Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes

Background Phenotypic overlap among the inherited bone marrow failure syndromes (IBMFSs) frequently limits the ability to establish a diagnosis based solely on clinical features. \u3e70 IBMFS genes have been identified, which often renders genetic testing prolonged and costly. Since correct diagnosis, treatment and cancer surveillance often depend on identifying the mutated gene, strategies that enable timely genotyping are essential. Methods To overcome these challenges, we developed a next-generation sequencing assay to analyse a panel of 72 known IBMFS genes. Cases fulfilling the clinical diagnostic criteria of an IBMFS but without identified causal genotypes were included. Results The assay was validated by detecting 52 variants previously found by Sanger sequencing. A total of 158 patients with unknown mutations were studied. Of 75 patients with known IBMFS categories (eg, Fanconi anaemia), 59% had causal mutations. Among 83 patients with unclassified IBMFSs, we found causal mutations and established the diagnosis in 18% of the patients. The assay detected mutant genes that had not previously been reported to be associated with the patient phenotypes. In other cases, the assay led to amendments of diagnoses. In 20% of genotype cases, the results indicated a cancer surveillance programme. Conclusions The novel assay is efficient, accurate and has a major impact on patient care

The impact of category, cytopathology and cytogenetics on development and progression of clonal and malignant myeloid transformation in inherited bone marrow failure syndromes

Inherited bone marrow failure syndromes are a group of rare, heterogeneous genetic disorders with a risk of clonal and malignant myeloid transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome and acute myeloid leukemia. The clinical characteristics, risk classification, prognostic factors and outcome of clonal and malignant myeloid transformation associated with inherited bone marrow failure syndromes are largely unknown. The aims of this study were to determine the impact of category, cytopathology and cytogenetics, the three components of the “Category Cytology Cytogenetics” classification of pediatric myelodysplastic syndrome, on the outcome of clonal and malignant myeloid transformation associated with inherited bone marrow failure. We used data from the Canadian Inherited Marrow Failure Registry. Among 327 patients with inherited bone marrow failure syndrome enrolled in the registry, the estimated risk of clonal and malignant myeloid transformation by the age of 18 years was 37%. The risk of clonal and malignant myeloid transformation varied according to the type of inherited bone marrow failure syndrome but was highest in Fanconi anemia. The development of clonal and malignant myeloid transformation significantly affected overall survival. Mortality varied based on cytopathological group. The largest group of patients had refractory cytopenia. Clonal marrow cytogenetic abnormalities were identified in 87% of patients with clonal and malignant myeloid transformation, and different cytogenetic groups had different impacts on disease progression. We conclude that category, cytopathology and cytogenetics in cases of clonal and malignant myeloid transformation associated with inherited bone marrow failure syndromes have an important impact on outcome and that the classification of such cases should incorporate these factors

Reanalysing genomic data by normalized coverage values uncovers CNVs in bone marrow failure gene panels

Inherited bone marrow failure syndromes (IBMFSs) are genetically heterogeneous disorders with cytopenia. Many IBMFSs also feature physical malformations and an increased risk of cancer. Point mutations can be identified in about half of patients. Copy number variation (CNVs) have been reported; however, the frequency and spectrum of CNVs are unknown. Unfortunately, current genome-wide methods have major limitations since they may miss small CNVs or may have low sensitivity due to low read depths. Herein, we aimed to determine whether reanalysis of NGS panel data by normalized coverage value could identify CNVs and characterize them. To address this aim, DNA from IBMFS patients was analyzed by a NGS panel assay of known IBMFS genes. After analysis for point mutations, heterozygous and homozygous CNVs were searched by normalized read coverage ratios and specific thresholds. Of the 258 tested patients, 91 were found to have pathogenic point variants. NGS sample data from 165 patients without pathogenic point mutations were re-analyzed for CNVs; 10 patients were found to have deletions. Diamond Blackfan anemia genes most commonly exhibited heterozygous deletions, and included RPS19, RPL11, and RPL5. A diagnosis of GATA2-related disorder was made in a patient with myelodysplastic syndrome who was found to have a heterozygous GATA2 deletion. Importantly, homozygous FANCA deletion were detected in a patient who could not be previously assigned a specific syndromic diagnosis. Lastly, we identified compound heterozygousity for deletions and pathogenic point variants in RBM8A and PARN genes. All deletions were validated by orthogonal methods. We conclude that careful analysis of normalized coverage values can detect CNVs in NGS panels and should be considered as a standard practice prior to do further investigations

Acceptability by parents and children of deception in pediatric research

OBJECTIVE: Deception has been used to investigate the role of developmental and behavioral factors in child health; however, its acceptability for use in pediatric research has received little empirical attention. This study examined the acceptability of deception in a pediatric pain research study as assessed through participating children's and parent's long-term perceptions of its use.  METHOD: Ninety-four children (52 boys; meanage = 12.77 yr) and their parents (86 mothers, 8 fathers) completed a structured interview that assessed perceptions of various aspects of deception in a pediatric pain study, 2.5 years after participating.  RESULTS: A minority of parents (25.5%) and children (13.8%) spontaneously recalled that deception was used. Overall, parents and children reported positive experiences with research participation, felt comfortable with the debriefing process, and deemed the research to be of societal importance. Opinions about researchers and psychologists were not negatively impacted, and most reported willingness to participate in research involving deception again.  CONCLUSION: When thoughtfully planned and disclosed, deception in pediatric research seems to be acceptable to parents and children. Future research should further examine the acceptability of deception and alternatives (e.g., authorized deception) among pediatric samples

Mass hierarchy, 2-3 mixing and CP-phase with Huge Atmospheric Neutrino Detectors

We explore the physics potential of multi-megaton scale ice or water Cherenkov detectors with low ($\sim 1$ GeV) threshold. Using some proposed characteristics of the PINGU detector setup we compute the distributions of events versus neutrino energy $E_\nu$ and zenith angle $\theta_z$, and study their dependence on yet unknown neutrino parameters. The $(E_\nu - \theta_z)$ regions are identified where the distributions have the highest sensitivity to the neutrino mass hierarchy, to the deviation of the 2-3 mixing from the maximal one and to the CP-phase. We evaluate significance of the measurements of the neutrino parameters and explore dependence of this significance on the accuracy of reconstruction of the neutrino energy and direction. The effect of degeneracy of the parameters on the sensitivities is also discussed. We estimate the characteristics of future detectors (energy and angle resolution, volume, etc.) required for establishing the neutrino mass hierarchy with high confidence level. We find that the hierarchy can be identified at $3\sigma$ -- $10\sigma$ level (depending on the reconstruction accuracies) after 5 years of PINGU operation.Comment: 39 pages, 21 figures. Description of Fig.3 correcte

The publication of ethically uncertain research: attitudes and practices of journal editors

<p>Abstract</p> <p>Background</p> <p>Publication of ethically uncertain research occurs despite well-published guidelines set forth in documents such as the Declaration of Helsinki. Such guidelines exist to aide editorial staff in making decisions regarding ethical acceptability of manuscripts submitted for publication, yet examples of ethically suspect and uncertain publication exist. Our objective was to survey journal editors regarding practices and attitudes surrounding such dilemmas.</p> <p>Methods</p> <p>The Editor-in-chief of each of the 103 English-language journals from the 2005 Abridged Index Medicus list publishing original research were asked to complete a survey sent to them by email between September-December 2007.</p> <p>Results</p> <p>A response rate of 33% (n = 34) was obtained from the survey. 18% (n = 6) of respondents had published ethically uncertain or suspect research within the last 10 years. 85% (n = 29) of respondents stated they would always reject ethically uncertain articles submitted for publication on ethical grounds alone. 12% (n = 4) of respondents stated they would approach each submission on a case-by-case basis. 3% (n = 1) stated they would be likely to publish such research, but only with accompanying editorial. Only 38% (n = 13) give reviewers explicit instruction to reject submissions on ethical grounds if found wanting.</p> <p>Conclusions</p> <p>Editorial compliance with the Declaration of Helsinki in rejecting research that is conducted unethically was difficult to ascertain because of a poor response rate despite multiple attempts using different modalities. Of those who did respond, the majority do reject ethically suspect research but few explicitly advise reviewers to do so. In this study editors did not take advantage of the opportunity to describe their support for the rejection of the publication of unethical research.</p

The Pandora multi-algorithm approach to automated pattern recognition of cosmic-ray muon and neutrino events in the MicroBooNE detector.

The development and operation of liquid-argon time-projection chambers for neutrino physics has created a need for new approaches to pattern recognition in order to fully exploit the imaging capabilities offered by this technology. Whereas the human brain can excel at identifying features in the recorded events, it is a significant challenge to develop an automated, algorithmic solution. The Pandora Software Development Kit provides functionality to aid the design and implementation of pattern-recognition algorithms. It promotes the use of a multi-algorithm approach to pattern recognition, in which individual algorithms each address a specific task in a particular topology. Many tens of algorithms then carefully build up a picture of the event and, together, provide a robust automated pattern-recognition solution. This paper describes details of the chain of over one hundred Pandora algorithms and tools used to reconstruct cosmic-ray muon and neutrino events in the MicroBooNE detector. Metrics that assess the current pattern-recognition performance are presented for simulated MicroBooNE events, using a selection of final-state event topologies

Results of Treatment for Patients With Multicentric or Bilaterally Predisposed Unilateral Wilms Tumor (AREN0534): A report from the Children’s Oncology Group

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156248/2/cncr32958_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156248/1/cncr32958.pd

Calibration of the charge and energy loss per unit length of the MicroBooNE liquid argon time projection chamber using muons and protons

We describe a method used to calibrate the position- and time-dependent response of the MicroBooNE liquid argon time projection chamber anode wires to ionization particle energy loss. The method makes use of crossing cosmic-ray muons to partially correct anode wire signals for multiple effects as a function of time and position, including cross-connected TPC wires, space charge effects, electron attachment to impurities, diffusion, and recombination. The overall energy scale is then determined using fully-contained beam-induced muons originating and stopping in the active region of the detector. Using this method, we obtain an absolute energy scale uncertainty of 2% in data. We use stopping protons to further refine the relation between the measured charge and the energy loss for highly-ionizing particles. This data-driven detector calibration improves both the measurement of total deposited energy and particle identification based on energy loss per unit length as a function of residual range. As an example, the proton selection efficiency is increased by 2% after detector calibration

Reconstruction and measurement of (100) MeV energy electromagnetic activity from π0 arrow γγ decays in the MicroBooNE LArTPC

We present results on the reconstruction of electromagnetic (EM) activity from photons produced in charged current νμ interactions with final state π0s. We employ a fully-automated reconstruction chain capable of identifying EM showers of (100) MeV energy, relying on a combination of traditional reconstruction techniques together with novel machine-learning approaches. These studies demonstrate good energy resolution, and good agreement between data and simulation, relying on the reconstructed invariant π0 mass and other photon distributions for validation. The reconstruction techniques developed are applied to a selection of νμ + Ar → μ + π0 + X candidate events to demonstrate the potential for calorimetric separation of photons from electrons and reconstruction of π0 kinematics