COVID-19: How to analyze data from whole-exome sequencing?

Background/Objectives: COVID-19 can affect anyone with the disease's symptoms ranging from mild to very severe. Although environmental, clinical, and social factors play an important role in the disease process, host genetic factors are not negligible either. In the present article, we attempted to elaborate on the spectrum of risk variants and genes identified in different ways and their possible relationship to COVID-19 severity and/or mortality. Method(s): We present three different approaches to search host genetic risk factors that influence the development of COVID-19 disease. First, we analyzed the exome sequencing data obtained from Slovak patients who died of COVID-19. Second, we selected risk factors/genes that were associated with COVID-19. Finally, we compared each group of found risk variants with data from dead patients and two control groups, worldwide public data of the Non-Finnish European population from the gnomAD database, and genetic data from Non-invasive prenatal testing in the Slovak population. Result(s): We illustrate the utility of genomic data showed strong association in meta-analyses conducted by the COVID-19 HGI Browser. Conclusion(s): To our knowledge, the present study is the first population analysis of COVID-19 variants worldwide and also in the Slovak population that provides different approaches to the analysis of genetic variants in whole-exome sequencing data from patients who have died of COVID-19.

Expanded prenatal syphilis screening in Manitoba, Canada: a direct short-term cost-avoidance analysis in an outbreak context.

OBJECTIVE: The objective of this study is to provide a direct short-term cost-avoidance analysis of expanded three-time prenatal syphilis screening in the context of Manitoba's ongoing outbreak. METHODS: A conservative modelling approach increased all financial costs of prenatal screening and minimized the direct costs of congenital syphilis treatment. The cost of syphilis screening was calculated using instrument, reagent and consumable costs as well as laboratory overhead and labour costs as documented by Cadham Provincial Laboratory. The short-term direct costs of treating congenital syphilis were calculated using hospital costs and doctor's billing fees. All costs were calculated in 2021 Canadian dollars. These numbers were applied to Manitoba's 2021 congenital syphilis statistics to provide a pragmatic cost-avoidance analysis. RESULTS: The cost of applying three-time prenatal syphilis screening to all 16,800 yearly pregnancies in Manitoba equalled CAD $139,608.00 per year. The direct short-term cost of treating one uncomplicated case of congenital syphilis was $18,151.40. As 81 cases of congenital syphilis were treated in Manitoba in 2021, the short-term direct cost of treating congenital syphilis in Manitoba in 2021 was $1,470,263.40. Applying screening costs to the 125 adequately prevented cases of congenital syphilis in 2021, the screening program is associated with a cost-avoidance ratio of 16.25. If no prenatal syphilis program existed in Manitoba, an expanded screening program would be associated with a cost-avoidance ratio of 26.8. CONCLUSION: Expanding prenatal syphilis screening is highly cost-avoidant in Manitoba. The 81 cases of congenital syphilis treated in Manitoba in 2021 highlight the need for novel community-based approaches to increase accessibility and engagement with prenatal care.

RéSUMé: OBJECTIF: Dans le contexte de l'éclosion de syphilis qui sévit actuellement au Manitoba, notre étude vise à présenter une analyse des coûts directs à court terme qui pourraient être évités en étendant le dépistage de la syphilis au cours des trois trimestres de la grossesse. MéTHODE: En adoptant une approche de modélisation prudente, nous avons accru tous les coûts financiers du dépistage anténatal et réduit les coûts de traitement directs de la syphilis congénitale. Les coûts de dépistage de la syphilis ont été calculés en utilisant les coûts des instruments, des réactifs et des consommables, ainsi que les frais généraux et les coûts de main-d'œuvre des laboratoires selon le Laboratoire provincial Cadham. Les coûts directs à court terme du traitement de la syphilis congénitale ont été calculés en utilisant les frais hospitaliers et les frais facturés par les médecins. Tous les coûts ont été calculés en dollars canadiens de 2021. Ces chiffres ont été appliqués aux statistiques de 2021 du Manitoba sur la syphilis congénitale pour produire une analyse pragmatique de prévention des coûts. RéSULTATS: Le coût d'étendre le dépistage de la syphilis au cours des trois trimestres de la grossesse aux 16 800 grossesses annuelles au Manitoba représentait 139 608 $ CAN par année. Le coût direct à court terme du traitement d'un cas de syphilis congénitale sans complications était de 18 151,40 $. Étant donné que 81 cas de syphilis congénitale ont été traités au Manitoba en 2021, le coût direct à court terme du traitement de syphilis congénitale dans la province en 2021 s'est élevé à 1 470 263,40 $. En appliquant les coûts de dépistage aux 125 cas de syphilis congénitale que l'on a réussi à prévenir en 2021, le programme de dépistage est associé à un rapport de prévention des coûts de 16,25. S'il n'existait aucun programme de dépistage anténatal de la syphilis au Manitoba, un programme de dépistage élargi serait associé à un rapport de prévention des coûts de 26,8. CONCLUSION: L'expansion du dépistage anténatal de la syphilis serait une mesure de prévention des coûts très efficace au Manitoba. Les 81 cas de syphilis congénitale traités dans la province en 2021 montrent qu'il faut adopter de nouvelles approches de proximité pour améliorer l'accès et la participation aux soins anténatals.

