries born at Magee-Womens Hospital (2010-2011, n=19,307), we selected all deliveries that screened positive for SMM (n=349) and a random sample of screen- negative deliveries (n=349). Screen-positives were those that had any of the following: 1 of the CDC ICD-9 Revision diagnosis and procedure codes for severe maternal morbidity; prolonged postpartum length of stay (>3 standard deviations beyond the mean length of stay by mode of delivery); maternal ICU admission; or administration of any blood product. We used the Gold Standard SMM Case Review Guidelines (ACOG/SMFM Obstetric Care Consensus 2016) to identify true cases after medical record review. We calculated positive and negative predictive value of the screening criteria. The study was approved by our institutional review board. Compared with women who screened negative for severe maternal morbidity, those who screened positive were more likely to be non-White (33% vs. 17%), obese (31% vs. 16%), and to have a preterm birth (38% vs. 6.9%) or small-for-gestational-age infant (17% vs. 7.5%). A total of 166 screen positive cases were true positives (48% positive predictive value), and 347 screen negative cases were true negatives (99% negative predictive value). Notably, 2 screen negative cases were false negatives-- one due to a coding error and another due to a postpartum readmission for pulmonary embolism that was not in the delivery database. If this false negative rate were applied to the largest SMM validation study (Main et al. AJOG 2016) of 67,468 birth, there would be nearly as many false negative (n=379) as true positives (n=491). The false negative cases in our study are driven by data entry error as well as limitations of delivery administrative data that do not capture the postpartum period. Understanding the false negatives is critical to institutions establishing comprehensive screen and review programs to improve obstetrical care.

Spanish Cultural Validation of the Modified Checklist for Autism in Toddlers, Revised

The Modified Checklist for Autism in Toddlers-revised/follow-up (M-CHAT-R/F) was developed to reduce the number of cases requiring telephone verification. The aim of this study was to validate a Spanish version of the M-CHAT-R/F in the Spanish public health system. The M-CHAT-R/F was translated, culturally adapted, and then administered to 6625 children. Of the 39 positive screening cases, 15 children were diagnosed with autism spectrum disorder (ASD) and 24 with non-ASD disorders or delays. The sensitivity was 0.79 and specificity of 0.99. Positive and negative predictive values were 0.39 and 0.99, respectively. These results are similar to the English equivalent, though observed prevalence was lower. This study supports Spanish National Health System policy makers to consider a universal ASD screening program.

Association of patient navigation with care coordination in an Lynch syndrome screening program.

Lynch syndrome (LS) identification leads to improved health outcomes. Universal tumor screening (UTS) facilitates LS identification among colorectal cancer (CRC) and uterine cancer (UC) cases; institutional management affects screening program implementation and outcomes. There has been limited study of institutional UTS program care coordination needs, including patient navigation of genetic counseling referrals. We examined the influence of patient navigators on access to cancer genetic services among LS UTS screen-positive cases within a single institution. Electronic health record review of screen-positive CRC and UC cases for a 12-month period assessed the relationship between patient navigation and follow-through to genetic services. Among 451 newly diagnosed CRC (n = 175) and UC (n = 276) cases, 96 (21%; 28 CRC/68 UC cases) had abnormal UTS results. Among these, 66 (69%) showed MLH1 promoter hypermethylation (i.e., screen-negative). Of 30 screen-positive cases, 16 (53%) received navigation services. Among these, 14/16 (88%) and 13/14 (81%) underwent genetic counseling and testing, respectively; 7/13 (54%) had pathogenic or likely pathogenic variants detected. Among non-navigated screen-positive patients, 2/14 (14%) were excluded due to incomplete UTS results. Five of the remaining 12 cases (42%) sought genetic counseling, 4/12 (33%) underwent genetic testing; 1/4 (25%) tested positive for a pathogenic variant. The difference in navigated (88%) versus non-navigated cases (42%) undergoing genetic counseling was statistically significant (p = .02). Patient navigation was associated with follow-through to genetic counseling and testing services among LS screen-positive cases. This model deserves additional prospective investigation to confirm these findings and to assess their generalizability.