The UK Biobank provides a rich collection of longitudinal clinical data coming from different healthcare providers and sources in England, Wales, and Scotland. Although extremely valuable and ...available to a wide research community, the heterogeneous dataset contains inconsistent medical terminology that is either aligned to several ontologies within the same category or unprocessed. To make these data useful to a research community, data cleaning, curation, and standardization are needed. Significant efforts to perform data reformatting, mapping to any selected ontologies (such as SNOMED-CT) and harmonization are required from any data user to integrate UK Biobank hospital inpatient and self-reported data, data from various registers with primary care (GP) data. The integrated clinical data would provide a more comprehensive picture of one's medical history.
We evaluated several approaches to map GP clinical Read codes to International Classification of Diseases (ICD) and Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) terminologies. The results were compared, mapping inconsistencies were flagged, a quality category was assigned to each mapping to evaluate overall mapping quality.
We propose a curation and data integration pipeline for harmonizing diagnosis. We also report challenges identified in mapping Read codes from UK Biobank GP tables to ICD and SNOMED CT.
Some of the challenges-the lack of precise one-to-one mapping between ontologies or the need for additional ontology to fully map terms-are general reflecting trade-offs to be made at different steps. Other challenges are due to automatic mapping and can be overcome by leveraging existing mappings, supplemented with automated and manual curation.
Mucopolysaccharidosis (MPS) II is a rare, X-linked lysosomal storage disease. Approximately two-thirds of patients have central nervous system involvement with some demonstrating progressive ...cognitive impairment (neuronopathic disease). The natural history of cognitive and adaptive function in patients with MPS II is not well-defined. This 2-year, prospective, observational study evaluated the neurodevelopmental trajectories of boys with MPS II aged greater than or equal to 2 years and < 18 years. Overall, 55 patients were enrolled. At baseline, mean (standard deviation SD) age was 5.60 (3.32) years; all patients were receiving intravenous idursulfase. Cognitive and adaptive function were assessed using the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) scores, respectively. Baseline mean (SD) DAS-II GCA and VABS-II ABC scores were 78.4 (19.11) and 83.7 (14.22), respectively, indicating low cognitive function and moderately low adaptive behavior. Over 24 months, modest deteriorations in mean (SD) scores were observed for DAS-II GCA (-3.8 12.7) and VABS-II ABC (-2.0 8.07). Changes in DAS-II GCA scores varied considerably, and data suggested the existence of four potential patient subgroups: (1) patients with marked early impairment and rapid subsequent decline, (2) patients with marked early impairment then stabilization, (3) patients with mild early impairment then stabilization, and (4) patients without impairment who remained stable. Subgroup analyses revealed numerically greater DAS-II GCA score reductions from baseline in patients aged < 7 years at baseline (vs. those aged greater than or equal to 7 years) and in patients with DAS-II GCA scores less than or equal to 70 at baseline (vs. those with scores > 70); between-group differences were nonsignificant. No clear subgroups or patterns were identified for individual changes in VABS-II ABC scores. In total, 49 patients (89.1%) reported greater than or equal to 1 adverse event (AE) and nine patients (16.4%) reported serious AEs. Some patients with MPS II had rapid declines in cognitive ability, whereas others remained relatively stable after an initial decline. These insights provide a basis for more detailed analyses of different patient subgroups, which may enhance the definition and understanding of factors that influence cognitive and adaptive function in MPS II.
Cis-regulatory elements (CREs) play a pivotal role in gene expression regulation, allowing cells to serve diverse functions and respond to external stimuli. Understanding CREs is essential for ...personalized medicine and disease research, as an increasing number of genetic variants associated with phenotypes and diseases overlap with CREs. However, existing databases often focus on subsets of regulatory elements and present each identified instance of element individually, confounding the effort to obtain a comprehensive view. To address this gap, we have created CREdb, a comprehensive database with over 10 million human regulatory elements across 1,058 cell types and 315 tissues harmonized from different data sources. We curated and aligned the cell types and tissues to standard ontologies for efficient data query. Data from 11 sources were curated and mapped to standard ontological terms. 11,223,434 combined elements are present in the final database, and these were merged into 5,666,240 consensus elements representing the combined ranges of the individual elements informed by their overlap. Each consensus element contains curated metadata including the number of elements supporting it and a hash linking to the source databases. The inferred activity of each consensus element in various cell-type and tissue context is also provided. Examples presented here show the potential utility of CREdb in annotating non-coding genetic variants and informing chromatin accessibility profiling analysis. We developed CREdb, a comprehensive database of CREs, to simplify the analysis of CREs by providing a unified framework for researchers. CREdb compiles consensus ranges for each element by integrating the information from all instances identified across various source databases. This unified database facilitates the functional annotation of non-coding genetic variants and complements chromatin accessibility profiling analysis. CREdb will serve as an important resource in expanding our knowledge of the epigenome and its role in human diseases.
Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can ...be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug's known mechanism of action. Also, the models predict each drug's potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets.
Wearable digital devices offer potential advantages over traditional methods for the collection of health‐related information, including continuous collection of dense data while study subjects are ...ambulatory or in remote settings. We assessed the utility of collecting continuous actigraphy and cardiac monitoring by deploying two US Food and Drug Administration (FDA) 510(k)‐cleared devices in a phase I clinical trial of a novel compound, which included the use of an amphetamine challenge. The Phillips Actiwatch Spectrum Pro (Actiwatch) was used to assess mobility and sleep. The Preventice BodyGuardian (BodyGuardian) was used for monitoring heart rate (HR) and respiratory rate (RR), via single‐lead electrocardiogram (ECG) recordings, together with physical activity. We measured data collection rates, compared device readouts with conventional measures, and monitored changes in HR measures during the amphetamine challenge. Completeness of data collection was good for the Actiwatch (96%) and lower for the BodyGuardian (80%). A good correlation was observed between device and in‐clinic measures for HR (r = 0.99; P < 0.001), but was poor for RR (r = 0.39; P = 0.004). Manual reviews of selected ECG strips corresponding to HR measures below, within, and above the normal range were consistent with BodyGuardian measurements. The BodyGuardian device detected clear HR responses after amphetamine administration while subjects were physically active, whereas conventional measures collected at predefined timepoints while subjects were resting and supine did not. Wearable digital technology shows promise for monitoring human subjects for physiologic changes and pharmacologic responses, although fit‐for‐purpose evaluation and validation continues to be important prior to the wider deployment of these devices.
