Development of a novel and more holistic approach for assessing impact in health and medical research: the Research Impact Assessment Framework.

Considered investment in health and medical research (HMR) is critical for fostering a healthcare system that is sustainable, effective, responsive, and innovative. While several tools exist to measure the impact of research, few assess the research environment that nurtures and supports impactful research and the strategic alignment of research with societal needs. This perspective article discusses the limitations of existing assessment tools and presents a novel Research Impact Assessment Framework designed to enable more strategic and targeted investment towards HMR, having the potential for significant public benefit.

Genetic influences on epilepsy outcomes: A whole-exome sequencing and health care records data linkage study.

OBJECTIVE: This study was undertaken to develop a novel pathway linking genetic data with routinely collected data for people with epilepsy, and to analyze the influence of rare, deleterious genetic variants on epilepsy outcomes. METHODS: We linked whole-exome sequencing (WES) data with routinely collected primary and secondary care data and natural language processing (NLP)-derived seizure frequency information for people with epilepsy within the Secure Anonymised Information Linkage Databank. The study participants were adults who had consented to participate in the Swansea Neurology Biobank, Wales, between 2016 and 2018. DNA sequencing was carried out as part of the Epi25 collaboration. For each individual, we calculated the total number and cumulative burden of rare and predicted deleterious genetic variants and the total of rare and deleterious variants in epilepsy and drug metabolism genes. We compared these measures with the following outcomes: (1) no unscheduled hospital admissions versus unscheduled admissions for epilepsy, (2) antiseizure medication (ASM) monotherapy versus polytherapy, and (3) at least 1 year of seizure freedom versus <1 year of seizure freedom. RESULTS: We linked genetic data for 107 individuals with epilepsy (52% female) to electronic health records. Twenty-six percent had unscheduled hospital admissions, and 70% were prescribed ASM polytherapy. Seizure frequency information was linked for 100 individuals, and 10 were seizure-free. There was no significant difference between the outcome groups in terms of the exome-wide and gene-based burden of rare and deleterious genetic variants. SIGNIFICANCE: We successfully uploaded, annotated, and linked genetic sequence data and NLP-derived seizure frequency data to anonymized health care records in this proof-of-concept study. We did not detect a genetic influence on real-world epilepsy outcomes, but our study was limited by a small sample size. Future studies will require larger (WES) data to establish genetic variant contribution to epilepsy outcomes.

Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis.

Background: The extent of cortical pathology is an important determinant of multiple sclerosis (MS) severity. Cortical demyelination and neurodegeneration are related to inflammation of the overlying leptomeninges, a more inflammatory CSF milieu and with parenchymal microglia and astroglia activation. These are all components of the compartmentalised inflammatory response. Compartmentalised inflammation is a feature of progressive MS, which is not targeted by disease modifying therapies. Complement is differentially expressed in the MS CSF and complement, and complement receptors, are associated with demyelination and neurodegeneration. Methods: To better understand if complement activation in the leptomeninges is associated with underlying cortical demyelination, inflammation, and microglial activation, we performed a neuropathological study of progressive MS (n = 22, 14 females), neuroinflammatory (n = 8), and non-neurological disease controls (n = 10). We then quantified the relative extent of demyelination, connective tissue inflammation, complement, and complement receptor positive microglia/macrophages. Results: Complement was elevated at the leptomeninges, subpial, and within and around vessels of the cortical grey matter. The extent of complement C1q immunoreactivity correlated with connective tissue infiltrates, whilst activation products C4d, Bb, and C3b associated with grey matter demyelination, and C3a receptor 1+ and C5a receptor 1+ microglia/macrophages closely apposed C3b labelled cells. The density of C3a receptor 1+ and C5a receptor 1+ cells was increased at the expanding edge of subpial and leukocortical lesions. C5a receptor 1+ cells expressed TNFα, iNOS and contained puncta immunoreactive for proteolipid protein, neurofilament and synaptophysin, suggesting their involvement in grey matter lesion expansion. Interpretation: The presence of products of complement activation at the brain surfaces, their association with the extent of underlying pathology and increased complement anaphylatoxin receptor positive microglia/macrophages at expanding cortical grey matter lesions, could represent a target to modify compartmentalised inflammation and cortical demyelination.

A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure.

Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterized by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Although the variant is present in population databases (at very low frequency), there is strong clinical, genetic, and functional evidence to support pathogenicity. Recurrent variants may be due to a founder event in which the variant has been inherited from a common ancestor. Here, we report evidence of a single founder event giving rise to the SCN1B c.363C>G variant in 14 independent families with epilepsy. A common haplotype was observed in all families, and the age of the most recent common ancestor was estimated to be approximately 800 years ago. Analysis of UK Biobank whole-exome-sequencing data identified 74 individuals with the same variant. All individuals carried haplotypes matching the epilepsy-affected families, suggesting all instances of the variant derive from a single mutational event. This unusual finding of a variant causing an autosomal dominant, early-onset disease in an outbred population that has persisted over many generations can be attributed to the relatively mild phenotype in most carriers and incomplete penetrance. Founder events are well established in autosomal recessive and late-onset disorders but are rarely observed in early-onset, autosomal dominant diseases. These findings suggest variants present in the population at low frequencies should be considered potentially pathogenic in mild phenotypes with incomplete penetrance and may be more important contributors to the genetic landscape than previously thought.

Sex-specific disease modifiers in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p = 0.001) and females (OR = 3.0, p < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p = 0.001), absence seizures (OR = 6.0, p < 0.001) and stress-precipitated seizures (OR = 5.3, p = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation.

Epilepsy mortality in Wales during COVID-19.

PURPOSE: The COVID-19 pandemic has increased mortality worldwide and those with chronic conditions may have been disproportionally affected. However, it is unknown whether the pandemic has changed mortality rates for people with epilepsy. We aimed to compare mortality rates in people with epilepsy in Wales during the pandemic with pre-pandemic rates. METHODS: We performed a retrospective study using individual-level linked population-scale anonymised electronic health records. We identified deaths in people with epilepsy (DPWE), i.e. those with a diagnosis of epilepsy, and deaths associated with epilepsy (DAE), where epilepsy was recorded as a cause of death on death certificates. We compared death rates in 2020 with average rates in 2015-2019 using Poisson models to calculate death rate ratios. RESULTS: There were 188 DAE and 628 DPWE in Wales in 2020 (death rates: 7.7/100,000/year and 25.7/100,000/year). The average rates for DAE and DPWE from 2015 to 2019 were 5.8/100,000/year and 23.8/100,000/year, respectively. Death rate ratios (2020 compared to 2015-2019) for DAE were 1.34 (95%CI 1.14-1.57, p<0.001) and for DPWE were 1.08 (0.99-1.17, p = 0.09). The death rate ratios for non-COVID deaths (deaths without COVID mentioned on death certificates) for DAE were 1.17 (0.99-1.39, p = 0.06) and for DPWE were 0.96 (0.87-1.05, p = 0.37). CONCLUSIONS: The significant increase in DAE in Wales during 2020 could be explained by the direct effect of COVID-19 infection. Non-COVID-19 deaths have not increased significantly but further work is needed to assess the longer-term impact.

Disparities among crop species in the evolution of growth rates: the role of distinct origins and domestication histories.

Growth rates vary widely among plants with different strategies. For crops, evolution under predictable and high-resource environments might favour rapid resource acquisition and growth, but whether this strategy has consistently evolved during domestication and improvement remains unclear. Here we report a comprehensive study of the evolution of growth rates based on comparisons among wild, landrace, and improved accessions of 19 herbaceous crops grown under common conditions. We also examined the underlying growth components and the influence of crop origin and history on growth evolution. Domestication and improvement did not affect growth consistently, that is growth rates increased or decreased or remained unchanged in different crops. Crops selected for fruits increased the physiological component of growth (net assimilation rate), whereas leaf and seed crops showed larger domestication effects on morphology (leaf mass ratio and specific leaf area). Moreover, climate and phylogeny contributed to explaining the effects of domestication and changes in growth. Crop-specific responses to domestication and improvement suggest that selection for high yield has not consistently changed growth rates. The trade-offs between morpho-physiological traits and the distinct origins and histories of crops accounted for the variability in growth changes. These findings have far-reaching implications for our understanding of crop performance and adaptation.

Epilepsy, antiepileptic drugs, and the risk of major cardiovascular events.

OBJECTIVE: This study was undertaken to determine whether epilepsy and antiepileptic drugs (including enzyme-inducing and non-enzyme-inducing drugs) are associated with major cardiovascular events using population-level, routinely collected data. METHODS: Using anonymized, routinely collected, health care data in Wales, UK, we performed a retrospective matched cohort study (2003-2017) of adults with epilepsy prescribed an antiepileptic drug. Controls were matched with replacement on age, gender, deprivation quintile, and year of entry into the study. Participants were followed to the end of the study for the occurrence of a major cardiovascular event, and survival models were constructed to compare the time to a major cardiovascular event (cardiac arrest, myocardial infarction, stroke, ischemic heart disease, clinically significant arrhythmia, thromboembolism, onset of heart failure, or a cardiovascular death) for individuals in the case group versus the control group. RESULTS: There were 10 241 cases (mean age = 49.6 years, 52.2% male, mean follow-up = 6.1 years) matched to 35 145 controls. A total of 3180 (31.1%) cases received enzyme-inducing antiepileptic drugs, and 7061 (68.9%) received non-enzyme-inducing antiepileptic drugs. Cases had an increased risk of experiencing a major cardiovascular event compared to controls (adjusted hazard ratio = 1.58, 95% confidence interval [CI] = 1.51-1.63, p < .001). There was no notable difference in major cardiovascular events between those treated with enzyme-inducing antiepileptic drugs and those treated with non-enzyme-inducing antiepileptic drugs (adjusted hazard ratio = .95, 95% CI = .86-1.05, p = .300). SIGNIFICANCE: Individuals with epilepsy prescribed antiepileptic drugs are at an increased risk of major cardiovascular events compared with population controls. Being prescribed an enzyme-inducing antiepileptic drug is not associated with a greater risk of a major cardiovascular event compared to treatment with other antiepileptic drugs. Our data emphasize the importance of cardiovascular risk management in the clinical care of people with epilepsy.

Fertile Crescent crop progenitors gained a competitive advantage from large seedlings.

Cereal domestication during the transition to agriculture resulted in widespread food production, but why only certain species were domesticated remains unknown. We tested whether seedlings of crop progenitors share functional traits that could give them a competitive advantage within anthropogenic environments, including higher germination, greater seedling survival, faster growth rates, and greater competitive ability.Fifteen wild grass species from the Fertile Crescent were grown individually under controlled conditions to evaluate differences in growth between cereal crop progenitors and other wild species that were never domesticated. Differences in germination, seedling survival, and competitive ability were measured by growing a subset of these species as monocultures and mixtures.Crop progenitors had greater germination success, germinated more quickly and had greater aboveground biomass when grown in competition with other species. There was no evidence of a difference in seedling survival, but seed size was positively correlated with a number of traits, including net assimilation rates, greater germination success, and faster germination under competition. In mixtures, the positive effect of seed mass on germination success and speed of germination was even more beneficial for crop progenitors than for other wild species, suggesting greater fitness. Thus, selection for larger seeded individuals under competition may have been stronger in the crop progenitors.The strong competitive ability of Fertile Crescent cereal crop progenitors, linked to their larger seedling size, represents an important ecological difference between these species and other wild grasses in the region. It is consistent with the hypothesis that competition within plant communities surrounding human settlements, or under early cultivation, benefited progenitor species, favoring their success as crops.

Incidence, Prevalence and Healthcare Outcomes in Idiopathic Intracranial Hypertension: A Population Study.

OBJECTIVE: To characterise trends in incidence, prevalence, and healthcare outcomes in the idiopathic intracranial hypertension (IIH) population in Wales using routinely collected healthcare data. METHODS: We used and validated primary and secondary care IIH diagnosis codes within the Secure Anonymised Information Linkage databank, to ascertain IIH cases and controls, in a retrospective cohort study between 2003 and 2017. We recorded body mass index (BMI), deprivation quintile, CSF diversion surgery and unscheduled hospital admissions in case and control cohorts. RESULTS: We analysed 35 million patient years of data. There were 1765 cases of IIH in 2017 (85% female). The prevalence and incidence of IIH in 2017 was 76/100,000 and 7.8/100,000/year, a significant increase from 2003 (corresponding figures=12/100,000 and 2.3/100,000/year) (p<0.001). IIH prevalence is associated with increasing BMI and increasing deprivation. The odds ratio for developing IIH in the least deprived quintile compared to the most deprived quintile, adjusted for gender and BMI, was 0.65 (95% CI 0.55 to 0.76). 9% of IIH cases had CSF shunts with less than 0.2% having bariatric surgery. Unscheduled hospital admissions were higher in the IIH cohort compared to controls (rate ratio=5.28, p<0.001) and in individuals with IIH and CSF shunts compared to those without shunts (rate ratio=2.02, p<0.01). CONCLUSIONS: IIH incidence and prevalence is increasing considerably, corresponding to population increases in BMI, and is associated with increased deprivation. This has important implications for healthcare professionals and policy makers given the comorbidities, complications and increased healthcare utilization associated with IIH.

Trait impulsivity in Juvenile Myoclonic Epilepsy.

OBJECTIVE: Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta-analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) moderated by specific seizure characteristics; and (iii) associated with psychiatric adverse effects of antiepileptic drugs (AEDs). METHODS: 322 participants with JME and 126 age and gender-matched controls completed the Barratt's Impulsiveness Scale (BIS-brief) alongside information on seizure history and AED use. We compared group BIS-brief scores and assessed associations of JME BIS-brief scores with seizure characteristics and AED adverse effects. RESULTS: The mean BIS-brief score in JME was 18.1 ± 4.4 compared with 16.2 ± 4.1 in controls (P = 0.0007). Elevated impulsivity was associated with male gender (P = 0.027), frequent absence seizures (P = 0.0004) and lack of morning predominance of myoclonus (P = 0.008). High impulsivity significantly increased the odds of a psychiatric adverse event on levetiracetam (P = 0.036), but not any other psychiatric or somatic adverse effects. INTERPRETATION: Trait impulsivity is elevated in JME and comparable to scores in personality and neurotic disorders. Increased seizure frequency and absence of circadian seizure pattern moderate BIS score, suggesting disruption of both cortico-striatal and thalamocortical networks as a shared mechanism between seizures and impulsivity in JME. These findings warrant consideration of impulsivity as a distinct target of intervention, and as a stratifying factor for AED treatment in JME, and perhaps other types of epilepsy. The role of impulsivity in treatment adherence and psychosocial outcome requires further investigation.

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy.

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Nav channel function.

Fast and furious: Early differences in growth rate drive short-term plant dominance and exclusion under eutrophication.

The reduction of plant diversity following eutrophication threatens many ecosystems worldwide. Yet, the mechanisms by which species are lost following nutrient enrichment are still not completely understood, nor are the details of when such mechanisms act during the growing season, which hampers understanding and the development of mitigation strategies.Using a common garden competition experiment, we found that early-season differences in growth rates among five perennial grass species measured in monoculture predicted short-term competitive dominance in pairwise combinations and that the proportion of variance explained was particularly greater under a fertilization treatment.We also examined the role of early-season growth rate in determining the outcome of competition along an experimental nutrient gradient in an alpine meadow. Early differences in growth rate between species predicted short-term competitive dominance under both ambient and fertilized conditions and competitive exclusion under fertilized conditions.The results of these two studies suggest that plant species growing faster during the early stage of the growing season gain a competitive advantage over species that initially grow more slowly, and that this advantage is magnified under fertilization. This finding is consistent with the theory of asymmetric competition for light in which fast-growing species can intercept incident light and hence outcompete and exclude slower-growing (and hence shorter) species. We predict that the current chronic nutrient inputs into many terrestrial ecosystems worldwide will reduce plant diversity and maintain a low biodiversity state by continuously favoring fast-growing species. Biodiversity management strategies should focus on controlling nutrient inputs and reducing the growth of fast-growing species early in the season.

The morphogenesis of fast growth in plants.

Growth rate represents a fundamental axis of life history variation. Faster growth associated with C4 photosynthesis and annual life history has evolved multiple times, and the resulting diversity in growth is typically explained via resource acquisition and allocation. However, the underlying changes in morphogenesis remain unknown. We conducted a phylogenetic comparative experiment with 74 grass species, conceptualising morphogenesis as the branching and growth of repeating modules. We aimed to establish whether faster growth in C4 and annual grasses, compared with C3 and perennial grasses, came from the faster growth of individual modules or higher rates of module initiation. Morphogenesis produces fast growth in different ways in grasses using C4 and C3 photosynthesis, and in annual compared with perennial species. C4 grasses grow faster than C3 species through a greater enlargement of shoot modules and quicker secondary branching of roots. However, leaf initiation is slower and there is no change in shoot branching. Conversely, faster growth in annuals than perennials is achieved through greater branching and enlargement of shoots, and possibly faster root branching. The morphogenesis of fast growth depends on ecological context, with C4 grasses tending to promote resource capture under competition, and annuals enhancing branching to increase reproductive potential.

Individual differences determine the strength of ecological interactions.

Biotic interactions are central to both ecological and evolutionary dynamics. In the vast majority of empirical studies, the strength of intraspecific interactions is estimated by using simple measures of population size. Biologists have long known that these are crude metrics, with experiments and theory suggesting that interactions between individuals should depend on traits, such as body size. Despite this, it has been difficult to estimate the impact of traits on competitive ability from ecological field data, and this explains why the strength of biotic interactions has empirically been treated in a simplistic manner. Using long-term observational data from four different populations, we show that large Trinidadian guppies impose a significantly larger competitive pressure on conspecifics than individuals that are smaller; in other words, competition is asymmetric. When we incorporate this asymmetry into integral projection models, the predicted size structure is much closer to what we see in the field compared with models where competition is independent of body size. This difference in size structure translates into a twofold difference in reproductive output. This demonstrates how the nature of ecological interactions drives the size structure, which, in turn, will have important implications for both the ecological and evolutionary dynamics.

Long-term outcomes after epilepsy surgery, a retrospective cohort study linking patient-reported outcomes and routine healthcare data.

OBJECTIVE: The objective of the study was to assess the long-term outcomes of epilepsy surgery between 1995 and 2015 in South Wales, UK, linking case note review, postal questionnaire, and routinely collected healthcare data. METHOD: We identified patients from a departmental database and collected outcome data from patient case notes, a postal questionnaire, and the QOLIE-31-P and linked with Welsh routinely collected data in the Secure Anonymised Information Linkage (SAIL) databank. RESULTS: Fifty-seven patients were included. Median age at surgery was 34 years (11-70), median: 24 years (2-56) after onset of habitual seizures. Median follow-up was 7 years (2-19). Twenty-eight (49%) patients were free from disabling seizures (Engel Class 1), 9 (16%) experienced rare disabling seizures (Class 2), 13 (23%) had worthwhile improvements (Class 3), and 7 (12%) had no improvement (Class 4). There was a 30% mean reduction in total antiepileptic drug (AED) load at five years postsurgery. Thirty-eight (66.7%) patients experienced tonic-clonic seizures presurgery verses 8 (14%) at last review. Seizure-free patients self-reported a greater overall quality of life (QOL; QOLIE-31-P) when compared with those not achieving seizure freedom. Seizure-free individuals scored a mean of 67.6/100 (100 is best), whereas those with continuing seizures scored 46.0/100 (p < 0.006). There was a significant decrease in the median rate of hospital admissions for any cause after epilepsy surgery (9.8 days per 1000 patient days before surgery compared with 3.9 after p < 0.005). SIGNIFICANCE: Epilepsy surgery was associated with significant improvements in seizures, a reduced AED load, and an improved QOL that closely correlated with seizure outcomes and reduced hospital admission rates following surgery. Despite this, there was a long delay from onset of habitual seizures to surgery. The importance of long-term follow-up is emphasized in terms of evolving medical needs and health and social care outcomes.

Re-analysis of archaeobotanical remains from pre- and early agricultural sites provides no evidence for a narrowing of the wild plant food spectrum during the origins of agriculture in southwest Asia.

