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Understanding patterns of drug-gene interactions (DGIs) is important for advancing the clinical implementation of pharmacogenetics (PGx) into routine practice. Prior studies have estimated the prevalence of DGIs, but few have confirmed DGIs in patients with known genotypes and prescriptions, nor have they evaluated clinician characteristics associated with DGI-prescribing. This retrospective chart review assessed prevalence of DGI, defined as a medication prescription in a patient with a PGx phenotype that has a clinical practice guideline recommendation to adjust therapy or monitor drug response, for patients enrolled in a research genetic biorepository linked to electronic health records (EHRs). The prevalence of prescriptions for medications with pharmacogenetic (PGx) guidelines, proportion of prescriptions with DGI, location of DGI prescription, and clinical service of the prescriber were evaluated descriptively. Seventy-five percent (57,058/75,337) of patients had a prescription for a medication with a PGx guideline. Up to 60% (n = 26,067/43,647) of patients had at least one DGI when considering recommendations to adjust or monitor therapy based on genotype. The majority (61%) of DGIs occurred in outpatient prescriptions. Proton pump inhibitors were the most common DGI medication for 11 of 12 clinical services. Almost 25% of patients (n = 10,706/43,647) had more than one unique DGI, and, among this group of patients, 61% had a DGI with more than one gene. These findings can inform future clinical implementation by identifying key stakeholders for initial DGI prescriptions, helping to inform workflows. The high prevalence of multigene interactions identified also support the use of panel PGx testing as an implementation strategy.

Supplemental Digital Content is available in the text., Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P=1.6×10−6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18–1.36]; PPRS=2.7×10−11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14–1.35]; PPRS=1.27×10−6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Concurrent model synchronization is the task of restoring consistency between two correlated models after they have been changed concurrently and independently. To determine whether such concurrent model changes conflict with each other and to resolve these conflicts taking domain- or user-specific preferences into account is highly challenging. In this paper, we present a framework for concurrent model synchronization algorithms based on Triple Graph Grammars (TGGs). TGGs specify the consistency of correlated models using grammar rules; these rules can be used to derive different consistency restoration operations. Using TGGs, we infer a causal dependency relation for model elements that enables us to detect conflicts non-invasively. Different kinds of conflicts are detected first and resolved by the subsequent conflict resolution process. Users configure the overall synchronization process by orchestrating the application of consistency restoration fragments according to several conflict resolution strategies to achieve individual synchronization goals. As proof of concept, we have implemented this framework in the model transformation tool eMoflon. Our initial evaluation shows that the runtime of our presented approach scales with the size of model changes and conflicts, rather than model size., Comment: 18 pages, 24 figures; to be published in: Proceedings of the 13th ACM SIGPLAN International Conference on Software Language Engineering (SLE '20)

Solving scheduling problems is important for a wide range of application domains including home care in the health care domain, allocation engineering in the automotive domain, and virtual network embedding in the network virtualisation domain. Standard solution approaches assume that an initially given problem definition (e.g. a set of constraints and an objective function) can be fixed, and does not have to be constantly changed and validated by domain experts. In this paper, we investigate an application where this is not the case: at dSPACE GmbH, a developer of software and hardware for mechatronic control systems, recurring manual tests must be executed in every development and release cycle. To allocate human resources (developers and testers) to perform these tests, a test schedule must be created and maintained during the testing process. Prior to our work, test scheduling at dSPACE was performed manually by a test manager, requiring more than one working day to create the initial schedule, and several hours of tedious, error-prone work every week to maintain the schedule. The novel challenge here is that an acceptable automation must be highly configurable by the test manager (the domain expert), who should be able to easily adapt and validate the problem definition on a regular basis. We demonstrate that techniques and results from consistency maintenance via triple graph grammars, and constraint solving via linear programming can be synergetically combined to yield a highly configurable and fully automated approach to test schedule generation. We evaluate our solution at dSPACE and show that it not only reduces the effort required to create and maintain schedules of acceptable quality, but that it can also be understood, configured, and validated by the test manager.

Incremental Graph Pattern Matching (IGPM) offers an elegant approach to find patterns in graph-based models, reporting newly added and recently removed pattern matches. However, analyzing these matches w.r.t. temporal and causal dependencies can in general only be done by extending not just the IGPM engine but also the underlying model, which often is impractical and sometimes even impossible. Therefore, we transform the stream of pattern matches to a stream of events and employ Complex Event Processing (CEP) to detect such dependencies and derive more complex events from them. For this purpose, we introduce GrapeL as a textual language to specify and generate integrated solutions using both IGPM and CEP to benefit from the synergy of both approaches, which we present in the context of a flight and booking scenario. Finally, we show that our solution can compete with an optimized hand-crafted version without GrapeL and CEP while offering a specification that yields a less tedious and error-prone design process.

A variety of restricted functor categories has been investigated independently and for different purposes to provide double-pushout-rewriting in the areas of model-driven development and graph transformation. We introduce S-cartesian functor categories as a unifying formal framework for these different examples. S-cartesian functor categories are certain subcategories of functor categories that preserve the adhesiveness of their base categories. We show the comprehensive theory of double-pushout-rewriting for S-cartesian functor categories which fulfill additional sufficient conditions. As a new application, we introduce the categories PTrG and APTrG of partial triple graphs and attributed partial triple graphs as S-cartesian functor categories and obtain all the classical results for double-pushout-rewriting in these categories by construction. Partial triple graphs have recently been used to improve model synchronization processes.

Model synchronization, i.e., the task of restoring consistency between two interrelated models after a model change, is a challenging task. Triple Graph Grammars (TGGs) specify model consistency by means of rules. They can be used to automatically derive specifications of edit operations for single models and repair rules that propagate model changes to related models. model (re-)synchronization activities more effectively, a construction mechanism for short-cut rules has been recently developed. They describe consistency-preserving complex edit operations across model boundaries. We show that edit and repair rules can be derived from short-cut rules. As proof of concept, we implemented the construction and application of short-cut edit and repair rules in eMoflon. Our evaluation shows that short-cut-rule-based repair processes have considerably decreased data loss and improved runtime compared to former model synchronization processes in eMoflon.

Synchronization and integration processes of correlated models that are formally based on triple graph grammars often suffer from the fact that elements are unnecessarily deleted and recreated losing information in the process. It has been shown that this undesirable loss of information can be softened by allowing partial correspondence morphisms in triple graphs. We provide a formal framework for this new synchronization process by introducing the category \(\mathbf {PTrG}\) of partial triple graphs and proving it to be adhesive. This allows for ordinary double pushout rewriting of partial triple graphs. To exhibit \(\mathbf {PTrG}\) as an adhesive category, we present a fundamental construction of subcategories of functor categories and show that these are adhesive HLR if the base category already is. Secondly, we consider an instantiation of this framework by triple graphs to illustrate its practical relevance and to have a concrete example at hand.

When using graph transformations to formalize model transformations, it is often desirable to design transformations that preserve consistency with respect to a given set of (model) integrity constraints. The standard approach is to equip transformations with suitable application conditions such that the introduction of constraint violations is prevented. This may lead to rules that are applicable seldom or even inapplicable at all, though. To supplement this approach, we present a new and systematic procedure to develop correct-by-construction transformations with respect to a special kind of constraints. Instead of controlling the applicability of a rule we complement its action in such a way that a given constraint holds after application: For every way in which the rule could introduce a violation of the constraint, we derive a supplementary action for the rule that remedies that violation. We formalize this construction in the setting of adhesive categories for monotonic rules and positive atomic constraints and present sufficient conditions for its correctness.

Sequences of rule applications in high-level replacement systems are difficult to adapt. Often, replacing a rule application at the beginning of a sequence, i.e., reverting a rule and applying another one instead, is prevented by structure created via rule applications later on in the sequence. A trivial solution would be to roll back all applications and reapply them in a proper way. This, however, has the disadvantage of being computationally expensive and, furthermore, may cause the loss of information in the process. Moreover, using existing constructions to compose the reversal of a rule with the application of another one, in particular the concurrent and amalgamated rule constructions, does not prevent the loss of information in case that the first rule deletes elements being recreated by the second one. To cope with both problems, we introduce a new kind of rule composition through ‘short-cut rules’. We present our new kind of rule composition for monotonic rules in adhesive HLR systems, as they provide a well-established generalization of graph-based transformation systems, and motivate it on the example of Triple Graph Grammars, a declarative and rule-based bidirectional transformation approach.

Triple Graph Grammars (TGGs) are a declarative, rule-based approach to model synchronisation with numerous implementations. TGG-based approaches derive typically a set of operational graph transformations from direction-agnostic TGG rules to realise model synchronisation. In addition to these derived graph transformations, however, further runtime analyses are required to calculate the consequences of model changes in a synchronisation run. This part of TGG-based synchronisation is currently manually implemented, which not only increases implementation and tool maintenance effort, but also requires tool or at least approach-specific proofs for correctness. In this paper, therefore, we discuss how incremental graph pattern matchers can be leveraged to simplify the runtime steps of TGG-based synchronisation. We propose to outsource the task of calculating the consequences of model changes to an underlying incremental pattern matcher. As a result, a TGG-based synchroniser is reduced to a component reacting solely to appearing and disappearing matches. This abstracts high-level synchronisation goals from low-level details of handling model changes, providing a viable and unifying foundation for a new generation of TGG tools.

Remote control of robots is often necessary to complete complex unstructured tasks in environments that are inaccessible (e.g. dangerous) for humans. Tele-operation of humanoid robots is often performed trough motion tracking to reduce the complexity deriving from manually controlling a high number of DOF. However, most commercial motion tracking apparatus are expensive and often uncomfortable. Moreover, a limitation of this approach is the need to maintain visual contact with the operated robot, or to employ a second human operator to independently maneuver a camera. As a result, even performing simple tasks heavily depends on the skill and synchronization of the two operators. To alleviate this problem we propose to use augmented-reality to provide the operator with first-person vision and a natural interface to directly control the camera, and at the same time the robot. By integrating recent off-the-shelf technologies, we provide an affordable and intuitive environment composed of Microsoft Kinect, Oculus Rift and haptic SensorGlove to tele-operate in first-person humanoid robots. We demonstrate on the humanoid robot iCub that this set-up allows to quickly and naturally accomplish complex tasks.