High-Definition Medicine Torkamani, Ali; Andersen, Kristian G.; Steinhubl, Steven R. ...
Cell,
08/2017, Volume:
170, Issue:
5
Journal Article
Peer reviewed
Open access
The foundation for a new era of data-driven medicine has been set by recent technological advances that enable the assessment and management of human health at an unprecedented level of ...resolution—what we refer to as high-definition medicine. Our ability to assess human health in high definition is enabled, in part, by advances in DNA sequencing, physiological and environmental monitoring, advanced imaging, and behavioral tracking. Our ability to understand and act upon these observations at equally high precision is driven by advances in genome editing, cellular reprogramming, tissue engineering, and information technologies, especially artificial intelligence. In this review, we will examine the core disciplines that enable high-definition medicine and project how these technologies will alter the future of medicine.
The foundation for a new era of data-driven medicine has been set by recent technological advances that enable the assessment and management of human health at an unprecedented level of resolution—what is referred to as high-definition medicine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although studies have identified hundreds of loci associated with human traits and diseases, pinpointing causal alleles remains difficult, particularly for non-coding variants. To address this ...challenge, we adapted the massively parallel reporter assay (MPRA) to identify variants that directly modulate gene expression. We applied it to 32,373 variants from 3,642 cis-expression quantitative trait loci and control regions. Detection by MPRA was strongly correlated with measures of regulatory function. We demonstrate MPRA’s capabilities for pinpointing causal alleles, using it to identify 842 variants showing differential expression between alleles, including 53 well-annotated variants associated with diseases and traits. We investigated one in detail, a risk allele for ankylosing spondylitis, and provide direct evidence of a non-coding variant that alters expression of the prostaglandin EP4 receptor. These results create a resource of concrete leads and illustrate the promise of this approach for comprehensively interrogating how non-coding polymorphism shapes human biology.
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•A new version of MPRA with greater throughput and sensitivity•Evaluation of 32,373 variants associated with eQTLs in lymphoblastoid cell lines•842 variants showed differential gene expression between alleles•Use of CRISPR/cas9 to identify a distal eQTL causal allele for PTGER4
A massively parallel reporter assay analyzes thousands of human polymorphisms to identify alleles that impact gene expression, providing a tool with which to move from disease-associated GWAS hits to the identification of functional variants.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The neurotransmitter transporters (NTTs) belonging to the solute carrier 6 (SLC6) gene family (also referred to as the neurotransmitter-sodium-symporter family or Na(+)/Cl(-)-dependent transporters) ...comprise a group of nine sodium- and chloride-dependent plasma membrane transporters for the monoamine neurotransmitters serotonin (5-hydroxytryptamine), dopamine, and norepinephrine, and the amino acid neurotransmitters GABA and glycine. The SLC6 NTTs are widely expressed in the mammalian brain and play an essential role in regulating neurotransmitter signaling and homeostasis by mediating uptake of released neurotransmitters from the extracellular space into neurons and glial cells. The transporters are targets for a wide range of therapeutic drugs used in treatment of psychiatric diseases, including major depression, anxiety disorders, attention deficit hyperactivity disorder and epilepsy. Furthermore, psychostimulants such as cocaine and amphetamines have the SLC6 NTTs as primary targets. Beginning with the determination of a high-resolution structure of a prokaryotic homolog of the mammalian SLC6 transporters in 2005, the understanding of the molecular structure, function, and pharmacology of these proteins has advanced rapidly. Furthermore, intensive efforts have been directed toward understanding the molecular and cellular mechanisms involved in regulation of the activity of this important class of transporters, leading to new methodological developments and important insights. This review provides an update of these advances and their implications for the current understanding of the SLC6 NTTs.
Spatiotemporal bias in genome sampling can severely confound discrete trait phylogeographic inference. This has impeded our ability to accurately track the spread of SARS-CoV-2, the virus responsible ...for the COVID-19 pandemic, despite the availability of unprecedented numbers of SARS-CoV-2 genomes. Here, we present an approach to integrate individual travel history data in Bayesian phylogeographic inference and apply it to the early spread of SARS-CoV-2. We demonstrate that including travel history data yields i) more realistic hypotheses of virus spread and ii) higher posterior predictive accuracy compared to including only sampling location. We further explore methods to ameliorate the impact of sampling bias by augmenting the phylogeographic analysis with lineages from undersampled locations. Our reconstructions reinforce specific transmission hypotheses suggested by the inclusion of travel history data, but also suggest alternative routes of virus migration that are plausible within the epidemiological context but are not apparent with current sampling efforts.
