Automated development of clinical prediction models using genetic programming

Genetic programming is an Evolutionary Computing technique, inspired by biological evolution, capable of discovering complex non-linear patterns in large datasets. Genetic programming is a general methodology, the specific implementation of which requires development of several different specific elements such as problem representation, fitness, selection and genetic variation. Despite the potential advantages of genetic programming over standard statistical methods, its applications to survival analysis are at best rare, primarily because of the difficulty in handling censored data. The aim of this work was to develop a genetic programming approach for survival analysis and demonstrate its utility for the automatic development of clinical prediction models using cardiovascular disease as a case study. We developed a tree-based untyped steady-state genetic programming approach for censored longitudinal data, comparing its performance to the de facto statistical method—Cox regression—in the development of clinical prediction models for the prediction of future cardiovascular events in patients with symptomatic and asymptomatic cardiovascular disease, using large observational datasets. We also used genetic programming to examine the prognostic significance of different risk factors together with their non-linear combinations for the prognosis of health outcomes in cardiovascular disease. These experiments showed that Cox regression and the developed steady-state genetic programming approach produced similar results when evaluated in common validation datasets. Despite slight relative differences, both approaches demonstrated an acceptable level of discriminative and calibration at a range of times points. Whilst the application of genetic programming did not provide more accurate representations of factors that predict the risk of both symptomatic and asymptomatic cardiovascular disease when compared with existing methods, genetic programming did offer comparable performance. Despite generally comparable performance, albeit in slight favour of the Cox model, the predictors selected for representing their relationships with the outcome were quite different and, on average, the models developed using genetic programming used considerably fewer predictors. The results of the genetic programming confirm the prognostic significance of a small number of the most highly associated predictors in the Cox modelling; age, previous atherosclerosis, and albumin for secondary prevention; age, recorded diagnosis of ’other’ cardiovascular disease, and ethnicity for primary prevention in patients with type 2 diabetes. When considered as a whole, genetic programming did not produce better performing clinical prediction models, rather it utilised fewer predictors, most of which were the predictors that Cox regression estimated be most strongly associated with the outcome, whilst achieving comparable performance. This suggests that genetic programming may better represent the potentially non-linear relationship of (a smaller subset of) the strongest predictors. To our knowledge, this work is the first study to develop a genetic programming approach for censored longitudinal data and assess its value for clinical prediction in comparison with the well-known and widely applied Cox regression technique. Using empirical data this work has demonstrated that clinical prediction models developed by steady-state genetic programming have predictive ability comparable to those developed using Cox regression. The genetic programming models were more complex and thus more difficult to validate by domain experts, however these models were developed in an automated fashion, using fewer input variables, without the need for domain specific knowledge and expertise required to appropriately perform survival analysis. This work has demonstrated the strong potential of genetic programming as a methodology for automated development of clinical prediction models for diagnostic and prognostic purposes in the presence of censored data. This work compared untuned genetic programming models that were developed in an automated fashion with highly tuned Cox regression models that was developed in a very involved manner that required a certain amount of clinical and statistical expertise. Whilst the highly tuned Cox regression models performed slightly better in validation data, the performance of the automatically generated genetic programming models were generally comparable. The comparable performance demonstrates the utility of genetic programming for clinical prediction modelling and prognostic research, where the primary goal is accurate prediction. In aetiological research, where the primary goal is to examine the relative strength of association between risk factors and the outcome, then Cox regression and its variants remain as the de facto approach

Risk of cardiovascular events, arrhythmia and all-cause mortality associated with clarithromycin versus alternative antibiotics prescribed for respiratory tract infections: a retrospective cohort study

