Distributed Queries for Quality Control Checks in Clinical Trials

Operational Quality Control (QC) checks are standard practice in clinical trials and ensure ongoing compliance with the study protocol, standard operating procedures (SOPs) and Good Clinical Practice (GCP). We present a method for defining QC checks as distributed queries over case report forms (CRF) and clinical imaging data- sources. Our distributed query system can integrate time-sensitive information in order to populate QC checks that can facilitate discrepancy resolution workflow in clinical trials

Lightweight distributed XML-based integration of translational data

A distributed XQuery engine sends sub queries to separate XML data sources, and then combines the results into a single XML composite result. The system is lightweight in that it is very simple to add a new data source. An illustrative example is given for integrating data from an electronic data capture (EDC) system and a separate specimen management system

A Partnership Approach for Electronic Data Capture in Small-Scale Clinical Trials

The data collection process for clinical trials can be a tedious and error-prone process, and even a barrier to initiating small-scale studies. Electronic Data Capture (EDC) software can meet the need for faster and more reliable collection of data, but these informatics solutions can also be difficult to for researchers to set up. Establishing a full-featured commercial Clinical Trials Management System (CTMS) ecosystem is not realistic due to current institutional resource constraints. As an alternative solution, our Biomedical Informatics core (BMI) provided the technical expertise to pilot each EDC system in partnership with research teams and performed a qualitative evaluation using criteria we had established with prior research.1 When we began our pilot process, we assumed that each system’s EDC functionality would be the most important aspect and we produced a whitepaper focused on functionality.2 However, as we worked with various study teams it became clear they were willing to work around limitations since any web-based EDC software was a step up from paper forms. In our evaluation we found that the design of the Catalyst Web Tools3 made it difficult to use for clinical trials. OpenClinica4 has the most advanced functionality, for example in site management and complex CRF design, but what documentation is available is written in less user-friendly technical language. REDCap5 had a very clear advantage due to its ease of use extensive tutorials, and online training materials. In early 2010, BMI decided on REDCap as the preferred EDC software to support for small-scale studies. Since then usage has steadily increased. As of August 2010 there were 98 active REDCap users and 16 production studies at the University of Washington, Seattle Children’s, Fred Hutchinson Cancer Research Center, and Bastyr University, with collaborators from many other institutions. Post-evaluation, in addition to maintaining our installation of REDCap we are concentrating on future work in two areas: partnerships with investigators to enhance the local usage of REDCap, and informatics research to solve problems in data integration and interoperability. BMI members have contributed to the Ontology of Clinical Research.7 Additionally through our i2b2 Cross-Institutional Clinical Translational Research (CICTR) project we have identified use cases for moving data between REDCap and i2b2.8 Lastly, in keeping with our “bottom up” philosophy we are applying lightweight data integration techniques to query across REDCap and other systems, such as freezer inventory

Lightweight XML-based query, integration and visualization of distributed, multimodality brain imaging data

A need of many neuroimaging researchers is to integrate multimodality brain data that may be stored in separate databases. To address this need we have developed a framework that provides a uniform XML-based query interface across multiple online data sources. The development of this framework is driven by the need to integrate neurosurgical and neuroimaging data related to language. The data sources for the language studies are 1) a web-accessible relational database of neurosurgical cortical stimulation mapping data (CSM) that includes patient-specific 3-D coordinates of each stimulation site mapped to an MRI reconstruction of the patient brain surface; and 2) an XML database of fMRI and structural MRI data and analysis results, created automatically by a batch program we have embedded in SPM. To make these sources available for querying each is wrapped as an XML view embedded in a web service. A top level web application accepts distributed XQueries over the sources, which are dispatched to the underlying web services. Returned results can be displayed as XML, HTML, CSV (Excel format), a 2-D schematic of a parcellated brain, or a 3-D brain visualization. In the latter case the CSM patient-specific coordinates returned by the query are sent to a transformation web-service for conversion to normalized space, after which they are sent to our 3-D visualization program MindSeer, which is accessed via Java WebStart through a generated link. The anatomical distribution of pooled CSM sites can then be visualized using various surfaces derived from brain atlases. As this framework is further developed and generalized we believe it will have appeal for researchers who wish to query, integrate and visualize results across their own databases as well as those of collaborators

Characteristics of Usual Physical Therapy Post-Total Knee Replacement and their Associations with Functional Outcomes

