Next-generation DNA sequencing (NGS) projects, such as the 1000 Genomes Project, are already revolutionizing our understanding of genetic variation among individuals. However, the massive data sets generated by NGS—the 1000 Genome pilot alone includes nearly five terabases—make writing feature-rich, efficient, and robust analysis tools difficult for even computationally sophisticated individuals. Indeed, many professionals are limited in the scope and the ease with which they can answer scientific questions by the complexity of accessing and manipulating the data produced by these machines. Here, we discuss our Genome Analysis Toolkit (GATK), a structured programming framework designed to ease the development of efficient and robust analysis tools for next-generation DNA sequencers using the functional programming philosophy of MapReduce. The GATK provides a small but rich set of data access patterns that encompass the majority of analysis tool needs. Separating specific analysis calculations from common data management infrastructure enables us to optimize the GATK framework for correctness, stability, and CPU and memory efficiency and to enable distributed and shared memory parallelization. We highlight the capabilities of the GATK by describing the implementation and application of robust, scale-tolerant tools like coverage calculators and single nucleotide polymorphism (SNP) calling. We conclude that the GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.

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The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data

Summary: Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.

Availability: http://www.broad.mit.edu/mpg/haploview/

Contact: jcbarret@broad.mit.edu

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Haploview: analysis and visualization of LD and haplotype maps

Motivation: DnaSP is a software package for a comprehensive analysis of DNA polymorphism data. Version 5 implements a number of new features and analytical methods allowing extensive DNA polymorphism analyses on large datasets. Among other features, the newly implemented methods allow for: (i) analyses on multiple data files; (ii) haplotype phasing; (iii) analyses on insertion/deletion polymorphism data; (iv) visualizing sliding window results integrated with available genome annotations in the UCSC browser.

Availability: Freely available to academic users from: http://www.ub.edu/dnasp

Contact: [email protected]

DnaSP v5

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

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Analysis of protein-coding genetic variation in 60,706 humans

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.

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An integrated map of genetic variation from 1,092 human genomes

The Science and Business of Ancestry Testing

Biomedical research is increasingly data intensive and computational, and "big data science" is migrating into the clinical arena. Unfortunately, ethicists, regulators, and policy-makers have barely begun to explore the ethical, legal, and social issues raised by the variety of analytical and computational approaches in use and under development in biology and medicine. Most scholarship concerning big data bioscience has focused on privacy, a vitally important consideration but not the only one. Among the issues raised by new computational technologies are questions about safety and safety assessment, justice, and how to obtain proper informed consent. These technologies also raise a myriad of regulatory issues that could influence the probability of translating new assays or computational tools to the clinical or public health spheres.

The Ethics of Translating High-Throughput Science into Clinical Practice

Despite concerns about negative neurocognitive effects of in utero substance exposure on child and brain development, research in this area is limited. This study gathered perspectives of persons with lived experience of substance use (eg, alcohol, prescription and illicit opioids, and other illicit substances) during a previous pregnancy to determine facilitators and barriers to research engagement in this vulnerable population. We conducted structured, in-depth, individual interviews and 2 focus groups of adult persons with lived experience of substance use during a previous pregnancy. Questions were developed by clinical, research, bioethics, and legal experts, with input from diverse stakeholders. They inquired about facilitators and barriers to research recruitment and retention, especially in long-term studies, with attention to bio-sample and neuroimaging data collection and legal issues. Interviews and focus groups were audio-recorded, transcribed, and analyzed using inductive coding qualitative analysis methods. Ten participants completed in-depth interviews and 7 participated in focus groups. Three main themes emerged as potential barriers to research engagement: shame of using drugs while pregnant, fear of punitive action, and mistrust of health care and research professionals. Facilitative factors included trustworthiness, compassion, and a nonjudgmental attitude among research personnel. Inclusion of gender-concordant recovery peer support specialists as research team members was the most frequently identified facilitator important for helping participants reduce fears and bolster trust in research personnel. In this qualitative study, persons with lived experience of substance use during a previous pregnancy identified factors critical for engaging this population in research, emphasizing the involvement of peer support specialists as research team members.