A comparative analysis of non-invasive prenatal testing in Ontario and Quebec: the role of governing style in health technology innovation & adoption.

BACKGROUND: While processes of adoption and the impacts of various health technologies have been extensively studied by health services and policy researchers, the influence of policy makers' governing styles on these processes have been largely neglected. Through a comparative analysis of non-invasive prenatal testing (NIPT) in the Canadian provinces of Ontario and Quebec, this article examines how decisions about this technology were shaped by contrasting political ideologies, resulting in vastly different innovation and adoption strategies and outcomes. METHODS: A comparative qualitative investigation comprising of a document analysis followed by semi-structured interviews with key informants. Interview participants were researchers, clinicians, and private sector medical laboratory employees based in Ontario and Quebec, Canada. Interviews were conducted both in person and virtually- owing partly to the COVID-19 pandemic - to garner perspectives regarding the adoption and innovation processes surrounding non-invasive prenatal testing in both provinces. All interviews were recorded and transcribed verbatim and data were analyzed using thematic analysis. RESULTS: Through an analysis of 21 in-depth interview transcripts and key documents, the research team identified three central themes: 1) health officials in each province demonstrated a unique approach to using the existing scholarly literature on NIPT; 2) each provincial government demonstrated its own preference for service delivery, with Ontario preferring private and Quebec preferring public; and finally, 3) both Ontario and Quebec's strategies to NIPT adoption and innovation was contextualized within each province's unique financial positioning and concerns. These findings illustrate how both Quebec's nationalist focus and use of industrial policy and Ontario's 'New Public Management' style had implications for how this emerging healthcare technology was made available within each province's publicly-financed health system. CONCLUSIONS: Our study reveals how these governments' differing approaches to using data and research, public versus private service delivery, and financial goals and concerns resulted in distinct testing technologies, access, and timelines for NIPT adoption. Our analysis demonstrates the need for health policy researchers, policy makers, and others to move beyond analyses solely considering clinical and health economic evidence to understand the impact of political ideologies and governing styles.

Decision-making process about prenatal genetic screening: how deeply do moms-to-be want to know from Non-Invasive Prenatal Testing?

BACKGROUND: Prenatal information may be obtained through invasive diagnostic procedures and non-invasive screening procedures. Several psychological factors are involved in the decision to undergo a non-invasive prenatal testing (NIPT) but little is known about the decision-making strategies involved in choosing a specific level of in-depth NIPT, considering the increased availability and complexity of NIPT options. The main aim of this work is to assess the impact of psychological factors (anxiety about pregnancy, perception of risk in pregnancy, intolerance to uncertainty), and COVID-19 pandemic on the type of NIPT chosen, in terms of the number of conditions that are tested. METHODS: A self-administered survey evaluated the decision-making process about NIPT. The final sample comprised 191 women (Mage = 35.53; SD = 4.79) who underwent a NIPT from one private Italian genetic company. Based on the test date, the sample of women was divided between "NIPT before COVID-19" and "NIPT during COVID-19". RESULTS: Almost all of the participants reported being aware of the existence of different types of NIPT and more than half reported having been informed by their gynecologist. Results showed no significant association between the period in which women underwent NIPT (before COVID-19 or during COVID-19) and the preferences for more expanded screening panel. Furthermore, regarding psychological variables, results showed a significant difference between perceived risk for the fetus based on the NIPT type groups, revealing that pregnant women who underwent the more expanded panel had a significantly higher level of perceived risk for the fetus than that reported by pregnant women who underwent the basic one. There was no statistically significant difference between the other psychological variables and NIPT type. CONCLUSIONS: Our findings indicate the paramount role of gynecologist and other health care providers, such as geneticists and psychologists, is to support decision-making process in NIPT, in order to overcome people's deficits in genetic knowledge, promote awareness about their preferences, and control anxiety related to the unborn child. Decision-support strategies are critical during the onset of prenatal care, according to the advances in prenatal genomics and to parent's needs.

Evaluation and limitations of different approaches among COVID-19 fatal cases using whole-exome sequencing data.