Archaeobotanical evidence from southwest Asia is often interpreted as showing that the spectrum of wild plant foods narrowed during the origins of agriculture, but it has long been acknowledged that the recognition of wild plants as foods is problematic. Here, we systematically combine compositional and contextual evidence to recognise the wild plants for which there is strong evidence of their deliberate collection as food at pre-agricultural and early agricultural sites across southwest Asia. Through sample-by-sample analysis of archaeobotanical remains, a robust link is established between the archaeological evidence and its interpretation in terms of food use, which permits a re-evaluation of the evidence for the exploitation of a broad spectrum of wild plant foods at pre-agricultural sites, and the extent to which this changed during the development of early agriculture. Our results show that relatively few of the wild taxa found at pre- and early agricultural sites can be confidently recognised as contributing to the human diet, and we found no evidence for a narrowing of the plant food spectrum during the adoption of agriculture. This has implications for how we understand the processes leading to the domestication of crops, and points towards a mutualistic relationship between people and plants as a driving force during the development of agriculture.

Why So Variable: Can Genetic Variance in Flowering Thresholds Be Maintained by Fluctuating Selection?

We use integral projection models (IPMs) and individual-based simulations to study the evolution of genetic variance in two monocarpic plant systems. Previous approaches combining IPMs with an adaptive dynamics-style invasion analysis predicted that genetic variability in the size threshold for flowering will not be maintained, which conflicts with empirical evidence. We ask whether this discrepancy can be resolved by making more realistic assumptions about the underlying genetic architecture, assuming a multilocus quantitative trait in an outcrossing diploid species. To do this, we embed the infinitesimal model of quantitative genetics into an IPM for a size-structured cosexual plant species. The resulting IPM describes the joint dynamics of individual size and breeding value of the evolving trait. We apply this general framework to the monocarpic perennials Oenothera glazioviana and Carlina vulgaris. The evolution of heritable variation in threshold size is explored in both individual-based models (IBMs) and IPMs, using a mutation rate modifier approach. In the Oenothera model, where the environment is constant, there is selection against producing genetically variable offspring. In the Carlina model, where the environment varies between years, genetically variable offspring provide a selective advantage, allowing the maintenance of genetic variability. The contrasting predictions of adaptive dynamics and quantitative genetics models for the same system suggest that fluctuating selection may be more effective at maintaining genetic variation than previously thought.

Using natural language processing to extract structured epilepsy data from unstructured clinic letters: development and validation of the ExECT (extraction of epilepsy clinical text) system.

OBJECTIVE: Routinely collected healthcare data are a powerful research resource but often lack detailed disease-specific information that is collected in clinical free text, for example, clinic letters. We aim to use natural language processing techniques to extract detailed clinical information from epilepsy clinic letters to enrich routinely collected data. DESIGN: We used the general architecture for text engineering (GATE) framework to build an information extraction system, ExECT (extraction of epilepsy clinical text), combining rule-based and statistical techniques. We extracted nine categories of epilepsy information in addition to clinic date and date of birth across 200 clinic letters. We compared the results of our algorithm with a manual review of the letters by an epilepsy clinician. SETTING: De-identified and pseudonymised epilepsy clinic letters from a Health Board serving half a million residents in Wales, UK. RESULTS: We identified 1925 items of information with overall precision, recall and F1 score of 91.4%, 81.4% and 86.1%, respectively. Precision and recall for epilepsy-specific categories were: epilepsy diagnosis (88.1%, 89.0%), epilepsy type (89.8%, 79.8%), focal seizures (96.2%, 69.7%), generalised seizures (88.8%, 52.3%), seizure frequency (86.3%-53.6%), medication (96.1%, 94.0%), CT (55.6%, 58.8%), MRI (82.4%, 68.8%) and electroencephalogram (81.5%, 75.3%). CONCLUSIONS: We have built an automated clinical text extraction system that can accurately extract epilepsy information from free text in clinic letters. This can enhance routinely collected data for research in the UK. The information extracted with ExECT such as epilepsy type, seizure frequency and neurological investigations are often missing from routinely collected data. We propose that our algorithm can bridge this data gap enabling further epilepsy research opportunities. While many of the rules in our pipeline were tailored to extract epilepsy specific information, our methods can be applied to other diseases and also can be used in clinical practice to record patient information in a structured manner.