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Bioinformatics was established at the IMGGE in collaboration with the Beijing Genomics Institute (BGI) and with the support of the Government of the Republic of Serbia. The Center was founded with the aim of accelerating the implementation of 4P medicine (Preventive, Predictive, Personalized, and Participatory), in our country by using the cutting-edge tools of molecular biology and information technology. As such, the center is unique in Serbia and the South East Europe region. The state-of-the-art equipment existing at the Center (DNBSEQ-G400 (BGI), NextSeq 550Dx, 2000 and MiSeq (Illumina) Sequencing Systems; MinION (OxfordNanopore); MGISP-9600 High-throughput Automated Sample Preparation System) offered a wide range of application: the whole genome and whole exome sequencing, targeted sequencing, transcriptome sequencing and more. The analysis of data was facilitated by the access to the National Platform for Artificial Intelligence providing space for secure data storage, and to a supercomputer (Nvidia), critical for processing and analyzing Big Data. Since its establishment more than 2000 SARS-CoV2 genomes were sequenced, 300 patient samples undervent diagnostic work-up. Pilot project for NIFTYPro screening was finished encompasing 58 pregnant women. First transcriptomes and metagenomes were analyzed. Further implementation of NGS methodology in research and for diagnostics, and intensive development of bioinformatics, by strengthening the hardware and software capacities and the education of the bioinformatics team, will lead us in becoming driving force of the development of biomedicine and biotechnology in Serbia, extending collaboration beyond our borders.

Introduction: The Non-Invasive Prenatal Testing (NIPT) guideline was issued and applied in 2013 by the Japanese Medical Association. Since being issued, the NIPT practice in Japan still has some problems related to indication, access, cost coverage and uniformity. Therefore, our study aimed to identify the Japanese challenges of adopting NIPT into prenatal diagnosis by comparing the system and process with other countries. Method: The United Kingdom, Germany, Italy, Sweden, and Taiwan were purposefully selected for comparison. All the countries, including Japan, introduced NIPT. The literature and information searches were conducted using PubMed, SCOPUS, Google Scholar, CiNii and Google searching engine. Results: The process of NIPT in Japan was very different from the other countries. Japan is the only country that indicated NIPT for only pregnant women over 35 years old in certificated facilities and did not have a policy regarding providing information on prenatal screening and NIPT to all women. Japan also did not have a policy regarding abortion due to fetal abnormalities. The practice of NIPT guidelines is different between non-certified and certified facilities. NIPT fee was the highest in Japan and was not covered by insurance. Conclusion: Pregnant women in Japan suffered from disparities in information access, economic burden, geographic location, and practice of NIPT guidelines between the certified and the non-certified facilities. Pregnant women-centered prenatal diagnosis policy, including NIPT, should be established in Japan by learning cases from other countries., International Journal of Environmental Research and Public Health, 19(24), art. no. 16404; 2022

Introduction: The Non-Invasive Prenatal Testing (NIPT) guideline was issued and applied in 2013 by the Japanese Medical Association. Since being issued, the NIPT practice in Japan still has some problems related to indication, access, cost coverage and uniformity. Therefore, our study aimed to identify the Japanese challenges of adopting NIPT into prenatal diagnosis by comparing the system and process with other countries. Method: The United Kingdom, Germany, Italy, Sweden, and Taiwan were purposefully selected for comparison. All the countries, including Japan, introduced NIPT. The literature and information searches were conducted using PubMed, SCOPUS, Google Scholar, CiNii and Google searching engine. Results: The process of NIPT in Japan was very different from the other countries. Japan is the only country that indicated NIPT for only pregnant women over 35 years old in certificated facilities and did not have a policy regarding providing information on prenatal screening and NIPT to all women. Japan also did not have a policy regarding abortion due to fetal abnormalities. The practice of NIPT guidelines is different between non-certified and certified facilities. NIPT fee was the highest in Japan and was not covered by insurance. Conclusion: Pregnant women in Japan suffered from disparities in information access, economic burden, geographic location, and practice of NIPT guidelines between the certified and the non-certified facilities. Pregnant women-centered prenatal diagnosis policy, including NIPT, should be established in Japan by learning cases from other countries., International Journal of Environmental Research and Public Health, 19(24), art. no. 16404; 2022

Since the introduction of cell-free (cf) DNA analysis, Non-Invasive Prenatal Testing (NIPT) underwent a deep revolution. Pregnancies at high risk for common fetal aneuploidies can now be easily identified through the analysis of chromosome-derived components found in maternal circulation, with the highest sensitivity and specificity currently available. Consequently, the last decade has witnessed a widespread growth in cfDNA-based NIPT use, enough to be often considered an alternative method to other screening modalities. Nevertheless, the use of NIPT in clinical practice is still not devoid of discordant results. Hereby, we report a case of confined placental mosaicism (CPM) in which a NIPT false-positive result for trisomy 13 required not only amniocentesis but also cordocentesis, to rule out the fetal aneuploidy, with the additional support of molecular cytogenetics on placental DNA at delivery. Relevant aspects allowing for precision genetic diagnosis and counselling, including the number of analysed metaphases on the different fetal cells compartments and a repeated multidisciplinary evaluation, are discussed.

Denmark was one of the first countries in the world to introduce a universal and free-of-charge offer of combined first-trimester screening for chromosomal anomalies to all pregnant women. In the present chapter, we describe the development and current status of the program and reflect on future directions in the era of exome sequencing and cell-based noninvasive testing. Now, prenatal screening programs differ vastly all over the world and even between countries that are often considered comparable, such as Denmark and Norway. In this chapter, we will present a few such comparisons but will focus mainly on a thorough description of the Danish context. The aim is to give the reader a point of reference to consider and compare their specific, national context.

