Newborn screening system: Safety, technology, advocacy.

Newborn screening (NBS) is more than 50 years old and has proven to be a powerful and successful public health system. NBS must be regarded as a system and not simply as a test. We need to work as a community to improve the culture of safety for the NBS system and thereby to reduce the risk of babies being missed by the NBS system. Adding new technologies will not prevent system failures; that will require adherence to the culture of safety. Some have argued that every newborn should have their genome sequenced at birth and this sequencing could be part of NBS. However, NBS has depended on biomarker phenotypes throughout its history and our understanding of the relationships between genotype and phenotype is imperfect. Therefore, we should avoid being seduced by genomic sequencing technology and continue to focus on phenotypic biomarkers in NBS.

Metabolite flux: A dynamic concept for inherited metabolic disorders as complex traits.

In 2000 and 2001, we described factors that lead to the phenotypes of individuals with "simple," "single" gene disorders, like inherited metabolic disorders, being complex, multi-genic traits. These factors include functional thresholds, genetic and environmental modifiers, and systems dynamics, encompassing metabolic control analysis and scale-free, hub-and-spoke networks. This mini-review will consider topics influencing complexity developed in the ensuing nearly two decades, such as "synergistic heterozygosity" and "moonlighting proteins." There will be a focus on the value of the measurement of flux in evaluating the metabolome to ascertain phenotypic variability and the potential role of the gut microbiome in metabolomic flux. A point-of-care metabolomics tool, under development to improve the real time, inter-operative ascertainment of tumor margins and similar devices, will provide opportunities to improve acute care and ongoing management of individuals with inherited metabolic disorders.

Modifier genes: Moving from pathogenesis to therapy.

This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms. Since one of the goals of research on modifier genes and networks is to identify novel therapeutic targets, the challenges to patient access and compliance because of the high costs of medications for rare genetic diseases must be recognized. A recent article explored protective modifiers, including plastin 3 (PLS3) and coronin 1C (CORO1C), in spinal muscular atrophy (SMA). SMA is an autosomal recessive deficit of survival motor neuron protein (SMN) caused by mutations in SMN1. However, the severity of SMA is determined primarily by the number of SMN2 copies, and this results in significant phenotypic variability. PLS3 was upregulated in siblings who were asymptomatic compared with those who had SMA2 or SMA3, but identical homozygous SMN1 deletions and equal numbers of SMN2 copies. CORO1C was identified by interrogation of the PLS3 interactome. Overexpression of these proteins rescued endocytosis in SMA models. In addition, antisense RNA for upregulation of SMN2 protein expression is being developed as another way of modifying the SMA phenotype. These investigations suggest the practical application of protective modifiers to rescue SMA phenotypes. Other examples of the potential therapeutic value of novel protective modifiers will be discussed, including in Duchenne muscular dystrophy and glycerol kinase deficiency. This work shows that while we live in an exciting era of genomic sequencing, a functional understanding of biology, the impact of its disruption, and possibilities for its repair have never been more important as we search for new therapies.

Newborn screening: A complex system that requires a culture of safety.

As health care providers and organizations, we have a responsibility to examine our practices and systems for opportunities to improve quality and health outcomes. Today a critical opportunity exists in the newborn screening (NBS) system, which touches every one of the approximately 4 million babies born annually in the United States. This opportunity involves improving the quality of NBS by developing a culture of safety to prevent errors that in NBS represent missed babies and preventable morbidity and mortality. This commentary will explore the "culture of safety" for NBS, including the high reliability organization (HRO) paradigm and normal accident theory (NAT), which have been effective in reducing systems failures in other complex environments.

Current estimate of Down Syndrome population prevalence in the United States.

