Merging Children’s Oncology Group Data with an External Administrative Database Using Indirect Patient Identifiers: A Report from the Children’s Oncology Group

Purpose

Clinical trials data from National Cancer Institute (NCI)-funded cooperative oncology group trials could be enhanced by merging with external data sources. Merging without direct patient identifiers would provide additional patient privacy protections. We sought to develop and validate a matching algorithm that uses only indirect patient identifiers.

Methods

We merged the data from two Phase III Children’s Oncology Group (COG) trials for de novo acute myeloid leukemia (AML) with the Pediatric Health Information Systems (PHIS). We developed a stepwise matching algorithm that used indirect identifiers including treatment site, gender, birth year, birth month, enrollment year and enrollment month. Results from the stepwise algorithm were compared against the direct merge method that used date of birth, treatment site, and gender. The indirect merge algorithm was developed on AAML0531 and validated on AAML1031.

Results

Of 415 patients enrolled on the AAML0531 trial at PHIS centers, we successfully matched 378 (91.1%) patients using the indirect stepwise algorithm. Comparison to the direct merge result suggested that 362 (95.7%) matches identified by the indirect merge algorithm were concordant with the direct merge result. When validating the indirect stepwise algorithm using the AAML1031 trial, we successfully matched 157 out of 165 patients (95.2%) and 150 (95.5%) of the indirectly merged matches were concordant with the directly merged matches.

Conclusions

These data demonstrate that patients enrolled on COG clinical trials can be successfully merged with PHIS administrative data using a stepwise algorithm based on indirect patient identifiers. The merged data sets can be used as a platform for comparative effectiveness and cost effectiveness studies.     

Safety of TNF-blocking agents in rheumatic patients with serology suggesting past hepatitis B state: results from a cohort of 21 patients

Introduction  

Reactivation of hepatitis B virus (HBV) infection in patients with past infection has been described in 5% to 10% of individuals undergoing immunosuppressive therapies. No data are available to date on the outcome of patients treated by tumour necrosis factor-alpha (TNFα) inhibitors for chronic arthritis with a serological pattern of past HBV infection. The aim of our study was to monitor HBV markers in HBV surface antigen (HBsAg)-negative/anti-HBcAb-positive patients treated with a TNFα inhibitor for inflammatory arthritides.     

Apolipoprotein A-V is a potential target for treating coronary artery disease: evidence from genetic and metabolomic analyses

Triglyceride (TG)-lowering LPL variants in combination with genetic LDL-C-lowering variants are associated with reduced risk of coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100 lipoprotein measurements in a combined sample from the Netherlands Epidemiology of Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73–0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the lipoprotein profile, which suggest apo A-V may be a potential novel therapeutic target for CAD prevention.     

Stomatal neighbor cell polarity and division in <Emphasis Type="Italic">Arabidopsis</Emphasis>

Asymmetric divisions are key to regulating the number and patterning of stomata in Arabidopsis thaliana (L.) Heynh. Many formative asymmetric divisions take place in neighbor cells (NCs), cells adjacent to a stoma or stomatal precursor. TOO MANY MOUTHS is a receptor-like protein required for the correct plane of NC division, resulting in the placement of the new precursor distal to the pre-existing stoma. Because plant cells usually become polarized before asymmetric division, we studied whether NCs display a cytological asymmetry as a function of cell stage and of possible division behavior. Cells that divided in the developing leaf epidermis were smaller than 400 micro m(-2) in area and included NCs as well as isolated cells. All NCs in the youngest complexes divided with comparable frequencies, but divisions became restricted to the smaller and most recently produced NCs as the stomatal complex matured. The majority of developing NCs had distally located nuclei, suggesting that nuclear position is actively regulated in NCs. NC stages exhibiting distally located nuclei were the likeliest to divide asymmetrically. However, a distal nucleus did not necessarily predict an asymmetric division, because more NCs had distal nuclei than were likely to divide. No defect was detected in nuclear distribution in tmm NCs. These data suggest that TMM uses intercellular signals to control the plane of asymmetric division after or independently of nuclear positioning.     

Native brook trout and invasive rainbow trout respond differently to seasonal weather variation: Spawning timing matters

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Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase

Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low concentrations and a defensive cytotoxin at higher concentrations. The high active site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a new specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents toward remote specificity pockets, which become accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active site conservation.     

American pika in a low‐elevation lava landscape: expanding the known distribution of a temperature‐sensitive species

In 2010, the American pika (Ochotona princeps fenisex) was denied federal protection based on limited evidence of persistence in low‐elevation environments. Studies in nonalpine areas have been limited to relatively few environments, and it is unclear whether patterns observed elsewhere (e.g., Bodie, CA) represent other nonalpine habitats. This study was designed to establish pika presence in a new location, determine distribution within the surveyed area, and evaluate influences of elevation, vegetation, lava complexity, and distance to habitat edge on pika site occupancy. In 2011 and 2012, we conducted surveys for American pika on four distinct subalpine lava flows of Newberry National Volcanic Monument, Oregon, USA. Field surveys were conducted at predetermined locations within lava flows via silent observation and active searching for pika sign. Site habitat characteristics were included as predictors of occupancy in multinomial regression models. Above and belowground temperatures were recorded at a subsample of pika detection sites. Pika were detected in 26% (2011) and 19% (2012) of survey plots. Seventy‐four pika were detected outside survey plot boundaries. Lava complexity was the strongest predictor of pika occurrence, where pika were up to seven times more likely to occur in the most complicated lava formations. Pika were two times more likely to occur with increasing elevation, although they were found at all elevations in the study area. This study expands the known distribution of the species and provides additional evidence for persistence in nonalpine habitats. Results partially support the predictive occupancy model developed for pika at Craters of the Moon National Monument, another lava environment. Characteristics of the lava environment clearly influence pika site occupancy, but habitat variables reported as important in other studies were inconclusive here. Further work is needed to gain a better understanding of the species’ current distribution and ability to persist under future climate conditions.     

An Integrated Mass-Spectrometry Pipeline Identifies Novel Protein Coding-Regions in the Human Genome

Background

Most protein mass spectrometry (MS) experiments rely on searches against a database of known or predicted proteins, limiting their ability as a gene discovery tool.

Results

Using a search against an in silico translation of the entire human genome, combined with a series of annotation filters, we identified 346 putative novel peptides [False Discovery Rate (FDR)<5%] in a MS dataset derived from two human breast epithelial cell lines. A subset of these were then successfully validated by a different MS technique. Two of these correspond to novel isoforms of Heterogeneous Ribonuclear Proteins, while the rest correspond to novel loci.

Conclusions

MS technology can be used for ab initio gene discovery in human data, which, since it is based on different underlying assumptions, identifies protein-coding genes not found by other techniques. As MS technology continues to evolve, such approaches will become increasingly powerful.