The introduction of non-invasive prenatal testing (NIPT) as a screening test for the detection of fetal aneuploidies has transformed prenatal screening worldwide. NIPT is a safe and reliable screening method to detect fetal aneuploidies in maternal blood. In April 2017, first-tier NIPT was implemented in the Netherlands for all pregnant women as part of the TRIDENT-2 study initiated by the Dutch NIPT consortium. This thesis aimed to evaluate the responsible introduction of first-tier NIPT in the Dutch prenatal screening program. The studies in this thesis focus on aspects related to the implementation of NIPT (part I) and the perspectives of pregnant women (part II).

Next generation sequencing (NGS) has enabled us to accurately determine the nucleotide sequence of short fragments of DNA at a massive scale, which has led to various clinical applications of human genome sequencing. To extract information from these NGS experiments, virtually all analyses make use of a reference assembly of the human genome to map sequenced reads. Importantly, in these experiments a large fraction (~12%) of the sequenced DNA fragments are ignored as the origin of these sequences cannot be traced back to a (single) position on the reference assembly. The origin of these ignored or unmapped fragments is dual. On the one hand these fragments originate from sequence that occurs more than once (repeats). On the other hand, these fragments originate from sequence that is absent from the reference assembly. In practice, many of these unmapped fragments originate from so-called structural variations (SVs) where the sequenced genome differs from the reference assembly. In Part 1 of this thesis, we study this source of sequence variation by making use of so-called long-read sequencing technology and introduce methods to do so. In Part 2 of this thesis, we specifically study the DNA fragments that can’t be traced back to the human reference assembly, but instead seem to originate from DNA viruses.

Many major structural fetal anomalies can be diagnosed by first trimester fetal anomaly scan. NIPT can accurately detect aneuploidies and large chromosomal aberrations in cfDNA in maternal blood plasma. This study shows how a patient-friendly first trimester screening for both chromosomal and structural fetal anomalies in only two outpatient visits can be provided. Genotype-first approach assures not only the earliest diagnosis of trisomy 21 (the most prevalent chromosome aberration), but also completion of the screening at 12–14 weeks. To ensure proper management and avoid unnecessary anxiety abnormal NIPT different from trisomy 21, 18 and 13 should be referred for genetic counseling.

In 1997 it was discovered that fragments of DNA circulate freely in the blood plasma and, in the case of pregnancy, this DNA consists of DNA belonging to both the mother and the fetus. This circulating free DNA has made it possible to test for chromosomal aberration in the fetus through non-invasive methods, thereby avoiding the 1 in 100 chance of causing a miscarriage. Since then, multiple methods have been developed to detect chromosomal abnormalities with increasing accuracy and decreasing costs. The current state-of-the-art WISECONDOR uses a within-sample reference set, which is then used to calculate the z-score on a sliding window to determine whether an aberration is present or not. Here, we introduce a deep learning approach to non-invasive prenatal testing in the form of a Long-Short Term Memory model, which takes a sequence of GC normalized read counts per bin on the genome and outputs the label healthy or aberrated per bin. To test the performance of both WISECONDOR and the newly proposed model, data is simulated, and multiple experiments are set up to test the influence of certain aspects of NIPT. When comparing the LSTM model to WISECONDOR, it was shown that the LSTM model is still too inconsistent in its performance. This is caused by its reliance on the initialization of the weights and its dependence on the training set's composition.

Non-invasive prenatal testing (NIPT) is a method of prenatal screening that became available in approximately 2011. It uses fetal DNA in the maternal bloodstream to screen for various genetic conditions, such as trisomy 21. It can also be used for single-gene disorders, microdeletions, and fetal sex determination. In Australia it costs A$400–500, although it is publicly funded in some countries, for example, Belgium. The technology of NIPT is developing rapidly and its scope may widen. This may allow for NIPT to screen for traits that may be considered “non-medical” or have no “clinical utility”, such as height or cognitive ability. However, concepts such as “clinical utility” are ill-defined and frequently misused. We need a clear ethical framework on how to address future possible uses of NIPT. I use an empirical bioethics approach based on normative reflective empirical equilibrium, where the moral intuitions from agents with “moral wisdom” stemming from personal experience, and morally relevant facts, are collected through empirical data. Such agents have used NIPT. To inform my ethical analysis, I used NIPT sex determination as a case study, as it is a non-medical trait that is already widely screened for through NIPT. One of the key ethical concerns about NIPT sex determination is that it may lead to sex-selective termination of pregnancy (SSTOP). I performed a review of the evidence linking NIPT to SSTOP, and found the evidence to be largely anecdotal. I then performed a critical interpretive review of the ethical literature relating to NIPT sex determination and SSTOP and identified five key areas of ethical debate: methods of sex selection; consequences of sex selection; concerns relating to intrinsic wrongs; freedom, liberty, and choice; and finally, the framing of SSTOP practices. I then designed a mixed-methods survey that aimed to assess the motivations, experiences, and attitudes of people who have used NIPT in Australia towards its use for sex determi

In 1997 it was discovered that fragments of DNA circulate freely in the blood plasma and, in the case of pregnancy, this DNA consists of DNA belonging to both the mother and the fetus. This circulating free DNA has made it possible to test for chromosomal aberration in the fetus through non-invasive methods, thereby avoiding the 1 in 100 chance of causing a miscarriage. Since then, multiple methods have been developed to detect chromosomal abnormalities with increasing accuracy and decreasing costs. The current state-of-the-art WISECONDOR uses a within-sample reference set, which is then used to calculate the z-score on a sliding window to determine whether an aberration is present or not. Here, we introduce a deep learning approach to non-invasive prenatal testing in the form of a Long-Short Term Memory model, which takes a sequence of GC normalized read counts per bin on the genome and outputs the label healthy or aberrated per bin. To test the performance of both WISECONDOR and the newly proposed model, data is simulated, and multiple experiments are set up to test the influence of certain aspects of NIPT. When comparing the LSTM model to WISECONDOR, it was shown that the LSTM model is still too inconsistent in its performance. This is caused by its reliance on the initialization of the weights and its dependence on the training set's composition.

