Integrating clinical decision support systems for pharmacogenomic testing into clinical routine - a scoping review of designs of user-system interactions in recent system development

Background: Pharmacogenomic clinical decision support systems (CDSS) have the potential to help overcome some of the barriers for translating pharmacogenomic knowledge into clinical routine. Before developing a prototype it is crucial for developers to know which pharmacogenomic CDSS features and user-system interactions have yet been developed, implemented and tested in previous pharmacogenomic CDSS efforts and if they have been successfully applied. We address this issue by providing an overview of the designs of user-system interactions of recently developed pharmacogenomic CDSS. Methods: We searched PubMed for pharmacogenomic CDSS published between January 1, 2012 and November 15, 2016. Thirty-two out of 118 identified articles were summarized and included in the final analysis. We then compared the designs of user-system interactions of the 20 pharmacogenomic CDSS we had identified. Results: Alerts are the most widespread tools for physician-system interactions, but need to be implemented carefully to prevent alert fatigue and avoid liabilities. Pharmacogenomic test results and override reasons stored in the local EHR might help communicate pharmacogenomic information to other internal care providers. Integrating patients into user-system interactions through patient letters and online portals might be crucial for transferring pharmacogenomic data to external health care providers. Inbox messages inform physicians about new pharmacogenomic test results and enable them to request pharmacogenomic consultations. Search engines enable physicians to compare medical treatment options based on a patient’s genotype. Conclusions: Within the last 5 years, several pharmacogenomic CDSS have been developed. However, most of the included articles are solely describing prototypes of pharmacogenomic CDSS rather than evaluating them. To support the development of prototypes further evaluation efforts will be necessary. In the future, pharmacogenomic CDSS will likely include prediction models to identify patients who are suitable for preemptive genotyping

Towards a New Science of a Clinical Data Intelligence

In this paper we define Clinical Data Intelligence as the analysis of data generated in the clinical routine with the goal of improving patient care. We define a science of a Clinical Data Intelligence as a data analysis that permits the derivation of scientific, i.e., generalizable and reliable results. We argue that a science of a Clinical Data Intelligence is sensible in the context of a Big Data analysis, i.e., with data from many patients and with complete patient information. We discuss that Clinical Data Intelligence requires the joint efforts of knowledge engineering, information extraction (from textual and other unstructured data), and statistics and statistical machine learning. We describe some of our main results as conjectures and relate them to a recently funded research project involving two major German university hospitals.Comment: NIPS 2013 Workshop: Machine Learning for Clinical Data Analysis and Healthcare, 201

Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease

Objective To determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms. Methods Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG-and AQP4-antibodies using live cell-based assays. Results 45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016). Conclusions 67% of all children presenting with NMO or limited forms tested positive for MOG-or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes

Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome

Objective: To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS). Methods: Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study. Results: Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (p = 0.0001), diagnosis of ADEM (p = 0.005), increased CSF cell counts (p = 0.011), and negative OCB (p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirtyfive children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (p = 0.0003) and older age at onset (p = 0.024). MS was predicted by MS-like MRI (p = 1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%. Conclusions: Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10−6, odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10−4). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical R

High-flexibility combinatorial peptide synthesis with laser-based transfer of monomers in solid matrix material

Laser writing is used to structure surfaces in many different ways in materials and life sciences. However, combinatorial patterning applications are still limited. Here we present a method for cost-efficient combinatorial synthesis of very-high-density peptide arrays with natural and synthetic monomers. A laser automatically transfers nanometre-thin solid material spots from different donor slides to an acceptor. Each donor bears a thin polymer film, embedding one type of monomer. Coupling occurs in a separate heating step, where the matrix becomes viscous and building blocks diffuse and couple to the acceptor surface. Furthermore, we can consecutively deposit two material layers of activation reagents and amino acids. Subsequent heat-induced mixing facilitates an in situ activation and coupling of the monomers. This allows us to incorporate building blocks with click chemistry compatibility or a large variety of commercially available non-activated, for example, posttranslationally modified building blocks into the array’s peptides with >17,000 spots per cm²

Braincase and endocranial anatomy of two thalattosuchian crocodylomorphs and their relevance in understanding their adaptations to the marine environment

Thalattosuchians are a group of Mesozoic crocodylomorphs known from aquatic deposits of the Early Jurassic–Early Cretaceous that comprises two main lineages of almost exclusively marine forms, Teleosauridae and Metriorhynchoidea. Teleosaurids were found in shallow marine, brackish and freshwater deposits, and have been characterized as semiaquatic near-shore forms, whereas metriorhynchids are a lineage of fully pelagic forms, supported by a large set of morphological characters of the skull and postcranial anatomy. Recent contributions on Thalattosuchia have been focused on the study of the endocranial anatomy. This newly available information provides novel evidence to suggest adaptations on the neuroanatomy, senses organs, vasculature, and behavioral evolution of these crocodylomorphs. However, is still not clear if the major morphological differences between teleosaurids and metriorhynchids were also mirrored by changes in the braincase and endocranial anatomy. Based on X-ray CT scanning and digital endocast reconstructions we describe the braincase and endocranial anatomy of two well-preserved specimens of Thalattosuchia, the semiaquatic teleosaurid Steneosaurus bollensis and the pelagic metriorhynchid Cricosaurus araucanensis. We propose that some morphological traits, such as: an enlarged foramen for the internal carotid artery, a carotid foramen ventral to the occipital condyle, a single CN XII foramen, absence of brain flexures, well-developed cephalic vascular system, lack of subtympanic foramina and the reduction of the paratympanic sinus system, are distinctive features of Thalattosuchia. It has been previously suggested that the enlarged foramen for the internal carotid artery, the absence of brain flexures, and the hypertrophied cephalic vascular system were synapomorphies of Metriorhynchidae; however, new information revealed that all of these features were already established at the base of Thalattosuchia and might have been exapted later on their evolutionary history. Also, we recognized some differences within Thalattosuchia that previously have not been received attention or even were overlooked (e.g., circular/bilobate trigeminal foramen, single/double CN XII foramen, separation of the cranioquadrate canal from the external otic aperture, absence/presence of lateral pharyngeal foramen). The functional significances of these traits are still unclear. Extending the sampling to other Thalattosuchia will help to test the timing of acquisition and distribution of these morphological modifications among the whole lineage. Also comparison with extant marine tetrapods (including physiological information) will be crucial to understand if some (and/or which) of the morphological peculiarities of thalattosuchian braincases are products of directional natural selection resulting in a fully adaptation to a nektonic life style

Presolar grains from meteorites: Remnants from the early times of the solar system

This review provides an introduction to presolar grains - preserved stardust from the interstellar molecular cloud from which our solar system formed - found in primitive meteorites. We describe the search for the presolar components, the currently known presolar mineral populations, and the chemical and isotopic characteristics of the grains and dust-forming stars to identify the grains' most probable stellar sources. Keywords: presolar grains, interstellar dust, asymptotic giant branch (AGB) stars, novae, supernovae, nucleosynthesis, isotopic ratios, meteoritesComment: 71 pages, 24 figures, 9 tables. Invited review. to appear in Chemie der Erd

Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project.

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. METHODS: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. RESULTS: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. CONCLUSIONS: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters