Comparing natural language processing representations of coded disease sequences for prediction in electronic health records.

OBJECTIVE: Natural language processing (NLP) algorithms are increasingly being applied to obtain unsupervised representations of electronic health record (EHR) data, but their comparative performance at predicting clinical endpoints remains unclear. Our objective was to compare the performance of unsupervised representations of sequences of disease codes generated by bag-of-words versus sequence-based NLP algorithms at predicting clinically relevant outcomes. MATERIALS AND METHODS: This cohort study used primary care EHRs from 6 286 233 people with Multiple Long-Term Conditions in England. For each patient, an unsupervised vector representation of their time-ordered sequences of diseases was generated using 2 input strategies (212 disease categories versus 9462 diagnostic codes) and different NLP algorithms (Latent Dirichlet Allocation, doc2vec, and 2 transformer models designed for EHRs). We also developed a transformer architecture, named EHR-BERT, incorporating sociodemographic information. We compared the performance of each of these representations (without fine-tuning) as inputs into a logistic classifier to predict 1-year mortality, healthcare use, and new disease diagnosis. RESULTS: Patient representations generated by sequence-based algorithms performed consistently better than bag-of-words methods in predicting clinical endpoints, with the highest performance for EHR-BERT across all tasks, although the absolute improvement was small. Representations generated using disease categories perform similarly to those using diagnostic codes as inputs, suggesting models can equally manage smaller or larger vocabularies for prediction of these outcomes. DISCUSSION AND CONCLUSION: Patient representations produced by sequence-based NLP algorithms from sequences of disease codes demonstrate improved predictive content for patient outcomes compared with representations generated by co-occurrence-based algorithms. This suggests transformer models may be useful for generating multi-purpose representations, even without fine-tuning.

The neuron mixer and its impact on human brain dynamics.

A signal mixer facilitates rich computation, which has been the building block of modern telecommunication. This frequency mixing produces new signals at the sum and difference frequencies of input signals, enabling powerful operations such as heterodyning and multiplexing. Here, we report that a neuron is a signal mixer. We found through ex vivo and in vivo whole-cell measurements that neurons mix exogenous (controlled) and endogenous (spontaneous) subthreshold membrane potential oscillations, producing new oscillation frequencies, and that neural mixing originates in voltage-gated ion channels. Furthermore, we demonstrate that mixing is evident in human brain activity and is associated with cognitive functions. We found that the human electroencephalogram displays distinct clusters of local and inter-region mixing and that conversion of the salient posterior alpha-beta oscillations into gamma-band oscillations regulates visual attention. Signal mixing may enable individual neurons to sculpt the spectrum of neural circuit oscillations and utilize them for computational operations.

RamanSPy: An Open-Source Python Package for Integrative Raman Spectroscopy Data Analysis.

Raman spectroscopy is a nondestructive and label-free chemical analysis technique, which plays a key role in the analysis and discovery cycle of various branches of science. Nonetheless, progress in Raman spectroscopic analysis is still impeded by the lack of software, methodological and data standardization, and the ensuing fragmentation and lack of reproducibility of analysis workflows thereof. To address these issues, we introduce RamanSPy, an open-source Python package for Raman spectroscopic research and analysis. RamanSPy provides a comprehensive library of tools for spectroscopic analysis that supports day-to-day tasks, integrative analyses, the development of methods and protocols, and the integration of advanced data analytics. RamanSPy is modular and open source, not tied to a particular technology or data format, and can be readily interfaced with the burgeoning ecosystem for data science, statistical analysis, and machine learning in Python. RamanSPy is hosted at https://github.com/barahona-research-group/RamanSPy, supplemented with extended online documentation, available at https://ramanspy.readthedocs.io, that includes tutorials, example applications, and details about the real-world research applications presented in this paper.

Assigning disease clusters to people: A cohort study of the implications for understanding health outcomes in people with multiple long-term conditions.

Background: Identifying clusters of co-occurring diseases may help characterise distinct phenotypes of Multiple Long-Term Conditions (MLTC). Understanding the associations of disease clusters with health-related outcomes requires a strategy to assign clusters to people, but it is unclear how the performance of strategies compare. Aims: First, to compare the performance of methods of assigning disease clusters to people at explaining mortality, emergency department attendances and hospital admissions over one year. Second, to identify the extent of variation in the associations with each outcome between and within clusters. Methods: We conducted a cohort study of primary care electronic health records in England, including adults with MLTC. Seven strategies were tested to assign patients to fifteen disease clusters representing 212 LTCs, identified from our previous work. We tested the performance of each strategy at explaining associations with the three outcomes over 1 year using logistic regression and compared to a strategy using the individual LTCs. Results: 6,286,233 patients with MLTC were included. Of the seven strategies tested, a strategy assigning the count of conditions within each cluster performed best at explaining all three outcomes but was inferior to using information on the individual LTCs. There was a larger range of effect sizes for the individual LTCs within the same cluster than there was between the clusters. Conclusion: Strategies of assigning clusters of co-occurring diseases to people were less effective at explaining health-related outcomes than a person's individual diseases. Furthermore, clusters did not represent consistent relationships of the LTCs within them, which might limit their application in clinical research.

Effect of timeframes to define long term conditions and sociodemographic factors on prevalence of multimorbidity using disease code frequency in primary care electronic health records: retrospective study.

Objective: To determine the extent to which the choice of timeframe used to define a long term condition affects the prevalence of multimorbidity and whether this varies with sociodemographic factors. Design: Retrospective study of disease code frequency in primary care electronic health records. Data sources: Routinely collected, general practice, electronic health record data from the Clinical Practice Research Datalink Aurum were used. Main outcome measures: Adults (≥18 years) in England who were registered in the database on 1 January 2020 were included. Multimorbidity was defined as the presence of two or more conditions from a set of 212 long term conditions. Multimorbidity prevalence was compared using five definitions. Any disease code recorded in the electronic health records for 212 conditions was used as the reference definition. Additionally, alternative definitions for 41 conditions requiring multiple codes (where a single disease code could indicate an acute condition) or a single code for the remaining 171 conditions were as follows: two codes at least three months apart; two codes at least 12 months apart; three codes within any 12 month period; and any code in the past 12 months. Mixed effects regression was used to calculate the expected change in multimorbidity status and number of long term conditions according to each definition and associations with patient age, gender, ethnic group, and socioeconomic deprivation. Results: 9 718 573 people were included in the study, of whom 7 183 662 (73.9%) met the definition of multimorbidity where a single code was sufficient to define a long term condition. Variation was substantial in the prevalence according to timeframe used, ranging from 41.4% (n=4 023 023) for three codes in any 12 month period, to 55.2% (n=5 366 285) for two codes at least three months apart. Younger people (eg, 50-75% probability for 18-29 years v 1-10% for ≥80 years), people of some minority ethnic groups (eg, people in the Other ethnic group had higher probability than the South Asian ethnic group), and people living in areas of lower socioeconomic deprivation were more likely to be re-classified as not multimorbid when using definitions requiring multiple codes. Conclusions: Choice of timeframe to define long term conditions has a substantial effect on the prevalence of multimorbidity in this nationally representative sample. Different timeframes affect prevalence for some people more than others, highlighting the need to consider the impact of bias in the choice of method when defining multimorbidity.

Integrated analysis of patient networks and plasmid genomes reveals a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying both blaIMP and mcr-9 genes.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of IMP-encoding CPE amongst diverse Enterobacterales species between 2016 and 2019 across a London regional network. METHODS: We performed a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE positive patients. Genomes of IMP-encoding CPE isolates were overlayed with patient contacts to imply potential transmission events. RESULTS: Genomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, E. coli); 86% (72/84) harboured an IncHI2 plasmid carrying blaIMP and colistin resistance gene mcr-9 (68/72). Phylogenetic analysis of IncHI2 plasmids identified three lineages showing significant association with patient contacts and movements between four hospital sites and across medical specialities, which was missed on initial investigations. CONCLUSIONS: Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multi-modal data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Plasmid-level outbreak analysis reveals that resistance spread may be wider than suspected, allowing more interventions to stop transmission within hospital networks.