OBJECTIVE: Although total knee replacement surgery (TKR) is highly prevalent and generally successful, functional outcomes post-TKR vary widely. Most patients receive some physical therapy (PT) following TKR, but PT practice is variable and associations between specific content and dosage of PT interventions and functional outcomes are unknown. Research has identified exercise interventions associated with better outcomes but studies have not assessed whether such evidence has been translated into clinical practice. We characterized the content, dosage and progression of usual post-acute PT services following TKR, and examined associations of specific details of post-acute PT with patients\u27 6-month functional outcomes. METHODS: Post-acute PT data were collected from patients undergoing primary unilateral TKR and participating in a clinical trial of a phone-based coaching intervention. PT records from the terminal episode of care were reviewed and utilization and exercise content data were extracted. Descriptive statistics and linear regression models characterized PT treatment factors and identified associations with 6-month outcomes. RESULTS: We analyzed 112 records from 30 PT sites. Content and dosage of specific exercises and incidence of progression varied widely. Open chain exercises were utilized more frequently than closed chain (median and interquartile range (21(4,49) vs 13(4,28.5)). Median (interquartile range) occurrence of progression of closed and open chain exercise was 0 (0,2) and 1 (0,3) respectively. Shorter timed stair climb was associated with greater total number of PT interventions and use and progression of closed chain exercises. DISCUSSION: Data suggest that evidence-based interventions are under-utilized and dosage may be insufficient to obtain optimal outcomes

Evidence That a Respiratory Shield in \u3cem\u3eEscherichia coli\u3c/em\u3e Protects a Low-Molecular-Mass Fe-\u3csup\u3eII\u3c/sup\u3e Pool from O\u3csub\u3e2\u3c/sub\u3e-Dependent Oxidation

Iron is critical for virtually all organisms, yet major questions remain regarding the systems\u27 level understanding of iron in whole cells. Here, we obtained Mössbauer and EPR spectra of Escherichia coli cells prepared under different nutrient iron concentrations, carbon sources, growth phases, and O2 concentrations to better understand their global iron content. We investigated wild-type cells and those lacking Fur, FtnA, Bfr, and Dps proteins. The coarse-grain iron content of exponentially growing cells consisted of iron-sulfur clusters, variable amounts of nonheme high-spin FeII species, and an unassigned residual quadrupole doublet. The iron in stationary-phase cells was dominated by magnetically-ordered FeIII ions due to oxyhydroxide nanoparticles. Analysis of cytosolic extracts by size-exclusion chromatography detected by an online inductively-coupled plasma mass spectrometer revealed a low-molecular-mass (4LMM) FeII pool consisting of two iron complexes with masses of ~ 500 (major) and ~1300 (minor) Da. They appeared to be high-spin FeII species with mostly O donor ligands, perhaps a few N donors, and probably no S donor. Surprisingly, the iron content of E. coli and its reactivity with O2 were remarkably similar to those of mitochondria. In both cases, a respiratory shield composed of membrane-bound iron-rich respiratory complexes may protect the LMM FeII pool from reacting with O2. When exponentially growing cells transition to stationary phase, the shield deactivates as metabolic activity declines. Given the universality of oxidative phosphorylation in aerobic biology, the iron content and respiratory shield in other aerobic prokaryotes might be similar to those of E. coli and mitochondria

Photoreversible interconversion of a phytochrome photosensory module in the crystalline state.

A major barrier to defining the structural intermediates that arise during the reversible photointerconversion of phytochromes between their biologically inactive and active states has been the lack of crystals that faithfully undergo this transition within the crystal lattice. Here, we describe a crystalline form of the cyclic GMP phosphodiesterases/adenylyl cyclase/FhlA (GAF) domain from the cyanobacteriochrome PixJ in Thermosynechococcus elongatus assembled with phycocyanobilin that permits reversible photoconversion between the blue light-absorbing Pb and green light-absorbing Pg states, as well as thermal reversion of Pg back to Pb. The X-ray crystallographic structure of Pb matches previous models, including autocatalytic conversion of phycocyanobilin to phycoviolobilin upon binding and its tandem thioether linkage to the GAF domain. Cryocrystallography at 150 K, which compared diffraction data from a single crystal as Pb or after irradiation with blue light, detected photoconversion product(s) based on Fobs - Fobs difference maps that were consistent with rotation of the bonds connecting pyrrole rings C and D. Further spectroscopic analyses showed that phycoviolobilin is susceptible to X-ray radiation damage, especially as Pg, during single-crystal X-ray diffraction analyses, which could complicate fine mapping of the various intermediate states. Fortunately, we found that PixJ crystals are amenable to serial femtosecond crystallography (SFX) analyses using X-ray free-electron lasers (XFELs). As proof of principle, we solved by room temperature SFX the GAF domain structure of Pb to 1.55-Å resolution, which was strongly congruent with synchrotron-based models. Analysis of these crystals by SFX should now enable structural characterization of the early events that drive phytochrome photoconversion

Distributed XQuery-based integration and visualization of multimodality data: Application to brain mapping.

