Developing a policy for paediatric biobanks: Principles for good practice

The participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective measures when they are enrolled in research. Research using biobanked biological samples from children poses additional ethical issues to those raised by research using adult biobanks. For example, small children have only limited capacity, if any, to understand the meaning and implications of the research and to give a documented agreement to it. Older minors are gradually acquiring this capacity. We describe principles for good practice related to the inclusion of minors in biobank research, focusing on issues related to benefits and subsidiarity, consent, proportionality and return of results. Some of these issues are currently heavily debated, and we conclude by providing principles for good practice for policy makers of biobanks, researchers and anyone involved in dealing with stored tissue samples from children. Actual implementation of the principles will vary according to different jurisdictions

Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected

Symplectic lattice gauge theories in the grid framework: Approaching the conformal window

Symplectic gauge theories coupled to matter fields lead to symmetry enhancement phenomena that have potential applications in such diverse contexts as composite Higgs, top partial compositeness, strongly interacting dark matter, and dilaton-Higgs models. These theories are also interesting on theoretical grounds, for example in reference to the approach to the large-N limit. A particularly compelling research aim is the determination of the extent of the conformal window in gauge theories with symplectic groups coupled to matter, for different groups and for field content consisting of fermions transforming in different representations. Such determination would have far-reaching implications, but requires overcoming huge technical challenges. Numerical studies based on lattice field theory can provide the quantitative information necessary to this endeavor. We developed new software to implement symplectic groups in the Monte Carlo algorithms within the Grid framework. In this paper, we focus most of our attention on the Sp(4) lattice gauge theory coupled to four (Wilson-Dirac) fermions transforming in the 2-index antisymmetric representation, as a case study. We discuss an extensive catalog of technical tests of the algorithms and present preliminary measurements to set the stage for future large-scale numerical investigations. We also include the scan of parameter space of all asymptotically free Sp(4) lattice gauge theories coupled to varying number of fermions transforming in the antisymmetric representation

European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death.

Sudden cardiac death (SCD) accounts for 10-20% of total mortality, i.e., one in five individuals will eventually die suddenly. Given the substantial genetic component of SCD in younger cases, postmortem genetic testing may be particularly useful in elucidating etiological factors in the cause of death in this subset. The identification of genes responsible for inherited cardiac diseases have led to the organization of cardiogenetic consultations in many countries worldwide. Expert recommendations are available, emphasizing the importance of genetic testing and appropriate information provision of affected individuals, as well as their relatives. However, the context of postmortem genetic testing raises some particular ethical, legal, and practical (including economic or financial) challenges. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with international experts, developed recommendations on management of SCD after a workshop sponsored by the Brocher Foundation and ESHG in November 2016. These recommendations have been endorsed by the ESHG Board, the European Council of Legal Medicine, the European Society of Cardiology working group on myocardial and pericardial diseases, the ERN GUARD-HEART, and the Association for European Cardiovascular Pathology. They emphasize the importance of increasing the proportion of both medical and medicolegal autopsies and educating the professionals. Multidisciplinary collaboration is of utmost importance. Public funding should be allocated to reach these goals and allow public health evaluation

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits

Azimuthal correlations of high transverse momentum jets at next-to-leading order in the parton branching method

AbstractThe azimuthal correlation, $$\Delta \phi _{12}$$ Δ ϕ 12 , of high transverse momentum jets in pp collisions at $$\sqrt{s}=13$$ s = 13  TeV is studied by applying PB-TMD distributions to NLO calculations via MCatNLO together with the PB-TMD parton shower. A very good description of the cross section as a function of $$\Delta \phi _{12}$$ Δ ϕ 12 is observed. In the back-to-back region of $${\Delta \phi _{12}}\rightarrow \pi$$ Δ ϕ 12 → π , a very good agreement is observed with the PB-TMD Set 2 distributions while significant deviations are obtained with the PB-TMD Set 1 distributions. Set 1 uses the evolution scale while Set 2 uses transverse momentum as an argument in $$\alpha _\mathrm {s}$$ α s , and the above observation therefore confirms the importance of an appropriate soft-gluon coupling in angular ordered parton evolution. The total uncertainties of the predictions are dominated by the scale uncertainties of the matrix element, while the uncertainties coming from the PB-TMDs and the corresponding PB-TMD shower are very small. The $$\Delta \phi _{12}$$ Δ ϕ 12 measurements are also compared with predictions using MCatNLO together Pythia8, illustrating the importance of details of the parton shower evolution.</jats:p

Azimuthal correlations of high transverse momentum jets at next-to-leading order in the parton branching method

AbstractThe azimuthal correlation, $$\Delta \phi _{12}$$ Δ ϕ 12 , of high transverse momentum jets in pp collisions at $$\sqrt{s}=13$$ s = 13  TeV is studied by applying PB-TMD distributions to NLO calculations via MCatNLO together with the PB-TMD parton shower. A very good description of the cross section as a function of $$\Delta \phi _{12}$$ Δ ϕ 12 is observed. In the back-to-back region of $${\Delta \phi _{12}}\rightarrow \pi$$ Δ ϕ 12 → π , a very good agreement is observed with the PB-TMD Set 2 distributions while significant deviations are obtained with the PB-TMD Set 1 distributions. Set 1 uses the evolution scale while Set 2 uses transverse momentum as an argument in $$\alpha _\mathrm {s}$$ α s , and the above observation therefore confirms the importance of an appropriate soft-gluon coupling in angular ordered parton evolution. The total uncertainties of the predictions are dominated by the scale uncertainties of the matrix element, while the uncertainties coming from the PB-TMDs and the corresponding PB-TMD shower are very small. The $$\Delta \phi _{12}$$ Δ ϕ 12 measurements are also compared with predictions using MCatNLO together Pythia8, illustrating the importance of details of the parton shower evolution.</jats:p