Allosteric communication and signal transduction in proteins.

Allostery is one of the cornerstones of biological function, as it plays a fundamental role in regulating protein activity. The modelling of allostery has gradually moved from a conformation-based framework, linked to structural changes, to dynamics-based allostery, whereby the effects of ligand binding propagate via signal transduction from the allosteric site to other regions of the protein via inter-residue interactions. Characterising such allosteric signalling pathways, which do not necessarily lead to conformational changes, has been pursued experimentally and complemented by computational analysis of protein networks to detect subtle dynamic propagation paths. Considering allostery from the perspective of signal transduction broadens the understanding of allosteric mechanisms, underscores the importance of protein topology, and can provide insights into allosteric drug design.

Kernel-Based Independence Tests for Causal Structure Learning on Functional Data.

Measurements of systems taken along a continuous functional dimension, such as time or space, are ubiquitous in many fields, from the physical and biological sciences to economics and engineering. Such measurements can be viewed as realisations of an underlying smooth process sampled over the continuum. However, traditional methods for independence testing and causal learning are not directly applicable to such data, as they do not take into account the dependence along the functional dimension. By using specifically designed kernels, we introduce statistical tests for bivariate, joint, and conditional independence for functional variables. Our method not only extends the applicability to functional data of the Hilbert-Schmidt independence criterion (hsic) and its d-variate version (d-hsic), but also allows us to introduce a test for conditional independence by defining a novel statistic for the conditional permutation test (cpt) based on the Hilbert-Schmidt conditional independence criterion (hscic), with optimised regularisation strength estimated through an evaluation rejection rate. Our empirical results of the size and power of these tests on synthetic functional data show good performance, and we then exemplify their application to several constraint- and regression-based causal structure learning problems, including both synthetic examples and real socioeconomic data.

Kernel-based joint independence tests for multivariate stationary and non-stationary time series.

Multivariate time-series data that capture the temporal evolution of interconnected systems are ubiquitous in diverse areas. Understanding the complex relationships and potential dependencies among co-observed variables is crucial for the accurate statistical modelling and analysis of such systems. Here, we introduce kernel-based statistical tests of joint independence in multivariate time series by extending the d-variable Hilbert-Schmidt independence criterion to encompass both stationary and non-stationary processes, thus allowing broader real-world applications. By leveraging resampling techniques tailored for both single- and multiple-realization time series, we show how the method robustly uncovers significant higher-order dependencies in synthetic examples, including frequency mixing data and logic gates, as well as real-world climate, neuroscience and socio-economic data. Our method adds to the mathematical toolbox for the analysis of multivariate time series and can aid in uncovering high-order interactions in data.

Multiscale mobility patterns and the restriction of human movement.

From the perspective of human mobility, the COVID-19 pandemic constituted a natural experiment of enormous reach in space and time. Here, we analyse the inherent multiple scales of human mobility using Facebook Movement maps collected before and during the first UK lockdown. Firstly, we obtain the pre-lockdown UK mobility graph and employ multiscale community detection to extract, in an unsupervised manner, a set of robust partitions into flow communities at different levels of coarseness. The partitions so obtained capture intrinsic mobility scales with better coverage than nomenclature of territorial units for statistics (NUTS) regions, which suffer from mismatches between human mobility and administrative divisions. Furthermore, the flow communities in the fine-scale partition not only match well the UK travel to work areas but also capture mobility patterns beyond commuting to work. We also examine the evolution of mobility under lockdown and show that mobility first reverted towards fine-scale flow communities already found in the pre-lockdown data, and then expanded back towards coarser flow communities as restrictions were lifted. The improved coverage induced by lockdown is well captured by a linear decay shock model, which allows us to quantify regional differences in both the strength of the effect and the recovery time from the lockdown shock.

Identifying potential biases in code sequences in primary care electronic healthcare records: a retrospective cohort study of the determinants of code frequency.

OBJECTIVES: To determine whether the frequency of diagnostic codes for long-term conditions (LTCs) in primary care electronic healthcare records (EHRs) is associated with (1) disease coding incentives, (2) General Practice (GP), (3) patient sociodemographic characteristics and (4) calendar year of diagnosis. DESIGN: Retrospective cohort study. SETTING: GPs in England from 2015 to 2022 contributing to the Clinical Practice Research Datalink Aurum dataset. PARTICIPANTS: All patients registered to a GP with at least one incident LTC diagnosed between 1 January 2015 and 31 December 2019. PRIMARY AND SECONDARY OUTCOME MEASURES: The number of diagnostic codes for an LTC in (1) the first and (2) the second year following diagnosis, stratified by inclusion in the Quality and Outcomes Framework (QOF) financial incentive programme. RESULTS: 3 113 724 patients were included, with 7 723 365 incident LTCs. Conditions included in QOF had higher rates of annual coding than conditions not included in QOF (1.03 vs 0.32 per year, p<0.0001). There was significant variation in code frequency by GP which was not explained by patient sociodemographics. We found significant associations with patient sociodemographics, with a trend towards higher coding rates in people living in areas of higher deprivation for both QOF and non-QOF conditions. Code frequency was lower for conditions with follow-up time in 2020, associated with the onset of the COVID-19 pandemic. CONCLUSIONS: The frequency of diagnostic codes for newly diagnosed LTCs is influenced by factors including patient sociodemographics, disease inclusion in QOF, GP practice and the impact of the COVID-19 pandemic. Natural language processing or other methods using temporally ordered code sequences should account for these factors to minimise potential bias.

Long- and short-term history effects in a spiking network model of statistical learning.

The statistical structure of the environment is often important when making decisions. There are multiple theories of how the brain represents statistical structure. One such theory states that neural activity spontaneously samples from probability distributions. In other words, the network spends more time in states which encode high-probability stimuli. Starting from the neural assembly, increasingly thought of to be the building block for computation in the brain, we focus on how arbitrary prior knowledge about the external world can both be learned and spontaneously recollected. We present a model based upon learning the inverse of the cumulative distribution function. Learning is entirely unsupervised using biophysical neurons and biologically plausible learning rules. We show how this prior knowledge can then be accessed to compute expectations and signal surprise in downstream networks. Sensory history effects emerge from the model as a consequence of ongoing learning.

Traumatismo dentoalveolar en niños y adultos del sistema de salud de la Armada de Chile, 2014-2019

Objetivo: Describir los casos notificados de traumatismos dentoalveolares en dientes temporales y definitivos en la Unidad Clínica de Traumatismo Dentoalveolar de la Armada de Chile en el período 2014-2019. Materiales y Métodos: Descriptivo de tipo transversal. Se incluyeron todos los casos atendidos con diagnóstico de traumatismo dentoalveolar entre 2 a 80 años en la población estudiada. Se realizó un análisis descriptivo utilizando medidas de tendencia central y un modelo de regresión logística. Resultados: Se analizó un total de 326 casos, predominando el género masculino, con una edad media de 25,4 años. El 38% correspondieron a subluxación, siendo la etiología más frecuente la caída con un 69% y el lugar de ocurrencia, el hogar con un 35,6%. La mayoría de los beneficiarios correspondieron a familiares con derecho a atención en el sistema naval, y demoraron menos de 7 días en consultar con un 54.6%. Conclusión: El tipo de traumatismo dentoalveolar más frecuente fue la subluxación. En cuanto a la etiología, destacan las caídas y golpes con objetos, en su mayoría, en el hogar, afectando principalmente a hombres menores de 30 años. El tiempo en consultar e iniciar el tratamiento correspondiente, fue dentro de 7 días.