This dissertation is an ethnographic and qualitative study of how healthcare organizationsconstruct and enact policies on the use of new prenatal technologies, and how such policiesconstruct the context for patients’ decision-making. Specifically, it examines how the systems thatorganizations create for new technologies shape the roles of women in motherhood and pregnancy.Using qualitative methods, the dissertation examines how one private California healthcareorganization constructed policies regarding a new prenatal genetic test: non-invasive prenatalscreening (NIPT) using cell free DNA.1 The rapid uptake of NIPT since 2013 has led toorganizational upheaval as healthcare administrators struggle to categorize these new tests, whichblends the ease of basic blood screening most women have been offered for years (just a blooddraw) with claims of diagnostic-level accuracy (99% for the condition of Down Syndrome),allowing women to forego an invasive procedure like amniocentesis. The study ethnographicallytraces the process of policy creation and its impact on the ground by (1) observing how a policycommittee dedicated to moving NIPT from a Genetics department at a regional healthcareorganization to its Obstetrics department made new policies on NIPT use, and the (2) observingthe impact of these new NIPT policies on “the ground” at local Obstetrics clinics.Little research has examined the process of policy-making for patient education. This study buildson literature on the constitutive nature of law and policy (Sarat and Kearns 1993) to show howorganizational policies can constitute what technology means: the roles, responsibilities andidentities of organizational personnel and those who use their services (e.g. women who arepregnant). More than simply processing patients who come through the door, organizationalpolicies, like law, redefine who patients are, and what they experience both empirically andnormatively. This dissertation studies how in this process institutio

This dissertation is an ethnographic and qualitative study of how healthcare organizationsconstruct and enact policies on the use of new prenatal technologies, and how such policiesconstruct the context for patients’ decision-making. Specifically, it examines how the systems thatorganizations create for new technologies shape the roles of women in motherhood and pregnancy.Using qualitative methods, the dissertation examines how one private California healthcareorganization constructed policies regarding a new prenatal genetic test: non-invasive prenatalscreening (NIPT) using cell free DNA.1 The rapid uptake of NIPT since 2013 has led toorganizational upheaval as healthcare administrators struggle to categorize these new tests, whichblends the ease of basic blood screening most women have been offered for years (just a blooddraw) with claims of diagnostic-level accuracy (99% for the condition of Down Syndrome),allowing women to forego an invasive procedure like amniocentesis. The study ethnographicallytraces the process of policy creation and its impact on the ground by (1) observing how a policycommittee dedicated to moving NIPT from a Genetics department at a regional healthcareorganization to its Obstetrics department made new policies on NIPT use, and the (2) observingthe impact of these new NIPT policies on “the ground” at local Obstetrics clinics.Little research has examined the process of policy-making for patient education. This study buildson literature on the constitutive nature of law and policy (Sarat and Kearns 1993) to show howorganizational policies can constitute what technology means: the roles, responsibilities andidentities of organizational personnel and those who use their services (e.g. women who arepregnant). More than simply processing patients who come through the door, organizationalpolicies, like law, redefine who patients are, and what they experience both empirically andnormatively. This dissertation studies how in this process institutio

Background: Women who receive negative results from non-invasive prenatal genetic testing (NIPT) may find that they later have mixed or ambivalent feelings, for example, feelings of accepting NIPT and regretting undergoing the test. This study aimed to investigate the factors generating ambivalent feelings among women who gave birth after having received negative results from NIPT. Methods: A questionnaire was sent to women who received a negative NIPT result, and a contents analysis was conducted focusing on ambivalent expressions for those 1562 women who responded the questionnaire. The qualitative data gathered from the questionnaire were analyzed using the N-Vivo software package. Results: Environmental factors, genetic counseling-related factors, and increased anticipatory anxiety, affected the feeling of ambivalence among pregnant women. Furthermore, pregnant women desired more information regarding the detailed prognosis for individuals with Down syndrome and living with them and/or termination, assuming the possibility that they were positive. Conclusions: Three major interrelated factors affected the feeling of ambivalence in women. Highlighting and discussing such factors during genetic counseling may resolve some of these ambivalences, thereby enhancing the quality of decisions made by pregnant women.

Les anomalies chromosomiques sont une cause majeure de morbidité et de mortalité périnatales. Le dépistage de ces affections a toujours été crucial pour une prise en charge optimale des femmes enceintes.Initialement, le dépistage de trisomie 21 était uniquement basé selon le risque lié à l’âge maternel. L’ajout de différents marqueurs biochimiques sériques constituant successivement les double, triple et quadruple tests a pu améliorer le taux de détection. Néanmoins, c’est en 1997 qu’apparaît un point tournant de l’histoire de dépistage des trisomies :l’introduction de la mesure de la clarté nucale à l’échographie du premier trimestre.Depuis 2011, de nouvelles recherches se sont concentrées sur le dépistage prénatal non invasif (DPNI) utilisant l'ADN fœtal libre circulant dans le sang maternel. Cette technique a suggéré directement une supériorité marquée pour la détection de la trisomie 21 comparée à toutes les autres méthodes de dépistage connues. Rapidement, ce test a été introduit en pratique clinique dans le monde entier sans une évaluation préalable et approfondie, que ce soit au niveau scientifique, technique ou éthique.Les objectifs de cette thèse étaient de fournir des réponses aux diverses questions persistantes concernant l’utilisation clinique des tests de dépistages basés sur ADN fœtal libre dans la circulation maternelle.À notre connaissance, nous sommes la première équipe à essayer d'évaluer le taux d'échec et la performance du DPNI effectué par différents laboratoires utilisant différentes méthodes analytiques. Nous avons démontré que les approches « DANSR » (approche ciblée sur les chromosomes d’intérêt) et « GW-MPS » (approche globale sur les séquences géniques reparties sur la totalité du génome par un séquençage à haut débit) offraient toutes les deux un taux échec bas avec une bonne performance dans la détection des trisomies 21, 13 et 18. Cependant, le niveau de fraction fœtale semble varier d'un laboratoire à l'autre et n’est, par conséquent, Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

The noninvasive prenatal test (NIPT) as the first trimester prenatal screening (FTS) for trisomies 21, 18, and 13 is offered to all pregnant women in the Netherlands. NIPT using genome sequencing allows for an expansion of the scope of FTS and the introduction of NIPT gives rise to ethical and societal concerns about deliberated decision-making, pressure to engage in screening, and possible lack of equal access due to the financial contribution (€175) to NIPT. We explored the opinions and experiences of pregnant women, who were offered FTS, about these concerns, and the possibility of a broadened scope. Nineteen pregnant women representing a diversity of backgrounds were interviewed using a semi-structured interview guide. Eight women did not opt for prenatal screening while 11 did (NIPT = 4, combined test = 7). Women experienced a free choice to accept or decline prenatal screening, despite sometimes receiving advice from others. Prior to pretest counseling, some women had already deliberated about what an abnormal test result would mean to them. Others accepted or declined FTS without deliberation. The current Dutch policy of requiring a co-payment was acceptable to some, who believed that it funct

Background: Two technological innovations in the last decade significantly influenced the diagnostic yield of prenatal cytogenetic testing: genomic microarray allowing high resolution analysis and noninvasive prenatal testing (NIPT) focusing on aneuploidy. To anticipate future trends in prenatal screening and diagnosis, we evaluated the number of invasive tests in our center and the number of aberrant cases diagnosed in the last decade. Methods: We retrospectively analyzed fetal chromosomal aberrations diagnosed in 2009–2018 in 8,608 pregnancies without ultrasound anomalies. Results: The introduction of NIPT as the first-tier test led to a substantial decrease in the number of invasive tests and a substantially increased diagnostic yield of aneuploidies in the first trimester. However, we have also noted a decreased detection of submicroscopic aberrations, since the number of invasive tests substantially decreased. We have observed that pregnant women were interested in broader scope of prenatal screening and diagnosis than detection of common trisomies. Conclusion: Since the frequency of syndromic disorders caused by microdeletions/ microduplications is substantial and current routine NIPT and ultrasound investigations are not able to detect them, we suggest that a noninvasive test with resolution comparable to microarrays should be developed, which will also meet patient's needs.

Since its introduction around the end of the 1970s, interphase fluorescence in situ hybridization (FISH) supports both classical and recent techniques for determining fetal karyotypes during prenatal diagnosis, quickly providing relevant information for the management of pregnancy. Interphase FISH plays an important role in the study of pregnancies with malformations, in mosaicism conditions, in confirming or excluding aneuploidy detected by non-invasive prenatal testing, and in the diagnosis of contiguous gene syndromes due to microdeletions. The availability of many commercial probes from different genomic regions makes this method versatile and easy to apply in the pathways of prenatal diagnosis and fetal care.

BACKGROUND: Various algorithms have been developed to predict fetal trisomies using cell-free DNA in non-invasive prenatal testing (NIPT). As basis for prediction, a control group of non-trisomy samples is needed. Prediction accuracy is dependent on the characteristics of this group and can be improved by reducing variability between samples and by ensuring the control group is representative for the sample analyzed. RESULTS: NIPTeR is an open-source R Package that enables fast NIPT analysis and simple but flexible workflow creation, including variation reduction, trisomy prediction algorithms and quality control. This broad range of functions allows users to account for variability in NIPT data, calculate control group statistics and predict the presence of trisomies. CONCLUSION: NIPTeR supports laboratories processing next-generation sequencing data for NIPT in assessing data quality and determining whether a fetal trisomy is present. NIPTeR is available under the GNU LGPL v3 license and can be freely downloaded from https://github.com/molgenis/NIPTeR or CRAN.

BACKGROUND: Various algorithms have been developed to predict fetal trisomies using cell-free DNA in non-invasive prenatal testing (NIPT). As basis for prediction, a control group of non-trisomy samples is needed. Prediction accuracy is dependent on the characteristics of this group and can be improved by reducing variability between samples and by ensuring the control group is representative for the sample analyzed. RESULTS: NIPTeR is an open-source R Package that enables fast NIPT analysis and simple but flexible workflow creation, including variation reduction, trisomy prediction algorithms and quality control. This broad range of functions allows users to account for variability in NIPT data, calculate control group statistics and predict the presence of trisomies. CONCLUSION: NIPTeR supports laboratories processing next-generation sequencing data for NIPT in assessing data quality and determining whether a fetal trisomy is present. NIPTeR is available under the GNU LGPL v3 license and can be freely downloaded from https://github.com/molgenis/NIPTeR or CRAN.

Uppsatsen är en diskursanalys av fosterdiagnostik och abort som erbjuds av staten och regleras i lagen i tre skandinaviska länder. Eftersom antalet barn födda med Downs syndrom har sjunkit markant under det senaste decenniet samtidigt som möjligheterna för och användandet av nya fosterdiagnostiska metoder har ökat är avsikten att skapa fördjupad kunskap om vad detta innebär genom att belysa trenden ur ett biopolitiskt perspektiv. Detta sker med utgångspunkt från Michel Foucaults begrepp biomakt och governmentalitet med fokus på tillgänglighet, rådgivning och användning av fosterdiagnostiska metoder. Uppsatsen redogör för etosdiskursen som en del av den alltomfattande governmentalitetsdiskursen vilket blottlägger en förklaring av en rationalitet karaktäriserad av vår tid som yttrar sig i en strävan att undvika barn med kromosomavvikelser., The essay is a discourse analysis of obstetric diagnosis and abortion offered by the state and regulated by laws in three Scandinavian countries. As the number of childbirths with Down’s syndrome has fallen sharply in recent decades, while the opportunities for and use of new Foetus diagnostic methods have increased, the intention is to create in-depth knowledge of what this means by highlighting the development from a biopolitical perspective. This is based on Michel Foucault's concept of biopower and governmentality with focus on availability, counselling and use of foetus diagnostic methods. The essay explains the ethos discourse as part of the allinclusive government discussion which shows exposes an explanation of a rationality characterizing to our time that expresses itself to avoid children with chromosomal disorders.

In this article I investigate the ways in which phenomenology could guide our views on the rights and/or wrongs of abortion. To my knowledge very few phenomenologists have directed their attention toward this issue, although quite a few have strived to better understand and articulate the strongly related themes of pregnancy and birth, most often in the context of feminist philosophy. After introducing the ethical and political contemporary debate concerning abortion, I introduce phenomenology in the context of medicine and the way phenomenologists have understood the human body to be lived and experienced by its owner. I then turn to the issue of pregnancy and discuss how the embryo or foetus could appear for us, particularly from the perspective of the pregnant woman, and what such showing up may mean from an ethical perspective. The way medical technology has changed the experience of pregnancy-for the pregnant woman as well as for the father and/or other close ones-is discussed, particularly the implementation of early obstetric ultra-sound screening and blood tests (NIPT) for Down's syndrome and other medical defects. I conclude the article by suggesting that phenomenology can help us to negotiate an upper time limit for legal abortion and, also, provide ways to determine what embryo-foetus defects to look for and in which cases these should be looked upon as good reasons for performing an abortion.

BACKGROUND: Various algorithms have been developed to predict fetal trisomies using cell-free DNA in non-invasive prenatal testing (NIPT). As basis for prediction, a control group of non-trisomy samples is needed. Prediction accuracy is dependent on the characteristics of this group and can be improved by reducing variability between samples and by ensuring the control group is representative for the sample analyzed. RESULTS: NIPTeR is an open-source R Package that enables fast NIPT analysis and simple but flexible workflow creation, including variation reduction, trisomy prediction algorithms and quality control. This broad range of functions allows users to account for variability in NIPT data, calculate control group statistics and predict the presence of trisomies. CONCLUSION: NIPTeR supports laboratories processing next-generation sequencing data for NIPT in assessing data quality and determining whether a fetal trisomy is present. NIPTeR is available under the GNU LGPL v3 license and can be freely downloaded from https://github.com/molgenis/NIPTeR or CRAN., CC BY 4.0

BACKGROUND: Various algorithms have been developed to predict fetal trisomies using cell-free DNA in non-invasive prenatal testing (NIPT). As basis for prediction, a control group of non-trisomy samples is needed. Prediction accuracy is dependent on the characteristics of this group and can be improved by reducing variability between samples and by ensuring the control group is representative for the sample analyzed. RESULTS: NIPTeR is an open-source R Package that enables fast NIPT analysis and simple but flexible workflow creation, including variation reduction, trisomy prediction algorithms and quality control. This broad range of functions allows users to account for variability in NIPT data, calculate control group statistics and predict the presence of trisomies. CONCLUSION: NIPTeR supports laboratories processing next-generation sequencing data for NIPT in assessing data quality and determining whether a fetal trisomy is present. NIPTeR is available under the GNU LGPL v3 license and can be freely downloaded from https://github.com/molgenis/NIPTeR or CRAN., CC BY 4.0

Uppsatsen är en diskursanalys av fosterdiagnostik och abort som erbjuds av staten och regleras i lagen i tre skandinaviska länder. Eftersom antalet barn födda med Downs syndrom har sjunkit markant under det senaste decenniet samtidigt som möjligheterna för och användandet av nya fosterdiagnostiska metoder har ökat är avsikten att skapa fördjupad kunskap om vad detta innebär genom att belysa trenden ur ett biopolitiskt perspektiv. Detta sker med utgångspunkt från Michel Foucaults begrepp biomakt och governmentalitet med fokus på tillgänglighet, rådgivning och användning av fosterdiagnostiska metoder. Uppsatsen redogör för etosdiskursen som en del av den alltomfattande governmentalitetsdiskursen vilket blottlägger en förklaring av en rationalitet karaktäriserad av vår tid som yttrar sig i en strävan att undvika barn med kromosomavvikelser., The essay is a discourse analysis of obstetric diagnosis and abortion offered by the state and regulated by laws in three Scandinavian countries. As the number of childbirths with Down’s syndrome has fallen sharply in recent decades, while the opportunities for and use of new Foetus diagnostic methods have increased, the intention is to create in-depth knowledge of what this means by highlighting the development from a biopolitical perspective. This is based on Michel Foucault's concept of biopower and governmentality with focus on availability, counselling and use of foetus diagnostic methods. The essay explains the ethos discourse as part of the allinclusive government discussion which shows exposes an explanation of a rationality characterizing to our time that expresses itself to avoid children with chromosomal disorders.