Objective: To determine whether treatment with clarithromycin for respiratory tract infections was associated with an increased risk of cardiovascular (CV) events, arrhythmias or all-cause mortality compared with other antibiotics. Design: Retrospective cohort design comparing clarithromycin monotherapy for lower (LRTI) or upper respiratory tract infection (URTI) with other antibiotic monotherapies for the same indication. Setting: Routine primary care data from the UK Clinical Practice Research Datalink and inpatient data from the Hospital Episode Statistics (HES). Participants: Patients aged ≥35 years prescribed antibiotic monotherapy for LRTI or URTI 1998–2012 and eligible for data linkage to HES. Main outcome measures: The main outcome measures were: adjusted risk of first-ever CV event, within 37 days of initiation, in commonly prescribed antibiotics compared with clarithromycin. Secondarily, adjusted 37-day risks of first-ever arrhythmia and allcause mortality. Results: Of 700 689 treatments for LRTI and eligible for the CV analysis, there were 2071 CV events (unadjusted event rate: 29.6 per 10 000 treatments). Of 691 998 eligible treatments for URTI, there were 688 CV events (9.9 per 10 000 treatments). In LRTI and URTI, there were no significant differences in CV risk between clarithromycin and all other antibiotics combined: OR=1.00 (95% CI 0.82 to 1.22) and 0.82 (0.54 to 1.25), respectively. Adjusted CV risk in LRTI versus clarithromycin ranged from OR=1.42 (cefalexin; 95% CI 1.08 to 1.86) to 0.92 (doxycycline; 0.64 to 1.32); in URTI, from 1.17 (co-amoxiclav; 0.68 to 2.01) to 0.67 (erythromycin; 0.40 to 1.11). Adjusted mortality risk versus clarithromycin in LRTI ranged from 0.42 to 1.32; in URTI, from 0.75 to 1.43. For arrhythmia, adjusted risks in LRTI ranged from 0.68 to 1.05; in URTI, from 0.70 to 1.22. Conclusions: CV events were more likely after LRTI than after URTI. When analysed by specific indication, CV risk associated with clarithromycin was no different to other antibiotics

Estimation of health-related utility (EQ-5D index) in subjects with seasonal allergic rhinoconjunctivitis to evaluate health gain associated with sublingual grass allergen immunotherapy

Background: Grass allergen immunotherapy (AIT) reduces symptom severity in seasonal allergic rhinoconjunctivitis (ARC) but its impact on general health-related utility has not been characterised for the purposes of economic evaluation. The aim of this study was to model the preferred measure of utility, EQ-5D index, from symptom severity and estimate incremental quality adjusted life years (QALYs) associated with SQ-standardised grass immunotherapy tablet (GRAZAX®, 75,000 SQ-T/2,800 BAU, ALK, Denmark). Methods: Data were analysed from five consecutive pollen seasons in a randomised placebo controlled trial of GRAZAX®. Binomial and Gaussian mixed effects modelling related weekly EQ-5D index score to daily symptom and medication scores (DSS & DMS respectively). In turn, daily EQ-5D index was estimated from ARC symptoms and medication use. Results: DSS and DMS were the principal predictors of ‘perfect’ health (EQ-5D = 1.000; binomial) and ‘imperfect’ health (EQ-5D < 1.000; Gaussian). Each unit increase in DSS and DMS reduced the odds of ‘perfect’ health (EQ-5D = 1.000) by 27% and 16% respectively, and reduced ‘imperfect’ health by 0.17 and 0.13, respectively. Gender remained the only other significant main fixed effect (Male odds ratio [OR] = 1.82). Incremental estimated EQ-5D index utility for GRAZAX® was observed from day -30 to day +70 of the pooled pollen season; mean daily utility for GRAZAX® = 0.938 units (95%CI 0.932-0.943) vs. 0.914 (0.907-0.921) for placebo, an incremental difference of 0.0238 (p < 0.001). This translates into an incremental 0.0324 Quality Adjusted Life Years over the five year study period. Conclusions: ARC symptoms and medication use are the main predictors of EQ-5D index. The incremental QALYs observed for GRAZAX® may not fully describe the health benefits of this treatment, suggesting that economic modelling may be conservative

An empirical approach to predicting heat transfer within single- and twin-skin automotive exhaust systems

This paper describes the further development of an exhaust system model based on the experimental characterization of heat transfer in a series of different pipe sections. Building on previous work published in this journal by the present authors, this study was undertaken to improve the operating range, accuracy, and usability of the original model as well as to introduce the ability to model twin-skin exhaust sections with an air gap. Convective heat transfer relationships for nine stainless steel exhaust bend sections of various wall thicknesses and radii were experimentally characterized over a range of steady state conditions. In each case a correlation between the observed Reynolds number Re and the Nusselt number Nu was developed. Based on measured experimental data, a generic model was built using MATLAB/Simulink; this model is capable of predicting the relationship between the Nusselt number and the Reynolds number for previously unseen pipe geometries falling within the experimental design range. To develop the usefulness of the model further, 15 twin-skin test sections, intended to represent a range of geometries applicable to production automotive gasoline exhaust systems, were also fabricated and characterized. Within the model, both skins of each pipe section were split into five axial elements and five radial elements with the inner and outer skins linked via the modelling of free convection and radiation between them. The predicted Reynolds–Nusselt relationships for each bend section and twin-skin configuration were validated using transient experimental data over a portion of the US06 drive cycle. The final model demonstrated an improved accuracy of exhaust gas temperature predictions, compared with the previous model iterations, with typical errors of less than ±1 per cent and a mean error over the US06 cycle of +0.2 per cent. </jats:p