Objective: To describe the reported cases of dentoalveolar trauma in temporary and permanent teeth in the Clinical Unit of Dentoalveolar Trauma of the Chilean Army in the period 2014-2019. Materials and Methods: Cross-sectional descriptive study. All cases attended with a diagnosis of dentoalveolar trauma between 2 and 80 years old were included in the study population. A descriptive analysis was performed using measures of central tendency and a logistic regression model. Results: A total of 326 cases were analyzed, predominantly male gender, with a mean age of 25.4 years. Thirty-eight percent corresponded to subluxation, the most frequent etiology being fall with 69% and the place of the event, home with 35.6%. Most of the beneficiaries were family members entitled to care in the army system, and took less than 7 days to come for attention with 54.6%. Conclusion: The most frequent type of dentoalveolar trauma was subluxation. As for the etiology, falls and hits with objects stand out, mostly at home, affecting mainly men under 30 years of age. The time to come for consultation and start the corresponding treatment was within 7 days.

Caracterización del Traumatismo Dentoalveolar Concomitante a Trauma Maxilofacial en Personal Profesional de Fuerzas Armadas: Revisión Narrativa

El trauma maxilofacial es un problema de salud pública, comúnmente asociado a traumatismo dentoalveolar. Su prevalencia es alta, siendo más frecuente en poblaciones de riesgo, como personal de Fuerzas Armadas, esto por sus actividades laborales, generando gran impacto en el paciente. Caracterizar, según la literatura, el traumatismo dentoalveolar concomitante a trauma maxilofacial en el personal profesional de Fuerzas Armadas. Se realizó una revisión narrativa en cuatro bases de datos, en octubre del 2020. Se incluyeron publicaciones de máximo 5 años de antigüedad, en inglés o español, con resumen disponible, estudios primarios y revisiones sistemáticas. Se excluyó publicaciones no disponibles en texto completo y reportes de casos. Se incluyeron 15 artículos. Existe un déficit de evidencia sobre la asociación que existe entre traumatismo dentoalveolar y traumatismo maxilofacial en la población estudiada. Encontrándose que solo el 6,7 % de estos incluía en su análisis la concomitancia entre ambos tipos de traumas. Sin embargo, los diagnósticos más prevalentes consistieron en fracturas coronarias y mandibulares, respectivamente, asociadas a actividades de entrenamiento y combate. Se establece que el tipo de trauma maxilofacial más frecuente en la población profesional de Fuerzas Armadas es la fractura mandibular y en relación al traumatismo dentoalveolar, la fractura coronaria. En cuanto a la etiología, destacan las heridas de bala, explosivos y accidentes en vehículos, afectando principalmente a personal del Ejército entre 18 a 30 años. Es importante mencionar que los artículos incluidos en esta revisión que hacen referencia a la concomitancia entre el traumatismo dentoalveolar y maxilofacial son escasos y no se encuentran actualizados, por lo que, se necesita continuar investigando en esta temática.

The maxillofacial injuries are a public health issue commonly associated to dentoalveolar injuries. Its high prevalence in risk population such as the Armed Forces personnel, due to their work activities, generates a great impact on the patient. Characterize, according to the literature, dentoalveolar injuries within the maxillofacial injuries in professional Armed Forces personnel. A narrative research was conducted on October 2020 with four data bases. Only 5-year-old publications were considered both in English and Spanish, including their available summary, primary studies and systematic revisions. Publications without full access or report cases were not included. Fifteen scientific papers were included. There is a deficit of evidence between maxillofacial and dentoalveolar injuries in the target population. Only 6.7 % of the research included a joint analysis between both traumas, however the most prevalent diagnosis consisted in coronaries and mandibular fractures, in that order, associated mainly to training and combat activities. The most frequent maxillofacial injury within the Armed Forces personnel is the mandibular fracture, and in relation with dentoalveolar injuries is the coronary fracture. Regarding the etiology, gunshot wounds, explosives and car accidents are featured affecting mainly between 18 to 30 years old army personnel. It's relevant to highlight that the scientific papers included in this revision about the association between dentoalveolar and maxillofacial injuries are poor and not updated. Further research is needed in this issue.

Sensitivity and spectral control of network lasers.

Recently, random lasing in complex networks has shown efficient lasing over more than 50 localised modes, promoted by multiple scattering over the underlying graph. If controlled, these network lasers can lead to fast-switching multifunctional light sources with synthesised spectrum. Here, we observe both in experiment and theory high sensitivity of the network laser spectrum to the spatial shape of the pump profile, with some modes for example increasing in intensity by 280% when switching off 7% of the pump beam. We solve the nonlinear equations within the steady state ab-initio laser theory (SALT) approximation over a graph and we show selective lasing of around 90% of the strongest intensity modes, effectively programming the spectrum of the lasing networks. In our experiments with polymer networks, this high sensitivity enables control of the lasing spectrum through non-uniform pump patterns. We propose the underlying complexity of the network modes as the key element behind efficient spectral control opening the way for the development of optical devices with wide impact for on-chip photonics for communication, sensing, and computation.

Allosteric Hotspots in the Main Protease of SARS-CoV-2.

Inhibiting the main protease of SARS-CoV-2 is of great interest in tackling the COVID-19 pandemic caused by the virus. Most efforts have been centred on inhibiting the binding site of the enzyme. However, considering allosteric sites, distant from the active or orthosteric site, broadens the search space for drug candidates and confers the advantages of allosteric drug targeting. Here, we report the allosteric communication pathways in the main protease dimer by using two novel fully atomistic graph-theoretical methods: Bond-to-bond propensity, which has been previously successful in identifying allosteric sites in extensive benchmark data sets without a priori knowledge, and Markov transient analysis, which has previously aided in finding novel drug targets in catalytic protein families. Using statistical bootstrapping, we score the highest ranking sites against random sites at similar distances, and we identify four statistically significant putative allosteric sites as good candidates for alternative drug targeting.

Prediction of hospital-onset COVID-19 infections using dynamic networks of patient contact: an international retrospective cohort study.

BACKGROUND: Real-time prediction is key to prevention and control of infections associated with health-care settings. Contacts enable spread of many infections, yet most risk prediction frameworks fail to account for their dynamics. We developed, tested, and internationally validated a real-time machine-learning framework, incorporating dynamic patient-contact networks to predict hospital-onset COVID-19 infections (HOCIs) at the individual level. METHODS: We report an international retrospective cohort study of our framework, which extracted patient-contact networks from routine hospital data and combined network-derived variables with clinical and contextual information to predict individual infection risk. We trained and tested the framework on HOCIs using the data from 51 157 hospital inpatients admitted to a UK National Health Service hospital group (Imperial College Healthcare NHS Trust) between April 1, 2020, and April 1, 2021, intersecting the first two COVID-19 surges. We validated the framework using data from a Swiss hospital group (Department of Rehabilitation, Geneva University Hospitals) during a COVID-19 surge (from March 1 to May 31, 2020; 40 057 inpatients) and from the same UK group after COVID-19 surges (from April 2 to Aug 13, 2021; 43 375 inpatients). All inpatients with a bed allocation during the study periods were included in the computation of network-derived and contextual variables. In predicting patient-level HOCI risk, only inpatients spending 3 or more days in hospital during the study period were examined for HOCI acquisition risk. FINDINGS: The framework was highly predictive across test data with all variable types (area under the curve [AUC]-receiver operating characteristic curve [ROC] 0·89 [95% CI 0·88-0·90]) and similarly predictive using only contact-network variables (0·88 [0·86-0·90]). Prediction was reduced when using only hospital contextual (AUC-ROC 0·82 [95% CI 0·80-0·84]) or patient clinical (0·64 [0·62-0·66]) variables. A model with only three variables (ie, network closeness, direct contacts with infectious patients [network derived], and hospital COVID-19 prevalence [hospital contextual]) achieved AUC-ROC 0·85 (95% CI 0·82-0·88). Incorporating contact-network variables improved performance across both validation datasets (AUC-ROC in the Geneva dataset increased from 0·84 [95% CI 0·82-0·86] to 0·88 [0·86-0·90]; AUC-ROC in the UK post-surge dataset increased from 0·49 [0·46-0·52] to 0·68 [0·64-0·70]). INTERPRETATION: Dynamic contact networks are robust predictors of individual patient risk of HOCIs. Their integration in clinical care could enhance individualised infection prevention and early diagnosis of COVID-19 and other nosocomial infections. FUNDING: Medical Research Foundation, WHO, Engineering and Physical Sciences Research Council, National Institute for Health Research (NIHR), Swiss National Science Foundation, and German Research Foundation.

Prediction of Protein Allosteric Signalling Pathways and Functional Residues Through Paths of Optimised Propensity.

Allostery commonly refers to the mechanism that regulates protein activity through the binding of a molecule at a different, usually distal, site from the orthosteric site. The omnipresence of allosteric regulation in nature and its potential for drug design and screening render the study of allostery invaluable. Nevertheless, challenges remain as few computational methods are available to effectively predict allosteric sites, identify signalling pathways involved in allostery, or to aid with the design of suitable molecules targeting such sites. Recently, bond-to-bond propensity analysis has been shown successful at identifying allosteric sites for a large and diverse group of proteins from knowledge of the orthosteric sites and its ligands alone by using network analysis applied to energy-weighted atomistic protein graphs. To address the identification of signalling pathways, we propose here a method to compute and score paths of optimised propensity that link the orthosteric site with the identified allosteric sites, and identifies crucial residues that contribute to those paths. We showcase the approach with three well-studied allosteric proteins: h-Ras, caspase-1, and 3-phosphoinositide-dependent kinase-1 (PDK1). Key residues in both orthosteric and allosteric sites were identified and showed agreement with experimental results, and pivotal signalling residues along the pathway were also revealed, thus providing alternative targets for drug design. By using the computed path scores, we were also able to differentiate the activity of different allosteric modulators.

Relative, local and global dimension in complex networks.

Dimension is a fundamental property of objects and the space in which they are embedded. Yet ideal notions of dimension, as in Euclidean spaces, do not always translate to physical spaces, which can be constrained by boundaries and distorted by inhomogeneities, or to intrinsically discrete systems such as networks. To take into account locality, finiteness and discreteness, dynamical processes can be used to probe the space geometry and define its dimension. Here we show that each point in space can be assigned a relative dimension with respect to the source of a diffusive process, a concept that provides a scale-dependent definition for local and global dimension also applicable to networks. To showcase its application to physical systems, we demonstrate that the local dimension of structural protein graphs correlates with structural flexibility, and the relative dimension with respect to the active site uncovers regions involved in allosteric communication. In simple models of epidemics on networks, the relative dimension is predictive of the spreading capability of nodes, and identifies scales at which the graph structure is predictive of infectivity. We further apply our dimension measures to neuronal networks, economic trade, social networks, ocean flows, and to the comparison of random graphs.

Reflection on modern methods: constructing directed acyclic graphs (DAGs) with domain experts for health services research.

Directed acyclic graphs (DAGs) are a useful tool to represent, in a graphical format, researchers' assumptions about the causal structure among variables while providing a rationale for the choice of confounding variables to adjust for. With origins in the field of probabilistic graphical modelling, DAGs are yet to be widely adopted in applied health research, where causal assumptions are frequently made for the purpose of evaluating health services initiatives. In this context, there is still limited practical guidance on how to construct and use DAGs. Some progress has recently been made in terms of building DAGs based on studies from the literature, but an area that has received less attention is how to create DAGs from information provided by domain experts, an approach of particular importance when there is limited published information about the intervention under study. This approach offers the opportunity for findings to be more robust and relevant to patients, carers and the public, and more likely to inform policy and clinical practice. This article draws lessons from a stakeholder workshop involving patients, health care professionals, researchers, commissioners and representatives from industry, whose objective was to draw DAGs for a complex intervention-online consultation, i.e. written exchange between the patient and health care professional using an online system-in the context of the English National Health Service. We provide some initial, practical guidance to those interested in engaging with domain experts to develop DAGs.