BACKGROUND: Various algorithms have been developed to predict fetal trisomies using cell-free DNA in non-invasive prenatal testing (NIPT). As basis for prediction, a control group of non-trisomy samples is needed. Prediction accuracy is dependent on the characteristics of this group and can be improved by reducing variability between samples and by ensuring the control group is representative for the sample analyzed. RESULTS: NIPTeR is an open-source R Package that enables fast NIPT analysis and simple but flexible workflow creation, including variation reduction, trisomy prediction algorithms and quality control. This broad range of functions allows users to account for variability in NIPT data, calculate control group statistics and predict the presence of trisomies. CONCLUSION: NIPTeR supports laboratories processing next-generation sequencing data for NIPT in assessing data quality and determining whether a fetal trisomy is present. NIPTeR is available under the GNU LGPL v3 license and can be freely downloaded from https://github.com/molgenis/NIPTeR or CRAN., CC BY 4.0

Objective: To determine the performance of a targeted microarray-based cell-free DNA (cfDNA) test (Harmony Prenatal Test®) for the identification of pregnancies at increased risk for 22q11.2 deletion. Methods: Test performance was determined in 2 steps including a total of 1,953 plasma samples. Analytical validation was performed in 1,736 plasma samples. Clinical verification of performance was performed in an additional 217 prospectively ascertained samples from pregnancies with fetal deletion status determined by diagnostic testing. Results: Analytical sensitivity was 75.4% (95% CI: 67.1-82.2%) based on 122 samples with deletions ranging from 1.96 to 3.25 Mb. In 1,614 presumed unaffected samples, specificity was determined to be at least 99.5% (95% CI: 99.0-99.7%). In the clinical cohort, 5 of 7 samples from pregnancies affected with 22q11.2 deletion were determined to have a high probability of deletion. There were no false positive results in the 210 unaffected samples in this cohort. These clinical data are consistent with the performance demonstrated in the analytical validation. Conclusions: cfDNA testing using a targeted microarray-based technology is able to identify pregnancies at increased risk for 22q11.2 deletions of 3.0 Mb and smaller while maintaining a low false positive rate., SCOPUS: ar.j, info:eu-repo/semantics/published

Non-invasive prenatal testing (NIPT) was recently introduced for prenatal testing of genetic disorders. Cell-free fetal DNA is present in maternal blood during pregnancy and enables detection of fetal chromosome aberrations in a maternal blood sample. The public perspective to this new, simple method has not been illuminated. The views of young people (i.e. future parents) are important to develop suitable counseling strategies regarding prenatal testing. The aim was to explore Swedish high school students' attitudes, knowledge and preferences regarding NIPT. A questionnaire was completed by 305 students recruited from one high school in Stockholm, November and December 2014. Most students (80 %) considered prenatal testing as good. The majority (65 %) was positive or very positive towards NIPT and 62 % stated that they potentially would like to undergo the test if they or their partner was pregnant. The vast majority (94 %) requested further information about NIPT. Most students (61 %) preferred verbal information, whereas 20 % preferred information via the Internet. The majority of the high school students was positive towards prenatal testing and most was positive towards NIPT. Further, information was requested by the vast majority before making a decision about NIPT. Most of the students preferred verbal information and to a lesser extent information via the Internet. The attitudes, knowledge and preferences for risk information concerning NIPT in young adults are important, in order to increase knowledge on how to educate and inform future parents.

Non-invasive prenatal testing (NIPT) was recently introduced for prenatal testing of genetic disorders. Cell-free fetal DNA is present in maternal blood during pregnancy and enables detection of fetal chromosome aberrations in a maternal blood sample. The public perspective to this new, simple method has not been illuminated. The views of young people (i.e. future parents) are important to develop suitable counseling strategies regarding prenatal testing. The aim was to explore Swedish high school students' attitudes, knowledge and preferences regarding NIPT. A questionnaire was completed by 305 students recruited from one high school in Stockholm, November and December 2014. Most students (80 %) considered prenatal testing as good. The majority (65 %) was positive or very positive towards NIPT and 62 % stated that they potentially would like to undergo the test if they or their partner was pregnant. The vast majority (94 %) requested further information about NIPT. Most students (61 %) preferred verbal information, whereas 20 % preferred information via the Internet. The majority of the high school students was positive towards prenatal testing and most was positive towards NIPT. Further, information was requested by the vast majority before making a decision about NIPT. Most of the students preferred verbal information and to a lesser extent information via the Internet. The attitudes, knowledge and preferences for risk information concerning NIPT in young adults are important, in order to increase knowledge on how to educate and inform future parents.

Non-invasive prenatal testing (NIPT) was recently introduced for prenatal testing of genetic disorders. Cell-free fetal DNA is present in maternal blood during pregnancy and enables detection of fetal chromosome aberrations in a maternal blood sample. The public perspective to this new, simple method has not been illuminated. The views of young people (i.e. future parents) are important to develop suitable counseling strategies regarding prenatal testing. The aim was to explore Swedish high school students' attitudes, knowledge and preferences regarding NIPT. A questionnaire was completed by 305 students recruited from one high school in Stockholm, November and December 2014. Most students (80 %) considered prenatal testing as good. The majority (65 %) was positive or very positive towards NIPT and 62 % stated that they potentially would like to undergo the test if they or their partner was pregnant. The vast majority (94 %) requested further information about NIPT. Most students (61 %) preferred verbal information, whereas 20 % preferred information via the Internet. The majority of the high school students was positive towards prenatal testing and most was positive towards NIPT. Further, information was requested by the vast majority before making a decision about NIPT. Most of the students preferred verbal information and to a lesser extent information via the Internet. The attitudes, knowledge and preferences for risk information concerning NIPT in young adults are important, in order to increase knowledge on how to educate and inform future parents.

Non-invasive prenatal testing (NIPT) was recently introduced for prenatal testing of genetic disorders. Cell-free fetal DNA is present in maternal blood during pregnancy and enables detection of fetal chromosome aberrations in a maternal blood sample. The public perspective to this new, simple method has not been illuminated. The views of young people (i.e. future parents) are important to develop suitable counseling strategies regarding prenatal testing. The aim was to explore Swedish high school students' attitudes, knowledge and preferences regarding NIPT. A questionnaire was completed by 305 students recruited from one high school in Stockholm, November and December 2014. Most students (80 %) considered prenatal testing as good. The majority (65 %) was positive or very positive towards NIPT and 62 % stated that they potentially would like to undergo the test if they or their partner was pregnant. The vast majority (94 %) requested further information about NIPT. Most students (61 %) preferred verbal information, whereas 20 % preferred information via the Internet. The majority of the high school students was positive towards prenatal testing and most was positive towards NIPT. Further, information was requested by the vast majority before making a decision about NIPT. Most of the students preferred verbal information and to a lesser extent information via the Internet. The attitudes, knowledge and preferences for risk information concerning NIPT in young adults are important, in order to increase knowledge on how to educate and inform future parents.

Non-invasive prenatal testing (NIPT) was recently introduced for prenatal testing of genetic disorders. Cell-free fetal DNA is present in maternal blood during pregnancy and enables detection of fetal chromosome aberrations in a maternal blood sample. The public perspective to this new, simple method has not been illuminated. The views of young people (i.e. future parents) are important to develop suitable counseling strategies regarding prenatal testing. The aim was to explore Swedish high school students' attitudes, knowledge and preferences regarding NIPT. A questionnaire was completed by 305 students recruited from one high school in Stockholm, November and December 2014. Most students (80 %) considered prenatal testing as good. The majority (65 %) was positive or very positive towards NIPT and 62 % stated that they potentially would like to undergo the test if they or their partner was pregnant. The vast majority (94 %) requested further information about NIPT. Most students (61 %) preferred verbal information, whereas 20 % preferred information via the Internet. The majority of the high school students was positive towards prenatal testing and most was positive towards NIPT. Further, information was requested by the vast majority before making a decision about NIPT. Most of the students preferred verbal information and to a lesser extent information via the Internet. The attitudes, knowledge and preferences for risk information concerning NIPT in young adults are important, in order to increase knowledge on how to educate and inform future parents.

[EN] This Master's Thesis focuses on the development of a unique section in an existing Obstetrics software module, that aims to collect medical information for a research study. The study in question aims to evaluate the effectiveness of the Non Invasive Prenatal Test (NIPT), which makes use of techniques based on cell free fetal DNA (cffDNA), in the context of the Netherlands' pregnancy routine care programme., [ES] El objetivo de este Trabajo Fin de Máster se centra en desarrollar la sección de un software ginecológico que ayude a tratar y clasificar la información de TRIDENT, un estudio de investigación, cuyo objetivo principal es la evaluación de la prueba NIPT (Non Invasive Prenatal Test). Esta prueba hace uso de técnicas basadas en cffDNA (cell free fetal DNA), y trata de estudiar su efectividad y observar de qué manera se podría mejorar su aplicabilidad en los Países Bajos.

[EN] This Master's Thesis focuses on the development of a unique section in an existing Obstetrics software module, that aims to collect medical information for a research study. The study in question aims to evaluate the effectiveness of the Non Invasive Prenatal Test (NIPT), which makes use of techniques based on cell free fetal DNA (cffDNA), in the context of the Netherlands' pregnancy routine care programme., [ES] El objetivo de este Trabajo Fin de Máster se centra en desarrollar la sección de un software ginecológico que ayude a tratar y clasificar la información de TRIDENT, un estudio de investigación, cuyo objetivo principal es la evaluación de la prueba NIPT (Non Invasive Prenatal Test). Esta prueba hace uso de técnicas basadas en cffDNA (cell free fetal DNA), y trata de estudiar su efectividad y observar de qué manera se podría mejorar su aplicabilidad en los Países Bajos.

[EN] This Master's Thesis focuses on the development of a unique section in an existing Obstetrics software module, that aims to collect medical information for a research study. The study in question aims to evaluate the effectiveness of the Non Invasive Prenatal Test (NIPT), which makes use of techniques based on cell free fetal DNA (cffDNA), in the context of the Netherlands' pregnancy routine care programme., [ES] El objetivo de este Trabajo Fin de Máster se centra en desarrollar la sección de un software ginecológico que ayude a tratar y clasificar la información de TRIDENT, un estudio de investigación, cuyo objetivo principal es la evaluación de la prueba NIPT (Non Invasive Prenatal Test). Esta prueba hace uso de técnicas basadas en cffDNA (cell free fetal DNA), y trata de estudiar su efectividad y observar de qué manera se podría mejorar su aplicabilidad en los Países Bajos.

__Background:__ Since non-invasive prenatal testing (NIPT) in maternal blood became available, we evaluated which chromosome aberrations found in our cohort of fetuses with an enlarged NT in the first trimester of pregnancy (tested with SNP microarray) could be detected by NIPT as well. __Method:__ 362 fetuses were referred for cytogenetic testing due to an enlarged NT (≥3.5 mm). Chromosome aberrations were investigated using QF-PCR, karyotyping and whole genome SNP array. __Results:__ After invasive testing a chromosomal abnormality was detected in 137/362 (38 %) fetuses. 100/362 (28 %) cases concerned trisomy 21, 18 or 13, 25/362 (7 %) an aneuploidy of sex chromosomes and 3/362 (0.8 %) triploidy. In 6/362 (1.6 %) a pathogenic structural unbalanced chromosome aberration was seen and in 3/362 (0.8 %) a susceptibility locus for neurodevelopmental disorders was found. We estimated that in 2-10 % of fetuses with enlarged NT a chromosome aberration would be missed by current NIPT approaches. __Conclusion:__ Based on our cohort of fetuses with enlarged NT we may conclude that NIPT, depending on the approach, will miss chromosome aberrations in a significant percentage of pregnancies. Moreover all abnormal NIPT results require confirmatory studies with invasive testing, which will delay definitive diagnosis in ca. 30 % of patients. These figures are important for pretest counseling enabling pregnant women to make informed choices on the prenatal test. Larger cohorts of fetuses with an enlarged NT should be investigated to assess the additional diagnostic value of high resolution array testing for this indication.

The practice of prenatal screening is undergoing important changes as a result of the introduction of genomic testing technologies at different stages of the screening trajectory. It is expected that eventually it will become possible to routinely obtain a comprehensive genome scan' of all fetuses. Although this will still take several years, there are clear continuities between present developments and this future scenario. As this review shows, behind the still limited scope of screening for common aneuploidies, a rapid widening of the range of conditions tested for is already taking shape at the invasive testing stage. But the continuities are not just technical; they are also ethical. If screening for Down's syndrome is a matter of providing autonomous reproductive choice, then why would providing the choice to have a full fetal genome scan be something entirely different? There is a clear need for a sustainable normative framework that will have to answer three challenges: the indeterminateness of the autonomy paradigm, the need to acknowledge the future child as an interested stakeholder, and the prospect of broad-scope genomic prenatal screening with a double purpose: autonomy and prevention.

The blood of a pregnant woman contains DNA from her unborn child. This DNA can be tested by taking a blood sample from the mother-to-be. In this dissertation, a blood sample was used to determine the sex of the baby and to test for the inheritance of myotonic dystrophy, a chronic muscular disorder. This dissertation also assessed the responsible use of this blood test to screen for Down's syndrome and less severe chromosomal disorders during pregnancy. All pregnant women will be able to request this test to screen for Down's syndrome as of April 2017.

The blood of a pregnant woman contains DNA from her unborn child. This DNA can be tested by taking a blood sample from the mother-to-be. In this dissertation, a blood sample was used to determine the sex of the baby and to test for the inheritance of myotonic dystrophy, a chronic muscular disorder. This dissertation also assessed the responsible use of this blood test to screen for Down's syndrome and less severe chromosomal disorders during pregnancy. All pregnant women will be able to request this test to screen for Down's syndrome as of April 2017.

The practice of prenatal screening is undergoing important changes as a result of the introduction of genomic testing technologies at different stages of the screening trajectory. It is expected that eventually it will become possible to routinely obtain a comprehensive genome scan' of all fetuses. Although this will still take several years, there are clear continuities between present developments and this future scenario. As this review shows, behind the still limited scope of screening for common aneuploidies, a rapid widening of the range of conditions tested for is already taking shape at the invasive testing stage. But the continuities are not just technical; they are also ethical. If screening for Down's syndrome is a matter of providing autonomous reproductive choice, then why would providing the choice to have a full fetal genome scan be something entirely different? There is a clear need for a sustainable normative framework that will have to answer three challenges: the indeterminateness of the autonomy paradigm, the need to acknowledge the future child as an interested stakeholder, and the prospect of broad-scope genomic prenatal screening with a double purpose: autonomy and prevention.

Il contributo affronta il tema delle questioni etiche sollevate dall'uso del test prenatale non invasivo (NIPT) basato sul DNA

Rapid progress in genomic medicine in recent years has made it possible to diagnose subtle genetic abnormalities in a clinical setting on routine basis. This has allowed for detailed genotype-phenotype correlations and the identification of the genetic basis of many congenital anomalies. In addition to the availability of chromosomal microarray analysis, exome and whole-genome sequencing on pre- and postnatal samples of cell-free DNA has revolutionized the field of prenatal diagnosis. Incorporation of these technologies in perinatal pathology is bound to play a major role in coming years. In this communication, we briefly present the current experience with use of classical chromosome analysis, fluorescence in situ hybridization, and microarray testing, development of whole-genome analysis by next-generation sequencing technology, offer a detailed review of the history and current status of non-invasive prenatal testing using cell-free DNA, and discuss the advents of these new genomic technologies in perinatal medicine.