This paper addresses the need for relatively small groups of collaborating investigators to integrate distributed and heterogeneous data about the brain. Although various national efforts facilitate large-scale data sharing, these approaches are generally too “heavyweight” for individual or small groups of investigators, with the result that most data sharing among collaborators continues to be ad hoc. Our approach to this problem is to create a “lightweight” distributed query architecture, in which data sources are accessible via web services that accept arbitrary query languages but return XML results. A Distributed XQuery Processor (DXQP) accepts distributed XQueries in which subqueries are shipped to the remote data sources to be executed, with the resulting XML integrated by DXQP. A web-based application called DXBrain accesses DXQP, allowing a user to create, save and execute distributed XQueries, and to view the results in various formats including a 3-D brain visualization. Example results are presented using distributed brain mapping data sources obtained in studies of language organization in the brain, but any other XML source could be included. The advantage of this approach is that it is very easy to add and query a new source, the tradeoff being that the user needs to understand XQuery and the schemata of the underlying sources. For small numbers of known sources this burden is not onerous for a knowledgeable user, leading to the conclusion that the system helps to fill the gap between ad hoc local methods and large scale but complex national data sharing efforts

Detection of Viruses from Bioaerosols Using Anion Exchange Resin

This protocol demonstrates a customized bioaerosol sampling method for viruses. In this system, anion exchange resin is coupled with liquid impingement-based air sampling devices for efficacious concentration of negatively-charged viruses from bioaerosols. Thus, the resin serves as an additional concentration step in the bioaerosol sampling workflow. Nucleic acid extraction of the viral particles is then performed directly from the anion exchange resin, with the resulting sample suitable for molecular analyses. Further, this protocol describes a custom-built bioaerosol chamber capable of generating virus-laden bioaerosols under a variety of environmental conditions and allowing for continuous monitoring of environmental variables such as temperature, humidity, wind speed, and aerosol mass concentration. The main advantage of using this protocol is increased sensitivity of viral detection, as assessed via direct comparison to an unmodified conventional liquid impinger. Other advantages include the potential to concentrate diverse negatively-charged viruses, the low cost of anion exchange resin (~$0.14 per sample), and ease of use. Disadvantages include the inability of this protocol to assess infectivity of resin-adsorbed viral particles, and potentially the need for the optimization of the liquid sampling buffer used within the impinger

Berkeley Supernova Ia Program I: Observations, Data Reduction, and Spectroscopic Sample of 582 Low-Redshift Type Ia Supernovae

In this first paper in a series we present 1298 low-redshift (z\leq0.2) optical spectra of 582 Type Ia supernovae (SNe Ia) observed from 1989 through 2008 as part of the Berkeley SN Ia Program (BSNIP). 584 spectra of 199 SNe Ia have well-calibrated light curves with measured distance moduli, and many of the spectra have been corrected for host-galaxy contamination. Most of the data were obtained using the Kast double spectrograph mounted on the Shane 3 m telescope at Lick Observatory and have a typical wavelength range of 3300-10,400 Ang., roughly twice as wide as spectra from most previously published datasets. We present our observing and reduction procedures, and we describe the resulting SN Database (SNDB), which will be an online, public, searchable database containing all of our fully reduced spectra and companion photometry. In addition, we discuss our spectral classification scheme (using the SuperNova IDentification code, SNID; Blondin & Tonry 2007), utilising our newly constructed set of SNID spectral templates. These templates allow us to accurately classify our entire dataset, and by doing so we are able to reclassify a handful of objects as bona fide SNe Ia and a few other objects as members of some of the peculiar SN Ia subtypes. In fact, our dataset includes spectra of nearly 90 spectroscopically peculiar SNe Ia. We also present spectroscopic host-galaxy redshifts of some SNe Ia where these values were previously unknown. [Abridged]Comment: 34 pages, 11 figures, 11 tables, revised version, re-submitted to MNRAS. Spectra will be released in January 2013. The SN Database homepage (http://hercules.berkeley.edu/database/index_public.html) contains the full tables, plots of all spectra, and our new SNID template