Comparing Breast Cancer Multiparameter Tests in the OPTIMA Prelim Trial: No Test Is More Equal Than the Others

Background: Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population. Methods: Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score >25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna. Results: Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval [CI] = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors. Conclusions: Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)–positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

A global collaboration to study intimate partner violence-related head trauma: The ENIGMA consortium IPV working group

Intimate partner violence includes psychological aggression, physical violence, sexual violence, and stalking from a current or former intimate partner. Past research suggests that exposure to intimate partner violence can impact cognitive and psychological functioning, as well as neurological outcomes. These seem to be compounded in those who suffer a brain injury as a result of trauma to the head, neck or body due to physical and/or sexual violence. However, our understanding of the neurobehavioral and neurobiological effects of head trauma in this population is limited due to factors including difficulty in accessing/recruiting participants, heterogeneity of samples, and premorbid and comorbid factors that impact outcomes. Thus, the goal of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium Intimate Partner Violence Working Group is to develop a global collaboration that includes researchers, clinicians, and other key community stakeholders. Participation in the working group can include collecting harmonized data, providing data for meta- and mega-analysis across sites, or stakeholder insight on key clinical research questions, promoting safety, participant recruitment and referral to support services. Further, to facilitate the mega-analysis of data across sites within the working group, we provide suggestions for behavioral surveys, cognitive tests, neuroimaging parameters, and genetics that could be used by investigators in the early stages of study design. We anticipate that the harmonization of measures across sites within the working group prior to data collection could increase the statistical power in characterizing how intimate partner violence-related head trauma impacts long-term physical, cognitive, and psychological health

Improvement in the Reproducibility and Accuracy of DNA Microarray Quantification by Optimizing Hybridization Conditions

BACKGROUND: DNA microarrays, which have been increasingly used to monitor mRNA transcripts at a global level, can provide detailed insight into cellular processes involved in response to drugs and toxins. This is leading to new understandings of signaling networks that operate in the cell, and the molecular basis of diseases. Custom printed oligonucleotide arrays have proven to be an effective way to facilitate the applications of DNA microarray technology. A successful microarray experiment, however, involves many steps: well-designed oligonucleotide probes, printing, RNA extraction and labeling, hybridization, and imaging. Optimization is essential to generate reliable microarray data. RESULTS: Hybridization and washing steps are crucial for a successful microarray experiment. By following the hybridization and washing conditions recommended by an oligonucleotide provider, it was found that the expression ratios were compressed greater than expected and data analysis revealed a high degree of non-specific binding. A series of experiments was conducted using rat mixed tissue RNA reference material (MTRRM) and other RNA samples to optimize the hybridization and washing conditions. The optimized hybridization and washing conditions greatly reduced the non-specific binding and improved the accuracy of spot intensity measurements. CONCLUSION: The results from the optimized hybridization and washing conditions greatly improved the reproducibility and accuracy of expression ratios. These experiments also suggested the importance of probe designs using better bioinformatics approaches and the need for common reference RNA samples for platform performance evaluation in order to fulfill the potential of DNA microarray technology

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Snow Ensemble Uncertainty Project (SEUP): quantification of snow water equivalent uncertainty across North America via ensemble land surface modeling

The Snow Ensemble Uncertainty Project (SEUP) is an effort to establish a baseline characterization of snow water equivalent (SWE) uncertainty across North America with the goal of informing global snow observational needs. An ensemble-based modeling approach, encompassing a suite of current operational models is used to assess the uncertainty in SWE and total snow storage (SWS) estimation over North America during the 2009–2017 period. The highest modeled SWE uncertainty is observed in mountainous regions, likely due to the relatively deep snow, forcing uncertainties, and variability between the different models in resolving the snow processes over complex terrain. This highlights a need for high-resolution observations in mountains to capture the high spatial SWE variability. The greatest SWS is found in Tundra regions where, even though the spatiotemporal variability in modeled SWE is low, there is considerable uncertainty in the SWS estimates due to the large areal extent over which those estimates are spread. This highlights the need for high accuracy in snow estimations across the Tundra. In midlatitude boreal forests, large uncertainties in both SWE and SWS indicate that vegetation–snow impacts are a critical area where focused improvements to modeled snow estimation efforts need to be made. Finally, the SEUP results indicate that SWE uncertainty is driving runoff uncertainty, and measurements may be beneficial in reducing uncertainty in SWE and runoff, during the melt season at high latitudes (e.g., Tundra and Taiga regions) and in the western mountain regions, whereas observations at (or near) peak SWE accumulation are more helpful over the midlatitudes

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of ch

Neocentromeres Form Efficiently at Multiple Possible Loci in Candida albicans

Centromeres are critically important for chromosome stability and integrity. Most eukaryotes have regional centromeres that include long tracts of repetitive DNA packaged into pericentric heterochromatin. Neocentromeres, new sites of functional kinetochore assembly, can form at ectopic loci because no DNA sequence is strictly required for assembly of a functional kinetochore. In humans, neocentromeres often arise in cells with gross chromosome rearrangements that rescue an acentric chromosome. Here, we studied the properties of centromeres in Candida albicans, the most prevalent fungal pathogen of humans, which has small regional centromeres that lack pericentric heterochromatin. We functionally delimited centromere DNA on Chromosome 5 (CEN5) and then replaced the entire region with the counter-selectable URA3 gene or other marker genes. All of the resulting cen5Δ::URA3 transformants stably retained both copies of Chr5, indicating that a functional neocentromere had assembled efficiently on the homolog lacking CEN5 DNA. Strains selected to maintain only the cen5Δ::URA3 homolog and no wild-type Chr5 homolog also grew well, indicating that neocentromere function is independent of the presence of any wild-type CEN5 DNA. Two classes of neocentromere (neoCEN) strains were distinguishable: “proximal neoCEN” and “distal neoCEN” strains. Neocentromeres in the distal neoCEN strains formed at loci about 200–450 kb from cen5Δ::URA3 on either chromosome arm, as detected by massively parallel sequencing of DNA isolated by CENP-ACse4p chromatin immunoprecipitation (ChIP). In the proximal neoCEN strains, the neocentromeres formed directly adjacent to cen5Δ::URA3 and moved onto the URA3 DNA, resulting in silencing of its expression. Functional neocentromeres form efficiently at several possible loci that share properties of low gene density and flanking repeated DNA sequences. Subsequently, neocentromeres can move locally, which can be detected by silencing of an adjacent URA3 gene, or can relocate to entirely different regions of the chromosome. The ability to select for neocentromere formation and movement in C. albicans permits mechanistic analysis of the assembly and maintenance of a regional centromere

Complete sequence of the 22q11.2 allele in 1,053 subjects with 22q11.2 deletion syndrome reveals modifiers of conotruncal heart defects

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression

Nested inversion polymorphisms predispose chromosome 22q11.2 to meiotic rearrangements [RETRACTED]

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders