Abstract Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that impair intrinsic-pathway-mediated coagulation-amplification. The standard-of-care for severe-HA-patients is regular infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called “FVIII-inhibitors (FEIs)” and become refractory. We used the PATH study and ImmunoChip to scan immune-mediated-disease (IMD)-genes for novel and/or replicated genomic-sequence-variations associated with baseline-FEI-status while accounting for non-independence of data due to genetic-relatedness and F8-mutational-heterogeneity. The baseline-FEI-status of 450 North American PATH subjects—206 with black-African-ancestry and 244 with white-European-ancestry—was the dependent variable. The F8-mutation-data and a genetic-relatedness matrix were incorporated into a binary linear-mixed model of genetic association with baseline-FEI-status. We adopted a gene-centric-association-strategy to scan, as candidates, pleiotropic-IMD-genes implicated in the development of either ³2 autoimmune-/autoinflammatory-disorders (AADs) or ³1 AAD and FEIs. Baseline-FEI-status was significantly associated with SNPs assigned to NOS2A (rs117382854; p=3.2E-6) and B3GNT2 (rs10176009; p=5.1E-6), which have functions in anti-microbial-/-tumoral-immunity. Among IMD-genes implicated in FEI-risk previously, we identified strong associations with CTLA4 assigned SNPs (p=2.2E-5). The F8-mutation-effect underlies ~15% of the total heritability for baseline-FEI-status. Additive genetic heritability and SNPs in IMD-genes account for >50% of the patient-specific variability in baseline-FEI-status. Race is a significant determinant independent of F8‑mutation-effects and non-F8-genetics.

Mission planning for multi-agent autonomous systems aims to generate feasible and optimal mission plans that satisfy given requirements. In this article, we propose a tool-supported mission-planning methodology that combines (i) a path-planning algorithm for synthesizing path plans that are safe in environments with complex road conditions, and (ii) a task-scheduling method for synthesizing task plans that schedule the tasks in the right and fastest order, taking into account the planned paths. The task-scheduling method is based on model checking, which provides means of automatically generating task execution orders that satisfy the requirements and ensure the correctness and efficiency of the plans by construction. We implement our approach in a tool named MALTA, which offers a user-friendly GUI for configuring mission requirements, a module for path planning, an integration with the model checker UPPAAL, and functions for automatic generation of formal models, and parsing of the execution traces of models. Experiments with the tool demonstrate its applicability and performance in various configurations of an industrial case study of an autonomous quarry. We also show the adaptability of our tool by employing it in a special case of an industrial case study.

Multi-UAV mission control requires a software solution that helps the operator to supervise individual UAVs and coordinate groups of units. This paper explores the experience and methodology of a User Interface for multi-UAVs systems developed for supporting a European project to aggregate heterogeneous UAVs in farming domain. The aim of the proposed system is to support the operator with the extra workload required for supervision of several UAVs while keeping their Situational Awareness (SA) high. The solution is evaluated with respect to workload and SA. A text-to-speech (TTS) approach is also evaluated to assess its effect on these metrics. The results show that while a TTS solution reduces the operator’s workload, over-reliance on the system can cause loss of SA for properties which are not directly presented by TTS.

With the rapidly growing use of Multi-Agent Systems (MASs), which can exponentially increase the system complexity, the problem of planning a mission for MASs became more intricate. In some MASs, human operators are still involved in various decision-making processes, including manual mission planning, which can be an ineffective approach for any non-trivial problem. Mission planning and re-planning can be represented as a combinatorial optimization problem. Computing a solution to these types of problems is notoriously difficult and not scalable, posing a challenge even to cutting-edge solvers. As time is usually considered an essential resource in MASs, automated solvers have a limited time to provide a solution. The downside of this approach is that it can take a substantial amount of time for the automated solver to provide a sub-optimal solution. In this work, we are interested in the interplay between a human operator and an automated solver and whether it is more efficient to let a human or an automated solver handle the planning and re-planning problems, or if the combination of the two is a better approach. We thus propose an experimental setup to evaluate the effect of having a human operator included in the mission planning and re-planning process. Our tests are performed on a series of instances with gradually increasing complexity and involve a group of human operators and a metaheuristic solver based on a genetic algorithm. We measure the effect of the interplay on both the quality and structure of the output solutions. Our results show that the best setup is to let the operator come up with a few solutions, before letting the solver improve them.

Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F) VIII gene ( F8) mutations and deficiencies in plasma FVIII coagulant activity (FVIII:C) that impair intrinsic pathway coagulation amplification. The standard-of-care for severe HA patients is regular infusions of therapeutic FVIII proteins (tFVIIIs) but ~25-30% of all such subjects develop neutralizing anti-tFVIII-antibodies called “FVIII inhibitors (FEIs)” that leave them refractory to treatment and necessitate use of alternative therapies that are less safe and effective, and extremely expensive. We used the ImmunoChip genotyping platform and subjects in the Personalized Alternative Therapies for Hemophilia (PATH) study to scan immune-mediated disease (IMD) genes for novel and/or replicated genomic sequence variations associated with FEI risk while accounting for non-independence of data due to genetic relatedness and F8 mutational heterogeneity. The “enrollment-FEI-status” of 450 North American PATH study subjects-which include 446 that self-identified as being only either black-African (n=204) or white-European (n=242), and four that self-identified as being both white-European and either black-African (n=3) or Asian (n=1)-was the dependent variable. The F8 mutation data and a genetic relatedness matrix were incorporated into a binary linear mixed model of genetic association with the novel FEI outcome of enrollment-FEI-status based on whether or not FEIs of any titer (AT) developed-Yes (AT:FEIs+) versus No (AT:FEI-)-regardless of their “historical-FEI-status', i.e., whether or not they had ever developed FEIs of AT prior to study entry. We adopted a gene-centric association strategy to scan as ”candidates“ a subset of 101 genes-of the ~2,000 total immune system genes that are interrogated by the naturally occurring sequence variations able to be genotyped simultaneously on the ImmunoChip-which comprise what we refer to herein as ”pleiotropic-IMD-genes“ because they have been implicated previously in the development of either (i) two or more autoimmune diseases (n=80) or (ii) at least one autoimmune disease if they were also implicated in FEI risk previously (n=25). (Note that four of the pleiotropic-IMD-genes previously implicated in FEI risk were also in the 80 genes implicated previously in the development of multiple autoimmune diseases such that we scanned 101 distinct pleiotropic-IMD-genes for association with FEI development in the PATH study.) Enrollment-FEI-status was significantly associated with SNPs in NOS2A ( Figure 1) and B3GNT2 ( Figure 2), which are involved directly and indirectly, respectively, in anti-microbial-/-tumoral-immunity. Among the pleiotropic-IMD-genes previously implicated in FEI risk, we identified strong associations with SNPs in CTLA4 (p=2.2E-5). We also quantified the influence of the different F8 mutation types on FEI risk for the first time and demonstrated that the F8-mutation-effect underlies ~15% of the total heritability of FEI development. The additive genetic heritability together with the SNPs in the pleiotropic-IMD-genes were found to account for >50% of the patient-specific variability in FEI risk. Finally, race was shown to be a significant determinant of FEI risk independent of the effects of F8 mutation types and non- F8-genetics.

Hemophilia-A (HA) is caused by heterogeneous factor (F) VIII gene ( F8) mutations, variably deficient plasma FVIII activity and reduced to absent intrinsic-pathway amplification of coagulation. Infused therapeutic-FVIII-proteins (tFVIIIs) prevent bleeding in all HA patients but ~30% with severe HA and ~7.5% with non-severe HA become refractory with the development of neutralizing anti-tFVIII-antibodies called “FVIII inhibitors (FEIs)”. HLA-class-II (HLAII) molecules are critical for the development of FEIs and several association studies on different HA patient populations clearly implicate an important role for the highly polymorphic encoding HLA-D loci in the variable frequency of immunogenicity observed for tFVIIIs infused in different subjects with HA. However, the results from these studies were often conflicting, and none have undergone true independent confirmation. We use the ImmunoChip to genotype each subject in the PATH study simultaneously for the >900 single-nucleotide-variations (SNVs) distributed across the extended MHC-class-II (MHCII) region-which includes the classical- and non-classical-HLAII-genes and -pseudogenes-and then evaluated each independently for associations with FEI risk while accounting for the non-independence of data due to genetic relatedness and F8 mutational heterogeneity using novel statistical methods. The “lifetime-FEI-status” of the 438 North American HA patients in PATH-whose racial-identity/ethnic-ancestry was self-reported as either black-African (n=200) or white-European (n=238)-was the dependent variable of interest. The F8-mutation data and a genetic-relatedness matrix were incorporated into a binary linear mixed model of genetic association with lifetime-FEI-status (Yes vs. No), with ‘Yes’ designating those patients having FEIs of either any titer (AT), i.e., >0.4 Bethesda Units (BUs) mL -1, or only high-titer (HT), i.e., ≥5.0 BUs mL -1. Following the analytical procedure used in prior studies designed to identify determinants of FEI risk, we conducted the extended-MHCII-region-wide association screen-against the 926 distinct SNVs with high-quality genotypes that passed QC-of lifetime-FEI-status on two groups of FEI-positive patients, i.e., those with AT-FEIs, or those with only HT-FEIs. HA patients in the HT-FEI group are suspected to be more homogeneous with respect to the underlying immunobiology as they appear clinically to have induced full adaptive immunity. In contrast, HA patients in the AT-FEI group are heterogenous as some will have transient FEIs, which spontaneously disappear, and others will have FEIs that may remain low-titer (LT) despite continued infusions of tFVIIIs. We found several SNPs that were not only significantly associated in both FEI groups-or significant and suggestive respectively in the HT- and AT-groups-but also increased in significance (i.e., their p-values decreased) under the HT analysis ( Figure 1). The latter observation indicates that these results correspond to true associations that became more apparent as sources of “noise” were removed upon going from the AT to HT analysis. These included a SNP in the 3'-UTR of DQB1 (rs1049225, p-value=5.7E-7) and two intergenic HLAII region SNPs (rs2647012, p-value=1.1E-5; and rs2858324, p-value=1.1E-5). The DQB1 SNP reached an ImmunoChip-wide significance threshold in the HT analysis (i.e., a p-value <5.9E-7) and extended-MHCII-region-wide significance in the AT analysis (i.e., p-value <5.4E-5). Although the two HLAII-intergenic SNPs were not ImmunoChip-wide significant, they were significant across the MHCII region (i.e., p-value <5.4E-5). We found two SNPs that were significant and suggestive, respectively, in the HT- and AT-FEI analyses (rs9276189, p-value=1.3E-5; and rs2856717, p-value=3.3E-5), as well as one SNP that was significant in the HT-FEI analyses but not significant or suggestive in the AT analysis (rs9271366, p-value=1.9E-6). Our results establish that a novel DQB1 genetic variant is associated with FEI risk and confirm that HLA-DQ-allotypes and race independently influence the rate of FEI development in HA ( Figure 2).

Emerging precision agriculture techniques rely on the frequent collection of high-quality data which can be acquired efficiently by unmanned aerial systems (UAS). The main obstacle for wider adoption of this technology is related to UAS operational costs. The path forward requires a high degree of autonomy and integration of the UAS and other cyber physical systems on the farm into a common Farm Management System (FMS) to facilitate the use of big data and artificial intelligence (AI) techniques for decision support. Such a solution has been implemented in the EU project AFarCloud (Aggregated Farming in the Cloud). The regulation of UAS operations is another important factor that impacts the adoption rate of agricultural UAS. An analysis of the new European UAS regulations relevant for autonomous operation is included. Autonomous UAS operation through the AFarCloud FMS solution has been demonstrated at several test farms in multiple European countries. Novel applications have been developed, such as the retrieval of data from remote field sensors using UAS and in situ measurements using dedicated UAS payloads designed for physical contact with the environment. The main findings include that (1) autonomous UAS operation in the agricultural sector is feasible once the regulations allow this; (2) the UAS should be integrated with the FMS and include autonomous data processing and charging functionality to offer a practical solution; and (3) several applications beyond just asset monitoring are relevant for the UAS and will help to justify the cost of this equipment.

Direct oral anticoagulants (DOAC) such as the thrombin inhibitor Dabigatran and the coagulation factor Xa inhibitors Apixaban and Rivaroxaban have been in clinical use for the past 5-6 years. Familiarity with their use in the general pediatric population with thrombosis secondary to inflammatory disorders and rheumatologic disease is currently not as prevalent due to the widespread more conventional anticoagulation practice with the fractionated heparins in particular Lovenox. In this report we would like to summarize our experience in a pediatric patient population ranging from 3- 17 years with thrombotic disease. Of 55 patients with various thrombotic events 16 patients were treated with DOAC. There were 5 patients who had underlying inflammatory disease including COVID. Thrombotic complications included arterial as well as venous thrombotic events. All patients had elevated D-Dimer levels ranging from 360-4000 mcg/ml on diagnosis and normalized with successful anticoagulation. All patients had resolution of thrombosis. Thrombelastogram (TEG) were obtained on isolated patients during therapy and were useful to balance anticoagulation to prevent hemorrhagic complications.

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders of erythropoiesis characterized by pathologic deposits of iron in the mitochondria of developing erythroblasts. Mutations in the mitochondrial glycine carrier SLC25A38 cause the most common recessive form of CSA. Nonetheless, the disease is still rare, there being fewer than 70 reported families. Here we describe the clinical phenotype and genotypes of 31 individuals from 24 families, including 11 novel mutations. We also review the spectrum of reported mutations and genotypes associated with the disease, describe the unique localization of missense mutations in transmembrane domains and account for the presence of several alleles in different populations.

A heterogeneous collection of >1500 distinct causative factor (F) VIII gene (F8) mutations have been identified thus far in unrelated severe Hemophilia A (HA) patients, who have less than 1% of normal FVIII activity in their plasmas and experience recurrent bleeding that often results in crippling arthropathies and can be life threatening. Curative gene therapies are being pursued intensely as the current standard of care, which involves 2-3 infusions/week of therapeutic FVIII (tFVIII) proteins throughout a patient's life, is extremely expensive and very demanding. Moreover, ~25% of patients with severe HA (PSHA) develop anti-tFVIII antibodies that neutralize the efficacy of their tFVIII proteins. Despite remarkable progress in clinical trials of various adeno-associated viruses (AAVs) as vectors for in vivo delivery of therapeutic F8 genes, it is not clear how widespread viral-mediated gene replacement therapy (GRT) will become due to current limitations that include the: (1) presence of existing immunity to the AAV capsid protein (CP) in ~30-70% of PSHA for whom GRT is contraindicated; (2) immunity to AAV-CP induced in all PSHA during the initial GRT that precludes subsequent dosing; (3) use of heterologous promoters which drive F8 expression in non-physiologic cells that may increase the encoded tFVIII protein's immunogenicity; and 4) episomal location of AAV-genome replication, which, together with "(2)" and "(3)", precludes GRT in children. These important unmet needs require new gene-based therapeutic strategies for HA. Our goal was to develop a virus-free, ex vivo personalized gene repair therapy that minimally manipulates the mutant F8 in autologous patient-derived blood outgrowth endothelial cells (BOECs)-the physiologically relevant cell type for FVIII production in vivo-followed by their expansion and reinfusion into the same individual patient. We chose to focus initially on the intron (I) 22 inversion (I22I) mutation initially as it is causative in >40% of all PSHA. CRISPR/Cas9 guide RNAs were designed to target the 3' end of F8 exon (E) 22. For initial experiments in K562 cells, a donor plasmid containing a restriction enzyme site was nucleofected with the CRISPR system encoding plasmid, which triggered successful homology-directed repair (HDR) at the target site (efficiency of 18.2%, n=2). Subsequently, a cDNA-based therapeutic donor plasmid was constructed containing all F8 coding sequences in E23-E26 followed by a bGH polyA signal. After appropriate informed consent was obtained, BOECs were cultured from the blood of 3 severe pediatric HA patients with the I22I (ages 6 years, 7 years, and 13 years). After nucleofecting the BOECs with the F8-specific CRISPR and HDR constructs, site-specific knock-in of the cDNA at the 3' end of E22 was confirmed via PCR (n=3). Direct Sanger sequencing of the resultant amplicons from the repaired I22-inverted F8 locus in treated BOECs from one representative patient confirmed complete and seamless knock-in of the therapeutic cDNA at the endogenous site of the mutant F8. Current efforts are to isolate clonal populations of the repaired BOECs and characterize their ability to secrete active FVIII in vitro. Similar experiments are underway using canine BOECs in the canine model of HA. The use of clonal populations of gene corrected autologous BOECs as the infused therapy allows whole genome sequencing analysis to be performed to confirm that no off-target cutting or integration occurred in the therapeutic cell preparation prior to infusion into the recipient patient, further strengthening the safety profile of this proposed autologous cell therapy. Overall, these current results lay promising proof-of-concept data for a potential new curative therapeutic alternative approach for HA which should overcome drawbacks of the current generations of AAV-based treatments. Disclosures Dinh: Haplogenics Corporation: Current Employment. Luu:Haplogenics Corporation: Current Employment. Mead:CSL Behring: Current Employment. Escobar:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Powell:Haplogenics Corporation: Membership on an entity's Board of Directors or advisory committees. Howard:Haplogenics Corporation: Membership on an entity's Board of Directors or advisory committees.

Complex underwater missions involving heterogeneous groups of AUVs and other types of vehicles require a number of steps from defining and planning the mission, orchestration during the mission execution, recovery of the vehicles, and finally post-mission data analysis. In this work the Mission Management Tool (MMT), a software solution for addressing the above-mentioned services is proposed. As demonstrated in the real-world tests the MMT is able to support the mission operators. The MMT hides the complex system consisting of software solutions, hardware, and vehicles from the user, and allows intuitive interaction with the vehicles involved in a mission. The tool can adapt to a wide spectrum of missions assuming different types of robotic systems and mission objectives.

The development of inhibitors against tFVIIIs represents a serious impediment to efficacious management of bleeding episodes in patients with hemophilia A (HA). It is therefore critical to understand the etiology of inhibitors to improve HA outcomes. Our group has recently presented evidence (Diego et al. Res Pract Thromb Haemost. 2019;3(Suppl. 1):50-51) on the validity of the Sequence Mismatch hypothesis, which posits that a sequence mismatch between the patient's endogenous FVIII sequence (i.e., due to the presence of a non-HA-causing non-synonymous single-nucleotide variation) and that underlying their tFVIII increases the risk that inhibitors will be induced during FVIII replacement therapy. For our study, 442 North American HA patients (237 Whites & 205 Blacks; 88% severely affected) were: 1) Immuno-Chip genotyped at ~167,000 SNPs in genes implicated in autoimmune disease risk; 2) Evaluated by Sanger DNA sequencing and assays for the recurrent intron (I)1- and I22-inversions to identify their F8-causal-mutations; and 3) Tested with the Nijmegen-modified Bethesda assay to determine their inhibitor status. The Immuno-Chip genotypes were used to construct a genetic-relationship matrix (GRM), and the F8 sequence data along with results from the I1- and I22-inversion (I22I) assays were used to construct a shared F8-mutation matrix (FMM). These matrices were used to estimate the heritable genetic and shared F8-mutation effects. Importantly, modeling a F8-mutation effect has the added advantage of accounting for the mutational heterogeneity in F8-mutations. We found that heritability and F8-mutation effects respectively accounted for 50% and 23% of the phenotypic variance in inhibitor (both p < 0.0001). Under the Sequence Mismatch hypothesis, it is assumed that tFVIII-derived peptides spanning the sequence mismatch must first be bound and presented on HLAcII molecules. In Diego et al. (2019), we reported a significant sequence mismatch effect but did not account for the effect of HLAcII binding. In a previous study of PATH data, it was shown using an area under the curve (AUC) estimate from receiver operator characteristic (ROC) curve analysis that HLAcII binding affinities estimated from the then-current version of NetMHCIIpan algorithm with respect to 15-mer peptides spanning sequence mismatches significantly predicted inhibitor status in a sample of 25 patients with the I22I mutation (Pandey et al. Nat Med. 2013;19(10): 1318-24). Here we adopt two strategies to extend this latter analysis to account for genetic relatedness and mutational heterogeneity. In the first strategy, we initially performed a Cholesky decomposition of the phenotypic covariance matrix expressed as a function of the GRM and FMM and their associated heritability and F8-mutation effect estimates, respectively. Following this, the derived Cholesky factor was used to decorrelate the HLAcII binding data, and then a bootstrap with replacement followed by ROC curve analysis each time (for 1,000 resampling's of the data) was used to generate an empirical distribution of the estimated AUC estimates. In the second strategy, we stratified the sample into the subset with the I22I mutation. We next performed a Cholesky decomposition of the GRM multiplied by the heritability and then used the resulting Cholesky factor to decorrelate the data for this subset. Finally, bootstrap with replacement followed by ROC curve analysis each time was used to generate an empirical distribution of the estimated AUC estimates. The p-values for both strategies are determined as the number of AUC estimates greater than that for the original transformed sample plus 1 divided by the total number of bootstraps plus 1. For the first time, we report results on the validity of the sequence mismatch hypothesis while modeling the effects of genetic relatedness, mutational heterogeneity, and HLAcII binding affinity. Disclosures Luu: Haplogenics Corporation: Employment. Chitlur:CSL-Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioveritiv/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dinh:Haplogenics