We assessed the performance of two US Food and Drug Administration (FDA) 510(k)‐cleared wearable digital devices and the operational feasibility of deploying them to augment data collection in a ...10‐day residential phase I clinical trial. The Phillips Actiwatch Spectrum Pro (Actiwatch) was used to assess mobility and sleep, and the Vitalconnect HealthPatch MD (HealthPatch) was used for monitoring heart rate (HR), respiratory rate (RR), and surface skin temperature (ST). We measured data collection rates, compared device readouts with anticipated readings and conventional in‐clinic measures, investigated data limitations, and assessed user acceptability. Six of nine study participants consented; completeness of data collection was adequate (> 90% for four of six subjects). A good correlation was observed between the HealthPatch device derived and in‐clinic measures for HR (Pearson r = 0.71; P = 2.2e‐16) but this was poor for RR (r = 0.08; P = 0.44) and ST (r = 0.14; P = 0.14). Manual review of electrocardiogram strips recorded during reported episodes of tachycardia > 180 beats/min showed that these were artefacts. The HealthPatch was judged to be not fit‐for‐purpose because of artefacts and the need for time‐consuming manual review. The Actiwatch device was suitable for monitoring mobility, collecting derived sleep data, and facilitating the interpretation of vital sign data. These results suggest the need for fit‐for‐purpose evaluation of wearable devices prior to their deployment in drug development studies.
Helicobacter pylori, one of the most common bacterial pathogens
of humans, colonizes the gastric mucosa, where it appears to persist throughout
the host's life unless the patient is treated. ...Colonization induces chronic
gastric inflammation which can progress to a variety of diseases, ranging
in severity from superficial gastritis and peptic ulcer to gastric cancer
and mucosal-associated lymphoma. Strain-specific genetic diversity
has been proposed to be involved in the organism's ability to cause different
diseases or even be beneficial to the infected host,
and to participate in the lifelong chronicity of infection.
Here we compare the complete genomic sequences of two unrelated H. pylori
isolates. This is, to our knowledge, the first such genomic comparison.
H. pylori was believed to exhibit a large degree of genomic and allelic
diversity, but we find that the overall genomic organization, gene order and
predicted proteomes (sets of proteins encoded by the genomes) of the two strains
are quite similar. Between 6 to 7% of the genes are specific to each strain,
with almost half of these genes being clustered in a single hypervariable
region.
Aberrant activation of signaling pathways drives many of the fundamental biological processes that accompany tumor initiation and progression. Inappropriate phosphorylation of intermediates in these ...signaling pathways are a frequently observed molecular lesion that accompanies the undesirable activation or repression of pro- and anti-oncogenic pathways. Therefore, methods which directly query signaling pathway activation via phosphorylation assays in individual cancer biopsies are expected to provide important insights into the molecular "logic" that distinguishes cancer and normal tissue on one hand, and enables personalized intervention strategies on the other.
We first document the largest available set of tyrosine phosphorylation sites that are, individually, differentially phosphorylated in lung cancer, thus providing an immediate set of drug targets. Next, we develop a novel computational methodology to identify pathways whose phosphorylation activity is strongly correlated with the lung cancer phenotype. Finally, we demonstrate the feasibility of classifying lung cancers based on multi-variate phosphorylation signatures.
Highly predictive and biologically transparent phosphorylation signatures of lung cancer provide evidence for the existence of a robust set of phosphorylation mechanisms (captured by the signatures) present in the majority of lung cancers, and that reliably distinguish each lung cancer from normal. This approach should improve our understanding of cancer and help guide its treatment, since the phosphorylation signatures highlight proteins and pathways whose phosphorylation should be inhibited in order to prevent unregulated proliferation.
We describe a simple, rapid technique for simultaneously isolating large numbers of cDNAs encoding secreted proteins. The technique makes use of a facile genetic selection performed in a strain of
...Saccharomyces cerevisiae deleted for its endogenous invertase gene. A cDNA cloning vector which carries a modified invertase gene lacking its leader sequence is used in conjunction with this strain. Heterologous secreted genes fused appropriately upstream of this defective invertase provide the necessary signals to restore secretion, allowing the yeast to grow on sugars such as sucrose or raffinose. This microbial growth selection facilitates scanning cDNA libraries containing millions of clones, enabling the wholesale identification of novel secreted proteins without the need for specific bioassays. The technique is similar to one previously described (
Klein et al. (1996)Proc. Natl. Acad. Sci. USA 93, 7108–7113). We describe results using a cDNA library derived from activated human peripheral blood mononuclear cells (PBMC). Genes identified from this library encoded signal sequences of proteins of diverse structure, function, and cellular location such as cytokines, type 1 and type 2 transmembrane proteins, and proteins found in intracellular organelles. In addition, a number of novel secreted proteins were identified, including a chemokine and a novel G-protein-coupled receptor. Since signal sequences possess features conserved throughout evolution, the procedure can be used to isolate genes encoding secreted proteins from both eukaryotes and prokaryotes.
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