Finding utility for genetic diagnostics in the developing world

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 61-64).Genetic testing companies have come under fire lately for an array of reasons. Many direct-to-consumer outfits are being challenged by the federal regulatory authorities, by the physicians' community and by the public itself. The desire to derive utility from the existing mass of genetic research is only outpaced by the sheer amount of new information being added to our understanding daily. These genetic testing companies are simultaneously trying to apply the existing knowledge, build a base for further study and be credible, going concerns from a business perspective. It is a worthy but difficult objective. The direct-to-consumer genetic initiatives face resistance from physicians who are the traditional intermediaries between medical insight and application of this insight. The companies also face a strong adversary in a government that wants to protect its constituents from fraudulent marketing claims and misinformation. Recent, informal studies have also exposed flaws in the product offerings and delivery of information by these companies. Finally, these are all for-profit entities which are struggling to become profitable. The objective of this thesis is to identify an attractive consumer base and opportunity that would allow for successful deployment of genetic diagnostic capability. I postulate that the success of a direct-to-consumer company would depend on finding a customer that values the genetic insight deeply and is able to take action from such insight. Based on those two fundamental criteria-perceived value and actionable utility-I build a profile of place, person and disease to test my hypothesis. Driven by the findings of my research, I anchored my hypothesis around an Indian consumer who pays for health care out-of-pocket, is vulnerable to certain genetic diseases due to narrow, endogamous customs and has grown up in a culture of arranged marriages. If this individual's religious and moral code forbids early termination of pregnancy or if financial and logistical circumstances make abortion impossible, I posit the desire for this cohort to use pre-marital genetic testing will increase. My research showed that people born in India and people who had considered arranged marriage as a viable option (the two groups overlapped but not completely) did display a greater likelihood of using genetic tests at the pre-marital and pre-natal stage to make informed decisions about family planning. These groups also showed a greater inclination towards early termination of pregnancy as well as reconsidering partner choice based on the outcome of genetic testing. However, the data also showed that those groups that did not believe in abortion still did not preferentially want a pre-marital genetic test.by Ridhi Tariyal.S.M

Menstruation: science and society

© 2020 The Authors Women's health concerns are generally underrepresented in basic and translational research, but reproductive health in particular has been hampered by a lack of understanding of basic uterine and menstrual physiology. Menstrual health is an integral part of overall health because between menarche and menopause, most women menstruate. Yet for tens of millions of women around the world, menstruation regularly and often catastrophically disrupts their physical, mental, and social well-being. Enhancing our understanding of the underlying phenomena involved in menstruation, abnormal uterine bleeding, and other menstruation-related disorders will move us closer to the goal of personalized care. Furthermore, a deeper mechanistic understanding of menstruation—a fast, scarless healing process in healthy individuals—will likely yield insights into a myriad of other diseases involving regulation of vascular function locally and systemically. We also recognize that many women now delay pregnancy and that there is an increasing desire for fertility and uterine preservation. In September 2018, the Gynecologic Health and Disease Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a 2-day meeting, “Menstruation: Science and Society” with an aim to “identify gaps and opportunities in menstruation science and to raise awareness of the need for more research in this field.” Experts in fields ranging from the evolutionary role of menstruation to basic endometrial biology (including omic analysis of the endometrium, stem cells and tissue engineering of the endometrium, endometrial microbiome, and abnormal uterine bleeding and fibroids) and translational medicine (imaging and sampling modalities, patient-focused analysis of menstrual disorders including abnormal uterine bleeding, smart technologies or applications and mobile health platforms) to societal challenges in health literacy and dissemination frameworks across different economic and cultural landscapes shared current state-of-the-art and future vision, incorporating the patient voice at the launch of the meeting. Here, we provide an enhanced meeting report with extensive up-to-date (as of submission) context, capturing the spectrum from how the basic processes of menstruation commence in response to progesterone withdrawal, through the role of tissue-resident and circulating stem and progenitor cells in monthly regeneration—and current gaps in knowledge on how dysregulation leads to abnormal uterine bleeding and other menstruation-related disorders such as adenomyosis, endometriosis, and fibroids—to the clinical challenges in diagnostics, treatment, and patient and societal education. We conclude with an overview of how the global agenda concerning menstruation, and specifically menstrual health and hygiene, are gaining momentum, ranging from increasing investment in addressing menstruation-related barriers facing girls in schools in low- to middle-income countries to the more recent “menstrual equity” and “period poverty” movements spreading across high-income countries

Lassa Fever in Post-Conflict Sierra Leone

Background: Lassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease. Methodology/Principal Findings Clinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects. Conclusions/Significance: Lassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to develop more effective and/or supplemental treatments for LF

Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis

A global reference for human genetic variation

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.Wellcome Trust (London, England) (Core Award 090532/Z/09/Z)Wellcome Trust (London, England) (Senior Investigator Award 095552/Z/11/Z )Wellcome Trust (London, England) (WT095908)Wellcome Trust (London, England) (WT109497)Wellcome Trust (London, England) (WT098051)Wellcome Trust (London, England) (WT086084/Z/08/Z)Wellcome Trust (London, England) (WT100956/Z/13/Z )Wellcome Trust (London, England) (WT097307)Wellcome Trust (London, England) (WT0855322/Z/08/Z )Wellcome Trust (London, England) (WT090770/Z/09/Z )Wellcome Trust (London, England) (Major Overseas program in Vietnam grant 089276/Z.09/Z)Medical Research Council (Great Britain) (grant G0801823)Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I02593X/1)Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I021213/1)Zhongguo ke xue ji shu qing bao yan jiu suo. Office of 863 Programme of China (2012AA02A201)National Basic Research Program of China (2011CB809201)National Basic Research Program of China (2011CB809202)National Basic Research Program of China (2011CB809203)National Natural Science Foundation of China (31161130357)Shenzhen Municipal Government of China (grant ZYC201105170397A)Canadian Institutes of Health Research (grant 136855)Quebec Ministry of Economic Development, Innovation, and Exports (PSR-SIIRI-195)Germany. Bundesministerium für Bildung und Forschung (0315428A)Germany. Bundesministerium für Bildung und Forschung (01GS08201)Germany. Bundesministerium für Bildung und Forschung (BMBF-EPITREAT grant 0316190A)Deutsche Forschungsgemeinschaft (Emmy Noether Grant KO4037/1-1)Beatriu de Pinos Program (2006 BP-A 10144)Beatriu de Pinos Program (2009 BP-B 00274)Spanish National Institute for Health (grant PRB2 IPT13/0001-ISCIII-SGEFI/FEDER)Japan Society for the Promotion of Science (fellowship number PE13075)Marie Curie Actions Career Integration (grant 303772)Fonds National Suisse del la Recherche, SNSF, Scientifique (31003A_130342)National Center for Biotechnology Information (U.S.) (U54HG3067)National Center for Biotechnology Information (U.S.) (U54HG3273)National Center for Biotechnology Information (U.S.) (U01HG5211)National Center for Biotechnology Information (U.S.) (U54HG3079)National Center for Biotechnology Information (U.S.) (R01HG2898)National Center for Biotechnology Information (U.S.) (R01HG2385)National Center for Biotechnology Information (U.S.) (RC2HG5552)National Center for Biotechnology Information (U.S.) (U01HG6513)National Center for Biotechnology Information (U.S.) (U01HG5214)National Center for Biotechnology Information (U.S.) (U01HG5715)National Center for Biotechnology Information (U.S.) (U01HG5718)National Center for Biotechnology Information (U.S.) (U01HG5728)National Center for Biotechnology Information (U.S.) (U41HG7635)National Center for Biotechnology Information (U.S.) (U41HG7497)National Center for Biotechnology Information (U.S.) (R01HG4960)National Center for Biotechnology Information (U.S.) (R01HG5701)National Center for Biotechnology Information (U.S.) (R01HG5214)National Center for Biotechnology Information (U.S.) (R01HG6855)National Center for Biotechnology Information (U.S.) (R01HG7068)National Center for Biotechnology Information (U.S.) (R01HG7644)National Center for Biotechnology Information (U.S.) (DP2OD6514)National Center for Biotechnology Information (U.S.) (DP5OD9154)National Center for Biotechnology Information (U.S.) (R01CA166661)National Center for Biotechnology Information (U.S.) (R01CA172652)National Center for Biotechnology Information (U.S.) (P01GM99568)National Center for Biotechnology Information (U.S.) (R01GM59290)National Center for Biotechnology Information (U.S.) (R01GM104390)National Center for Biotechnology Information (U.S.) (T32GM7790)National Center for Biotechnology Information (U.S.) (P01GM99568)National Center for Biotechnology Information (U.S.) (R01HL87699)National Center for Biotechnology Information (U.S.) (R01HL104608)National Center for Biotechnology Information (U.S.) (T32HL94284)National Center for Biotechnology Information (U.S.) (HHSN268201100040C)National Center for Biotechnology Information (U.S.) (HHSN272201000025C)Lundbeck Foundation (grant R170-2014-1039Simons Foundation (SFARI award SF51)National Science Foundation (U.S.) (Research Fellowship DGE-1147470