Genome sequencing has become a powerful tool for studying emerging infectious diseases; however, genome sequencing directly from clinical samples (i.e., without isolation and culture) remains ...challenging for viruses such as Zika, for which metagenomic sequencing methods may generate insufficient numbers of viral reads. Here we present a protocol for generating coding-sequence-complete genomes, comprising an online primer design tool, a novel multiplex PCR enrichment protocol, optimized library preparation methods for the portable MinION sequencer (Oxford Nanopore Technologies) and the Illumina range of instruments, and a bioinformatics pipeline for generating consensus sequences. The MinION protocol does not require an Internet connection for analysis, making it suitable for field applications with limited connectivity. Our method relies on multiplex PCR for targeted enrichment of viral genomes from samples containing as few as 50 genome copies per reaction. Viral consensus sequences can be achieved in 1-2 d by starting with clinical samples and following a simple laboratory workflow. This method has been successfully used by several groups studying Zika virus evolution and is facilitating an understanding of the spread of the virus in the Americas. The protocol can be used to sequence other viral genomes using the online Primal Scheme primer designer software. It is suitable for sequencing either RNA or DNA viruses in the field during outbreaks or as an inexpensive, convenient method for use in the lab.
A dichotomous choice for metazoan cells is between proliferation and differentiation. Measuring tRNA pools in various cell types, we found two distinct subsets, one that is induced in proliferating ...cells, and repressed otherwise, and another with the opposite signature. Correspondingly, we found that genes serving cell-autonomous functions and genes involved in multicellularity obey distinct codon usage. Proliferation-induced and differentiation-induced tRNAs often carry anticodons that correspond to the codons enriched among the cell-autonomous and the multicellularity genes, respectively. Because mRNAs of cell-autonomous genes are induced in proliferation and cancer in particular, the concomitant induction of their codon-enriched tRNAs suggests coordination between transcription and translation. Histone modifications indeed change similarly in the vicinity of cell-autonomous genes and their corresponding tRNAs, and in multicellularity genes and their tRNAs, suggesting the existence of transcriptional programs coordinating tRNA supply and demand. Hence, we describe the existence of two distinct translation programs that operate during proliferation and differentiation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We present constraints on the tensor-to-scalar ratio r using a combination of BICEP/Keck 2018 (BK18) and Planck PR4 data allowing us to fit for r consistently with the six parameters of the ΛCDM ...model. We discuss the sensitivity of constraints on r to uncertainties in the ΛCDM parameters as defined by the Planck data. In particular, we are able to derive a constraint on the reionization optical depth τ and thus propagate its uncertainty into the posterior distribution for r. While Planck sensitivity to r is slightly lower than the current ground-based measurements, the combination of Planck with BK18 and baryon-acoustic-oscillation data yields results consistent with r=0 and tightens the constraint to r<0.032 at 95% confidence.
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Although several hundred regions of the human genome harbor signals of positive natural selection, few of the relevant adaptive traits and variants have been elucidated. Using full-genome sequence ...variation from the 1000 Genomes (1000G) Project and the composite of multiple signals (CMS) test, we investigated 412 candidate signals and leveraged functional annotation, protein structure modeling, epigenetics, and association studies to identify and extensively annotate candidate causal variants. The resulting catalog provides a tractable list for experimental follow-up; it includes 35 high-scoring nonsynonymous variants, 59 variants associated with expression levels of a nearby coding gene or lincRNA, and numerous variants associated with susceptibility to infectious disease and other phenotypes. We experimentally characterized one candidate nonsynonymous variant in Toll-like receptor 5 (TLR5) and show that it leads to altered NF-κB signaling in response to bacterial flagellin.
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► Genome-wide scan in 1000 Genomes sequence data fine maps 412 signals of selection ► Adaptive candidates include 35 nonsynonymous and 59 loci with eQTLs ► L→F variant in TLR5 reduces NF-κB signaling in response to bacterial flagellin ► Catalog provides a tractable set of selected variants for experimental follow up
Analysis of human sequence data from the 1000 Genomes Project reveals hundreds of potential adaptive variants, providing a road map for understanding human biological history and modern-day variability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hydroxyethyl starch (HES) corrected is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.
In ...this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization.
Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval CI, 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.
Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.).
We present constraints on the tensor-to-scalar ratio
r
using
Planck
data. We use the latest release of
Planck
maps, processed with the
NPIPE
code, which produces calibrated frequency maps in ...temperature and polarisation for all
Planck
channels from 30 GHz to 857 GHz using the same pipeline. We computed constraints on
r
using the
BB
angular power spectrum, and we also discuss constraints coming from the
TT
spectrum. Given
Planck
’s noise level, the
TT
spectrum gives constraints on
r
that are cosmic-variance limited (with
σ
r
= 0.093), but we show that the marginalised posterior peaks towards negative values of
r
at about the 1.2
σ
level. We derived
Planck
constraints using the
BB
power spectrum at both large angular scales (the ‘reionisation bump’) and intermediate angular scales (the ‘recombination bump’) from
ℓ
= 2 to 150 and find a stronger constraint than that from
TT
, with
σ
r
= 0.069. The
Planck
BB
spectrum shows no systematic bias and is compatible with zero, given both the statistical noise and the systematic uncertainties. The likelihood analysis using
B
modes yields the constraint
r
< 0.158 at 95% confidence using more than 50% of the sky. This upper limit tightens to
r
< 0.069 when
Planck
EE
,
BB
, and
EB
power spectra are combined consistently, and it tightens further to
r
< 0.056 when the
Planck
TT
power spectrum is included in the combination. Finally, combining
Planck
with BICEP2/Keck 2015 data yields an upper limit of
r
< 0.044.
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