BACKGROUND: COVID-19 caused by the SARS-CoV-2 infection may result in various disease symptoms and severity, ranging from asymptomatic, through mildly symptomatic, up to very severe and even fatal cases. Although environmental, clinical, and social factors play important roles in both susceptibility to the SARS-CoV-2 infection and progress of COVID-19 disease, it is becoming evident that both pathogen and host genetic factors are important too. In this study, we report findings from whole-exome sequencing (WES) of 27 individuals who died due to COVID-19, especially focusing on frequencies of DNA variants in genes previously associated with the SARS-CoV-2 infection and the severity of COVID-19. RESULTS: We selected the risk DNA variants/alleles or target genes using four different approaches: 1) aggregated GWAS results from the GWAS Catalog; 2) selected publications from PubMed; 3) the aggregated results of the Host Genetics Initiative database; and 4) a commercial DNA variant annotation/interpretation tool providing its own knowledgebase. We divided these variants/genes into those reported to influence the susceptibility to the SARS-CoV-2 infection and those influencing the severity of COVID-19. Based on the above, we compared the frequencies of alleles found in the fatal COVID-19 cases to the frequencies identified in two population control datasets (non-Finnish European population from the gnomAD database and genomic frequencies specific for the Slovak population from our own database). When compared to both control population datasets, our analyses indicated a trend of higher frequencies of severe COVID-19 associated risk alleles among fatal COVID-19 cases. This trend reached statistical significance specifically when using the HGI-derived variant list. We also analysed other approaches to WES data evaluation, demonstrating its utility as well as limitations. CONCLUSIONS: Although our results proved the likely involvement of host genetic factors pointed out by previous studies looking into severity of COVID-19 disease, careful considerations of the molecular-testing strategies and the evaluated genomic positions may have a strong impact on the utility of genomic testing.

Prenatal genetic screening and diagnostic testing during the COVID-19 pandemic in the Bronx, NY

Introduction: The Coronavirus Disease (COVID-19) pandemic has changed the landscape of both inpatient and outpatient healthcare. During the height of the pandemic, most elective and many nonelective procedures were halted. Prenatal care services including ultrasound and genetic screening and testing remained active (given gestational age dependence) while shifting from in-person towards telehealth counseling. NewYork Citywas at the epicenter of the pandemic fromMarch through June 2020. Elective procedures at Montefiore Medical Center, which serves a diverse urban population in the Bronx, NY,were cancelled from March 16, 2020 to June 20, 2020. Prenatal ultrasound shifted from a dating ultrasound and a nuchal translucency ultrasound to one first trimester ultrasound and anatomy scans were scheduled at 20–22 weeks gestation rather than 18–20 weeks. The majority of counseling sessions were conducted via telehealth and prenatal diagnostic procedures (including amniocentesis and chorionic villus sampling [CVS]) were performed with a limited team to adhere to COVID-19 protocols. We examined the impact of this shift on rates of prenatal genetic screening and diagnostic procedures before and during the COVID-19 pandemic. Previous literature has revealed that since the advent of noninvasive prenatal screening (NIPS), prenatal genetic diagnostic procedures rates have been on the decline.We hypothesized that the rate of genetic diagnostic procedure rates would decrease and NIPS would increase as compared to the similar period in 2019. Methods: Retrospective analysis of data collected in a secure institutional logbook at Montefiore Medical Center Department of Obstetrics & Gynecology and Women’s Health (Division of Reproductive and Medical Genetics and Division of Fetal Medicine and Ultrasound) from January 1, 2019–December 31, 2020. Collected data included number of procedures, gestational age, and indication for procedure (categorized as advanced maternal age (AMA), ultrasound anomalies, positive screening test, hereditary disease in the family possibly affecting fetus (including family history or genetic carrier), or other. Procedures for multiple gestations were considered as a single procedure.. Results: 503 diagnostic procedures (359 amniocenteses and 144 CVS) were included. Most common indication (ultrasound anomaly) and average gestational age (13 weeks for CVS and 19 weeks for amniocentesis) were the same in 2019 and 2020. In total, 275 procedures were performed in 2019 as compared to 228 in 2020 (20.6% decrease) ( p = 0.018). Specifically, amniocentesis decreased from 187 to 172 (8% decrease) ( p = 0.214) and CVS decreased from 88 to 56 (36% decrease) ( p = 0.004). NIPS increased from 1,312 tests in 2019 to 1727 tests in 2020 (31.6%) ( p < 0.001). The same data points were then analyzed during the four-month period at the height of the pandemic in New York City. We compared numbers of procedures from the period March 1, 2019–June 30, 2019 to March 1, 2020–June 30, 2020. Total prenatal diagnostic procedures during this period were 91 in 2019 and 81 in 2020 (12.3% decrease). This included 59 amniocenteses compared with 60 in the same period in 2020 (1.6% increase) and 32 CVS in 2019 compared to 21 in 2020 (34.3% decrease). Noninvasive prenatal screening increased from 348 to 510 (increase of 46.5%) during this period. Discussion: At Montefiore Medical Center in the Bronx, NY, prenatal genetic diagnostic procedures decreased while NIPS rates increased during the pandemic. This trend may reflect patient’s concerns for a COVID-19 exposure during in-office procedures, shift to telehealth counseling, or be reflective of the overall trends seen since the widespread offering of NIPS to prenatal patients. The decrease in CVS may be explained by an intentional system delay of combining ultrasound and blood draw to a single visit at the end of the first trimester. Future studies should investigate how access to care and gestational age at the time of presentation influenced prenatal genetic screening and testing cho ces during the pandemic, in order to better explain the identified trends.