Discovery of Novel Rhabdoviruses in the Blood of Healthy Individuals from West Africa

Next-generation sequencing (NGS) has the potential to transform the discovery of viruses causing unexplained acute febrile illness (UAFI) because it does not depend on culturing the pathogen or a priori knowledge of the pathogen’s nucleic acid sequence. More generally, it has the potential to elucidate the complete human virome, including viruses that cause no overt symptoms of disease, but may have unrecognized immunological or developmental consequences. We have used NGS to identify RNA viruses in the blood of 195 patients with UAFI and compared them with those found in 328 apparently healthy (i.e., no overt signs of illness) control individuals, all from communities in southeastern Nigeria. Among UAFI patients, we identified the presence of nucleic acids from several well-characterized pathogenic viruses, such as HIV-1, hepatitis, and Lassa virus. In our cohort of healthy individuals, however, we detected the nucleic acids of two novel rhabdoviruses. These viruses, which we call Ekpoma virus-1 (EKV-1) and Ekpoma virus-2 (EKV-2), are highly divergent, with little identity to each other or other known viruses. The most closely related rhabdoviruses are members of the genus Tibrovirus and Bas-Congo virus (BASV), which was recently identified in an individual with symptoms resembling hemorrhagic fever. Furthermore, by conducting a serosurvey of our study cohort, we find evidence for remarkably high exposure rates to the identified rhabdoviruses. The recent discoveries of novel rhabdoviruses by multiple research groups suggest that human infection with rhabdoviruses might be common. While the prevalence and clinical significance of these viruses are currently unknown, these viruses could have previously unrecognized impacts on human health; further research to understand the immunological and developmental impact of these viruses should be explored. More generally, the identification of similar novel viruses in individuals with and without overt symptoms of disease highlights the need for a broader understanding of the human virome as efforts for viral detection and discovery advance

Sequencing results and schematic representation of the EKV-1 and -2 genome organization.

<p>(<b>A</b>) Overview of the data generated for each novel rhabdovirus. (<b>B</b>) A schematic showing the assembled genomes, consisting of the following genes: <i>nucleoprotein</i> (N), <i>phosphoprotein</i> (P), <i>matrix</i> (M), <i>U1</i>/<i>U2</i>/<i>U3</i> (uncharacterized accessory proteins), <i>glycoprotein</i> (G), and <i>polymerase</i> (L). We indicate in orange (EKV-1) and blue (EKV-2) segments of the viral genomes that could not be assembled from Illumina reads and instead Sanger sequenced. (<b>C</b>) Coverage plots of the final viral genomes.</p

Sero-positivity to EKV-1 and EKV-2.

<p>A serosurvey for EKV-1 and EKV-2 was performed on Nigerian samples (n = 320). Cut-off values were based on the mean of US normals (n = 137) plus either 3xSD or 5xSD (SD = standard deviation).</p><p>Sero-positivity to EKV-1 and EKV-2.</p

Examples of rhabdoviruses reported in Africa.

<p>A map depicting examples of rhabdoviruses isolated in sub-Saharan Africa. This map does not depict the current distribution of rhabdoviruses in Sub-Saharan Africa, nor is it meant as a comprehensive listing of all rhabdoviruses isolated in Africa; rather its purpose is to illustrate that many rhabdoviruses have been discovered throughout Africa over the past half-century. Country refers to the sample’s country of origin. Abbreviations: CAR, Central African Republic; DRC, Democratic Republic of Congo.</p