Corporation: Employment. Mead:CSL Behring: Employment. Powell:Haplogenics: Membership on an entity's Board of Directors or advisory committees. Escobar:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Howard:Haplogenics Corporation: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Here we apply state-of-the-art statistical genetic approaches toward investigating the genetic architecture of factor VIII (FVIII) inhibitor (FEI) development in Hemophilia A (HA). A total of 442 North American HA patients (237 Whites and 205 Blacks; 88% severely affected) enrolled in the PATH Study were: 1) ImmunoChip genotyped at ~167,000 single nucleotide polymorphisms (SNPs) in genes previously implicated in autoimmune disease risk; 2) Evaluated by DNA sequencing and assays for the recurrent intron (I)1 and I22 inversions to identify their causative F8 mutations; and 3) Tested with the Bethesda assay to determine their FEI status. The ImmunoChip genotypes were used to construct a genetic relationship matrix (GRM), denoted by K, following our previously published method,1 and the F8 sequence data along with results from the I1 and I22 inversion assays were used to construct a shared F8-mutation matrix, denoted by F. We analyzed a dichotomous FEI variable under the statistical genetic threshold/liability model (a probit regression in the fixed effects) in conjunction with a variance components model for the FEI liability phenotypic covariance matrix, denoted by P, to model potentially important random effects. For the latter, we specifically assumed independent additive genetic, F8-mutation, and residual environmental random effects. By the independence assumption, the covariance matrix is then decomposable as a sum of the additive genetic (Va), F8-mutation (Vf), and residual environmental (Ve) variances respectively structured by K, F, and the identity matrix I. The variance component model is given as: P = K*Va + F*Vf + I*Ve. Heritability, denoted by h2, is defined as the ratio of Va to the total phenotypic variance (Vp): h2 = Va / Vp. We can further speak of the total heritability given as: h2t = h2r + h2f + h2snp, where the subscripts t, r, f, and snp respectively denote total, residual additive genetic, F8-mutation-specific, and SNP heritabilities. Using eigenstructure methods,2 we can compute power under a simpler model in which Va and Vf are combined as a single variance component. We computed power to detect genetic association as measured by SNP-specific heritability for a set of 403 SNPs in or near 14 candidate immune response genes previously implicated in FEI risk. To account for multiple hypothesis testing, power was computed at the Bonferroni-adjusted significance level of 0.05/403 = 1.2 × 10-4. Under the simplified model, we computed the statistical power to detect causal SNPs for our sample and study design for the sample FEI prevalences, denoted by Kp, for Whites (22.5%) and Blacks (45%), across a range of total heritabilities, h2t = 15%, 35%, and 55%, where the lattermost total heritability was observed for FEI liability in the current study (Figure 1). It should be noted that because the liability heritability is known to be biased upward, we applied the Dempster-Lerner correction to both the total and SNP-specific heritabilities.3 Close inspection of Figure 1 reveals that varying h2t from 15% to 35% to 55% results in slight decreases in power due to the decreasing ratio of the SNP-specific heritability to the total heritability. However, as seen in all three panels, the more important determinant of power is clearly the FEI prevalence in that the power curve for a Kp of 45% is associated with greater power than the power curve for a Kp of 22.5% across the range of total heritabilities examined. As seen in Figure 1, we have adequate power to detect SNP heritabilities as low as 5% and 6%, respectively, for a Kp of 45% and 22.5%. As noted above, we observed a FEI liability total heritability of 55% consisting of a 47% residual additive genetic heritability (p = 0.019) and 8% F8-mutation specific heritability (p = 0.005). This is the first study to use a GRM based on genotype data and a shared causal F8 mutation matrix to model additive genetic and F8-mutation specific effects.Almeida M, Peralta J, Farook V, …, Blangero J. Pedigree-based random effect tests to screen gene pathways. BMC Proc. 2014; 8(Suppl 1 Genetic Analysis Workshop): S100.Blangero J, Diego VP, Dyer T, …, Göring H. A kernel of truth: statistical advances in polygenic variance component models for complex human pedigrees. Adv Genetics. 2013; 81: 1-31.Glahn D, Williams J, McKay D, …, Blangero J. Discovering schizophrenia endophenotypes in randomly ascertained pedigrees. Biol Psychiatry. 2015; 77(1): 75-83.