OBJECTIVE: To calculate a reliable estimate of the population prevalence of Down syndrome in the US. STUDY DESIGN: The annual number of births of infants with Down syndrome were estimated by applying published birth prevalence rates of Down syndrome by maternal age to US data from the Centers for Disease Control and Prevention for the years for which births by maternal age were available (1940-2008). Death certificate data for persons with Down syndrome were available for the years 1968-2007. We estimated the number of people with Down syndrome on January 1, 2008, using a life table approach based on proportions of deaths by age. Monte Carlo sampling was used to create 90% uncertainty intervals (UIs) for our estimates. RESULTS: We estimated the January 1, 2008, population prevalence of Down syndrome as approximately 250700 (90% UI, 185900-321700) based on proportions of deaths by age from the most recent 2 years (2006-2007) of death certificate data. This estimate corresponds to a prevalence of 8.27 people with Down syndrome per 10000 population (90% UI, 6.14-10.62). CONCLUSION: Our estimate of Down syndrome prevalence is roughly 25%-40% lower than estimates based solely on current birth prevalence. The results presented here can be considered a starting point for facilitating policy and services planning for persons with Down syndrome.

Acute leukemias in children with Down syndrome.

Children with Down syndrome (DS) often present with hematopoietic abnormalities, and are at increased risk of developing leukemia. Specifically, 3-10% of newborns with DS are diagnosed with transient myeloproliferative disease, and children with DS are 500 times more likely to develop acute megakaryoblastic leukemia (AMKL) and 20 times more likely to develop acute lymphoblastic leukemia (ALL) than typical children. This review examines the characteristics of these leukemias and their development in the unique genetic background of trisomy 21. A discussion is also provided for areas of future research and potential therapeutic development.

Call for change in prenatal counseling for Down syndrome.

The American Journal of Medical Genetics Part A is to be congratulated for taking a leadership role by publishing a number of papers challenging the status quo of prenatal counseling for Down syndrome and of care for children and adults with Down syndrome. Parents want to know about the future abilities and potential of their fetus with Down syndrome, not simply negative medical information that may be outdated. Those providing counseling and those providing medical care could benefit from contact with individuals with Down syndrome outside the medical context. It is imperative that each person with Down syndrome be viewed as a unique individual with particular talents. Medical care providers should work with parents to help the child or adult with Down syndrome reach his/her goals.

Down syndrome: coercion and eugenics.

Experts agree that coercion by insurance companies or governmental authorities to limit reproductive choice constitutes a eugenic practice. We discuss discrimination against families of children with Down syndrome who chose not to have prenatal testing or chose to continue a pregnancy after a prenatal diagnosis. We argue that this discrimination represents economic and social coercion to limit reproductive choice, and we present examples of governmental rhetoric and policies condoning eugenics and commercial policies meeting criteria established by experts for eugenics. Our purpose is to sensitize the clinical genetics community to these issues as we attempt to provide the most neutral nondirective prenatal genetic counseling we can, and as we provide postnatal care and counseling to children with Down syndrome and their families. We are concerned that if eugenic policies and practices targeting individuals with Down syndrome and their families are tolerated by clinical geneticists and the broader citizenry, then we increase the probability of eugenics directed toward other individuals and communities.

Moving toward personalized cell-based interventions for adrenal cortical disorders: part 1--Adrenal development and function, and roles of transcription factors and signaling proteins.

Transdifferentiation of an individual's own cells into functional differentiated cells to replace an organ's lost function would be a personalized approach to therapeutics. In this two part series, we will describe the progress toward establishing functional transdifferentiated adrenal cortical cells. In this article (Part 1), we describe adrenal development and function, and discuss genes involved in these processess and selected for use in our pilot studies of transdifferentiation that are presented in the second article (Part 2).

Moving toward personalized cell-based interventions for adrenal cortical disorders: part 2--Human diseases and tissue engineering.

Transdifferentiation of an individual's own cells into functional differentiated cells to replace an organ's lost function would be a personalized approach to therapeutics. In this two part series, we will describe the progress toward establishing functional transdifferentiated adrenal cortical cells. In this article (Part 2), we describe the disorders of the adrenal cortex, therefore establishing why there is the need for personalized cell-based therapy for individuals with these disorders. We then present our pilot studies of cell transdifferentiation toward an adrenal cortical fate using genes described in the first article of this pair (Part 1).

Down syndrome: issues to consider in a national registry, research database and biobank.

As the quality of life for individuals with Down syndrome continues to improve due to anticipatory healthcare, early intervention, mainstreaming in schools, and increased expectations, the lack of basic information regarding individuals with Down syndrome is being recognized, and the need to facilitate research through a national registry, research database and biobank is being discussed. We believe that there should not be ownership of the samples and information, but instead prefer stewardship of the samples and information to benefit the participants who provided them. We endorse a model with data and sample managers and a research review board to interface between the investigators and participants. Information and samples would be coded, and only a few data managers would know the relationship between the codes and identifying information. Research results once published should be included in an online newsletter. If appropriate, individual results should be shared with participants. A Down syndrome registry, research database and biobank should be accountable to participants, families, medical care providers, government, and funding sources.

Personalized medicine for individuals with Down syndrome.

As the cost of whole genome analysis decreases, we have the opportunity to explore the interactions of various gene changes in an individual that lead to their particular phenotype. This will provide the ability to move from the epidemiologic study of groups, in which, the individuals are treated collectively and homogenously, to personalized medicine, and a model in which the individual is recognized and treated as a distinct entity. We will be applying personalized medicine to individuals with Down syndrome in order to understand and develop biomarkers for increased risk of co-morbidities. Personalized medicine will change the "culture of intractability" of Down syndrome.

Glycerol homeostasis and metabolism in glycerol kinase carrier mice.

To examine glycerol homeostasis and metabolism is essential for understanding of pathogenesis and evaluation of treatment efficacy in disorders of glycerol metabolism. In this study, we designed the intraperitoneal glycerol tolerance test (IPGlyTT) and studied glycerol tolerance in vivo using glycerol kinase (Gyk) carrier (C) and wild type (WT) mice. Serum glycerol concentrations in WT almost normalized at 90 min after injection, whereas Gyk C mice retained high serum glycerol concentrations at least until 180 min after injection. These results showed that glycerol tolerance was impaired in Gyk C mice compared to WT mice. The IPGlyTT is useful in accessing glycerol homeostasis and metabolism in animal models such as Gyk C mice and will be valuable in assessing therapeutic interventions in Gyk KO mice.

Down syndrome: national conference on patient registries, research databases, and biobanks.

A December 2010 meeting, "Down Syndrome: National Conference on Patient Registries, Research Databases, and Biobanks," was jointly sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) in Bethesda, MD, and the Global Down Syndrome Foundation (GDSF)/Linda Crnic Institute for Down Syndrome based in Denver, CO. Approximately 70 attendees and organizers from various advocacy groups, federal agencies (Centers for Disease Control and Prevention, and various NIH Institutes, Centers, and Offices), members of industry, clinicians, and researchers from various academic institutions were greeted by Drs. Yvonne Maddox, Deputy Director of NICHD, and Edward McCabe, Executive Director of the Linda Crnic Institute for Down Syndrome. They charged the participants to focus on the separate issues of contact registries, research databases, and biobanks through both podium presentations and breakout session discussions. Among the breakout groups for each of the major sessions, participants were asked to generate responses to questions posed by the organizers concerning these three research resources as they related to Down syndrome and then to report back to the group at large with a summary of their discussions. This report represents a synthesis of the discussions and suggested approaches formulated by the group as a whole.

Knowledge and attitudes towards contraceptives among adolescents and young adults.

BACKGROUND: Despite endorsements supporting the use of intrauterine devices (IUDs) for adolescents and young adult women (AYA), they have limited knowledge about them Male partners can influence contraceptive decisions, however their perceived knowledge about IUDs is lower than their objective knowledge. We aim to establish current AYA baseline contraceptive knowledge and attitudes so providers can better target their sexual health educational interventions. METHODS: Females and males, aged 13 to 23 years old, from our suburban adolescent clinic, completed an anonymous survey that assessed their knowledge and attitudes towards methods of contraception, with an emphasis on the IUD. RESULTS: Completed surveys totaled 130 (99 females/31 males). Demographic results revealed 31.3% Black/African-American, 30.5% Latino/Hispanic, 17.6% White, 3.0% Asian, and 14.5% Other. The majority of participants (80%) were sexually active. The majority (69.5%) stated they/their partner were currently using a contraceptive method; only 2.6% used IUDs. Half of females (56.6%) and 10.1% of males had heard of IUDs. Despite this, male and female participants lacked knowledge regarding specific IUD facts. Of the participants who had used emergency contraception (EC), only 6.4% knew the copper IUD could be used for EC. CONCLUSION: Contraceptive knowledge deficits, especially regarding the IUD, continue to exist for AYA patients. Many participants stated they required EC despite "satisfaction" with their birth control method(s) and most were unaware that the copper IUD could be used as EC. These discrepancies highlight the importance of comprehensive contraceptive education for AYA patients. Enhanced and consistent contraceptive options counseling can help providers ensure that their AYA patients make well-informed decisions about family planning, thus improving their quality of life.

Explaining the Black-White Disparity in Preterm Birth: A Consensus Statement From a Multi-Disciplinary Scientific Work Group Convened by the March of Dimes.

In 2017-2019, the March of Dimes convened a workgroup with biomedical, clinical, and epidemiologic expertise to review knowledge of the causes of the persistent Black-White disparity in preterm birth (PTB). Multiple databases were searched to identify hypothesized causes examined in peer-reviewed literature, 33 hypothesized causes were reviewed for whether they plausibly affect PTB and either occur more/less frequently and/or have a larger/smaller effect size among Black women vs. White women. While definitive proof is lacking for most potential causes, most are biologically plausible. No single downstream or midstream factor explains the disparity or its social patterning, however, many likely play limited roles, e.g., while genetic factors likely contribute to PTB, they explain at most a small fraction of the disparity. Research links most hypothesized midstream causes, including socioeconomic factors and stress, with the disparity through their influence on the hypothesized downstream factors. Socioeconomic factors alone cannot explain the disparity's social patterning. Chronic stress could affect PTB through neuroendocrine and immune mechanisms leading to inflammation and immune dysfunction, stress could alter a woman's microbiota, immune response to infection, chronic disease risks, and behaviors, and trigger epigenetic changes influencing PTB risk. As an upstream factor, racism in multiple forms has repeatedly been linked with the plausible midstream/downstream factors, including socioeconomic disadvantage, stress, and toxic exposures. Racism is the only factor identified that directly or indirectly could explain the racial disparities in the plausible midstream/downstream causes and the observed social patterning. Historical and contemporary systemic racism can explain the racial disparities in socioeconomic opportunities that differentially expose African Americans to lifelong financial stress and associated health-harming conditions. Segregation places Black women in stressful surroundings and exposes them to environmental hazards. Race-based discriminatory treatment is a pervasive stressor for Black women of all socioeconomic levels, considering both incidents and the constant vigilance needed to prepare oneself for potential incidents. Racism is a highly plausible, major upstream contributor to the Black-White disparity in PTB through multiple pathways and biological mechanisms. While much is unknown, existing knowledge and core values (equity, justice) support addressing racism in efforts to eliminate the racial disparity in PTB.

Inborn Errors of Metabolism: the metabolome is our world. Presidential address for the 11th International Congress of Inborn Errors of Metabolism (ICIEM).