Voices of Women With Lived Experience of Substance Use During Pregnancy

ISSN: 1526-5161 (Print) 1536-0075 (Online) Journal homepage: http://www.tandfonline.com/loi/uajb20 Fairness in Manufacturing Cellular Therapies Amritava Das, Krishanu Saha & Pilar N. Ossorio To cite this article: Amritava Das, Krishanu Saha & Pilar N. Ossorio (2018) Fairness in Manufacturing Cellular Therapies, The American Journal of Bioethics, 18:4, 68-70, DOI: 10.1080/15265161.2018.1445792 To link to this article: https://doi.org/10.1080/15265161.2018.1445792

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Fairness in Manufacturing Cellular Therapies

David Resnik and Kenneth De Ville (2002) propose ave criteria that should be met before the government would be justiaed in manufacturing or distributing a patented drug without the patent holder’s express authorization. The authors describe this use as an exercise of the government’s eminent-domain powers and a taking of private property. I argue that such use is not a taking. Applying takings doctrine to intellectual property may inappropriately essentialize the concept of property and obscure important analytical approaches to patent-policy problems. Scholars generally agree that property consists of a “bundle of rights,” and that different properties and different types of property are composed of different bundles. Patents and real property consist of nonidentical but slightly overlapping bundles. We generally understand real and personal property as involving rights to use, possess, exclude, and alienate (transfer by gift or sale). These are rights against private parties and the state. Recognition of these rights is a background assumption, developed through the complex interplay of law and custom. The precise contours of these rights vary greatly, depending on the particular property and the social context. Against this background, depriving an owner of the use or possession of her land, without her authorization or without strong justiacation, is viewed as a legal and moral wrong. Thus, under the Fifth Amendment to the U.S. Constitution it is unconstitutional for the government to take private property for public use without “just compensation.” Eminent domain and takings are real-property doctrines. The government may take title or some lesser rights (e.g., easements) in privately held land by exercising its powers of eminent domain (40 U.S.C.A. secs. 257, 258a). Private landowners must be appropriately compensated when they are deprived of possessory or use rights through eminent domain. The government may also effect a taking by regulation. Regulation that “goes too far” in diminishing or eliminating an owner’s economically beneacial uses of her land will be considered an unconstitutional taking of property, unless the landowner is adequately compensated (Palazzolo v. Rhode Island, 533 U.S. 606 [2001]). Since the 1920s the U.S. Supreme Court has struggled to articulate a standard by which to determine when regulations have gone too far. The Court recognizes that government would cease to function if every decrease in land value incident to regulation necessitated compensation. On the other hand, a compensation requirement prevents the government from “forcing some people alone to bear the burdens which, in all fairness and justice, should be borne by the public as a whole” (Palozzolo, 618). The Court has held that the private landowner’s reasonable, investment-backed expectations should play a role in determining the degree to which State regulation can modify her property rights without compensation (Palazzolo, 626–27). Of course, this formulation may be viewed as a mere moving of the goal posts; because now one must ask which of the landowner’s expectations are reasonable and why. If regulations deprive an owner of all economic beneat from her land, they may be sustained without compensation only if the use interests proscribed were never part of the owner’s title to begin with (Lucas v. South Carolina Coastal Council, 505 U.S. 1003 [1992], 1027). Unlike real and personal property, patent rights are deaned by federal statute (35 U.S.C. sec. 154). Patents do not include positive rights to use or possess the patented invention (Ossorio 2002). A patentee is granted the right to exclude others from making, using, selling, offering for sale, or importing the invention for a limited term of years. However, as noted by Resnik and De Ville, patents do not include the right to exclude the federal govern-

Pilar N. Ossorio

Papers

The Science and Business of Ancestry Testing

The Ethics of Translating High-Throughput Science into Clinical Practice

Voices of Women With Lived Experience of Substance Use During Pregnancy

Fairness in Manufacturing Cellular Therapies

Not Taking, Just Borrowing: Government Use of Patented Drugs