Coagulation Factor VII occupies a key role in the coagulation system in that it activates Factor X to Xa when bound to Tissue Factor and also activates IX to IXa that in turn leads to Xa activation via an augmentation pathway of blood coagulation. Factor VII deficiency is usually transmitted in an autosomal recessive fashion and predisposition for bleeding manifestations may be highly variable and does not correlate with plasma factor VII activity levels. More than often patients are compound heterozygous for two different amino acid substitutions and it is difficult to predict the impact that each one of these mutations may have on a patients bleeding predisposition. In this report, we describe a patient with a compound heterozygous deletion insertion and missense variant, manifesting as moderate bleeding disorder.

This deliverable (D4.5) is in the format of a sequence of two user manuals (versions 1 and 2). The aim of the deliverable is to provide the learners and teachers with guides and tutorials on using the eCraft2Learn’s Unified User Interface for programming computer-supported artefacts, 3D modelling, DIY electronics simulation and printing. The contents of this version compliment D4.3 and D4.4 and can be used to employ the functionalities mentioned in those deliverables.

Congenital disorders of glycosylation are a group of inherited disorders affecting the addition of a carbohydrate moiety to a protein. A defect in this pathway can cause adverse effects in most organ systems, often presenting early in life. The most common of these disorders is CDG type 1a / PMM2-CDG). In this disorder the loss of the enzyme phosphomannomutase-2 prevents the conversion of mannose-6-phosphate to mannose-1-phosphate. This has previously been associated with deficiencies of protein C, protein S, antithrombin III, factor IX and factor XI and a subsequent imbalance of coagulation pathways leading to thrombotic events. We present the case of a 14-year-old male with known history of CDG1a and previous bleeding complications following left orchiopexy at age 3, at that time coagulation screening showed a normal PT/PTT and surgery was deemed safe. The patient now presented to our pediatric hematology/oncology clinic for further evaluation of coagulation abnormalities prior to pediatric surgery performing right orchiopexy. Laboratory values at this time showed coagulation deficiencies, of ATIII, Factor XI, Protein C and Protein S, PT/ PTT , F VIII, FIX and vWF where normal. Prior to surgery, patient was given fresh frozen plasma and ATIII concentrate the patient underwent a successful Stage One Fowler-Stephen Procedure with adequate hemostasis. Several months later the patient developed leg swelling and was diagnosed right femoral DVT. This resolved with ATIII substitution and anticoagulation with LMW heparin. The patient9s immediate family was tested for bleeding/clotting disorders and results were found to be normal. This report not only supports the association of bleeding but also thrombosis with CDG1a. We propose that in patients with known CDG routine PT/PTT will not uncover a hemostatic abnormality but further screening isolated factor deficiency need to be performed and prophylactic factor substitution be performed prior to any surgical interventions. Also an awareness of the highly procoagulant state in these patients that predispose to DVT and central nervous system vascular thrombosis need to be present. Disclosures No relevant conflicts of interest to declare.