Thank you for honoring me by allowing me to serve as president of the 11th International Congress of Inborn Errors of Metabolism (ICIEM). The science brought by the IEM community to the Congress was quite impressive and demonstrated the quality of research within this community. In this address, I will consider briefly the history of IEMs to determine how we have arrived where we are, and will spend more time ascertaining our place in the current biomedical community and our role in determining the future of personalized medicine. In the 1950s-1970s new tools were added to expand our ability to interrogate the metabolome and the result was an explosive increase in the number of IEMs. This set the stage for expanded newborn screening (NBS) by tandem mass spectrometry (MS/MS) to identify these patients and to intervene pre-symptomatically. The complexity of the metabolome has led us to utilize the mathematical algorithms of systems biology to reduce high dimensionality data to low dimensionality output. However, the metabolome does not exist in isolation and we must learn how to integrate the metabolome with other xomics. The metabolome is our world and the IEM community has much to share with the broader xomics communities by integrating what we have learned with the other xomics communities. They are seeking access to the metabolome as a closer measure of phenotype, and we are already extremely comfortable and competent in the metabolomic space. But we should not be insular in our occupation of this space. NBS should be the model for personalized medicine, because it is already functioning as testing system for predictive, preventive and personalized care. We have been working in the area of NBS for nearly a half century and have many lessons learned that will be valuable to the practitioners of personalized medicine - lessons that they should not have to rediscover. We must embrace the international IEM community to meet population trends and to improve the care for individuals - children and adults - with IEMs. Demographic projections indicate the countries with largest population growth during the next four decades will be in Asia and we need to work collaboratively to build capacity in the IEM community in Asia and beyond to other underserved regions of the world.

The effects of hyperglycemia on adrenal cortex function and steroidogenesis in the zebrafish.

Since the 1950s, scientists have attempted to characterize the relationship between diabetes mellitus (DM) and the hypothalamic-pituitary-adrenal (HPA) axis. Similar complications are seen in patients with diabetes and Cushing's syndrome, leading some to suggest that an underlying abnormality in the HPA axis may be responsible among those with DM. By inducing hyperglycemia in a zebrafish animal model, we show a direct correlation between glucose and cortisol levels.

ff1b, the SF1 ortholog, is important for pancreatic islet cell development in zebrafish.

The adrenal cortex and pancreatic islets have endocrine functions, producing steroid-based hormones and insulin, respectively. Cells of the adrenal cortex originate in the mesoderm while the cells of pancreatic islets originate in the endoderm. The zebrafish is a powerful model for understanding organ development due to its ease of genetic and molecular manipulation, transparent embryos, and large number of progeny for statistically powerful experiments. Like humans, the zebrafish pancreas has both exocrine and endocrine functions; unlike humans, there is only one endocrine islet cell group, instead of multiple islets. Using an eGFP-transgenic line of zebrafish, we have observed that the steroidogenic factor 1 (SF1) ortholog, ff1b, which is critical for adrenal cortex development and function in the zebrafish, is also implicated in zebrafish pancreatic islet development. We show that interruption of ff1b expression using an ff1b-morpholino (MO) disrupts development of insulin expressing cells. We conclude that ff1b-MO alters pancreatic islet development in zebrafish, demonstrating the utility of the zebrafish as a model for studying pancreatic development. This work is consistent with previous studies in mouse and human that have suggested SF1 participates in the vascular and ductal development of the pancreas, and disruption of SF1 function leads to abnormal development of the pancreatic islets due to poor vascularization.

Pathway analysis software: annotation errors and solutions.

Genetic databases contain a variety of annotation errors that often go unnoticed due to the large size of modern genetic data sets. Interpretation of these data sets requires bioinformatics tools that may contribute to this problem. While providing gene symbol annotations for identifiers (IDs) such as microarray probe set, RefSeq, GenBank, and Entrez Gene is seemingly trivial, the accuracy is fundamental to any subsequent conclusions. We examine gene symbol annotations and results from three commercial pathway analysis software (PAS) packages: Ingenuity Pathways Analysis, GeneGO, and Pathway Studio. We compare gene symbol annotations and canonical pathway results over time and among different input ID types. We find that PAS results can be affected by variation in gene symbol annotations across software releases and the input ID type analyzed. As a result, we offer suggestions for using commercial PAS and reporting microarray results to improve research quality. We propose a wiki type website to facilitate communication of bioinformatics software problems within the scientific community.