Detailed quantification of glacier elevation and mass changes in South Georgia

Most glaciers in South America and on the Antarctic Peninsula are retreating and thinning. They are considered strong contributors to global sea level rise. However, there is a lack of glacier mass balance studies in other areas of the Southern Hemisphere, such as the surrounding Antarctic Islands. Here, we present a detailed quantification of the 21st century glacier elevation and mass changes for the entire South Georgia Island using bi-static synthetic aperture radar interferometry between 2000 and 2013. The results suggest a significant mass loss since the beginning of the present century. We calculate an average glacier mass balance of -1.04 0.09 m w.e.a(-1) and a mass loss rate of 2.28 0.19 Gt a(-1) (2000-2013), contributing 0.006 0.001 mm a(-1) to sea-level rise. Additionally, we calculate a subaqueous mass loss of 0.77 0.04 Gt a(-1) (2003-2016), with an area change at the marine and lake-terminating glacier fronts of -6.58 0.33 km(2) a(-1), corresponding to similar to 4% of the total glacier area. Overall, we observe negative mass balance rates in South Georgia, with the highest thinning and retreat rates at the large outlet glaciers located at the north-east coast. Although the spaceborne remote sensing dataset analysed in this research is a key contribution to better understanding of the glacier changes in South Georgia, more detailed field measurements, glacier dynamics studies or further long-term analysis with high-resolution regional climate models are required to precisely identify the forcing factors

High ions towards white dwarfs: circumstellar line shifts and stellar temperature

Based on a compilation of OVI, CIV, SiIV and NV data from IUE, FUSE, GHRS, STIS, and COS, we derive an anti- correlation between the stellar temperature and the high ion velocity shift w.r.t. to the photosphere, with positive (resp. negative) velocity shifts for the cooler (resp. hotter) white dwarfs. This trend probably reflects more than a single process, however such a dependence on the WD's temperature again favors a CS origin for a very large fraction of those ion absorptions, previously observed with IUE, HST-STIS, HST-GHRS, FUSE, and now COS, selecting objects for which absorption line radial velocities, stellar effective temperature and photospheric velocity can be found in the literature. Interestingly, and gas in near-equilibrium in the star vicinity. It is also probably significant that the temperature that corresponds to a null radial velocity, i.e. \simeq 50,000K, also corresponds to the threshold below which there is a dichotomy between pure or heavy elements atmospheres as well as some temperature estimates for and a form of balance between radiation pressure and gravitation. This is consistent with ubiquitous evaporation of orbiting dusty material. Together with the fact that the fraction of stars with (red-or blue-) shifted lines and the fraction of stars known to possess heavy species in their atmosphere are of the same order, such a velocity-temperature relationship is consistent with quasi-continuous evaporation of orbiting CS dusty material, followed by accretion and settling down in the photosphere. In view of these results, ion measurements close to the photospheric or the IS velocity should be interpreted with caution, especially for stars at intermediate temperatures. While tracing CS gas, they may be erroneously attributed to photospheric material or to the ISM, explaining the difficulty of finding a coherent pattern of the high ions in the local IS 3D distribution.Comment: Accepted by A&A. Body of paper identical to v1. This submission has a more appropriate truncation of the original abstrac

Protein trafficking through the endosomal system prepares intracellular parasites for a home invasion

Toxoplasma (toxoplasmosis) and Plasmodium (malaria) use unique secretory organelles for migration, cell invasion, manipulation of host cell functions, and cell egress. In particular, the apical secretory micronemes and rhoptries of apicomplexan parasites are essential for successful host infection. New findings reveal that the contents of these organelles, which are transported through the endoplasmic reticulum (ER) and Golgi, also require the parasite endosome-like system to access their respective organelles. In this review, we discuss recent findings that demonstrate that these parasites reduced their endosomal system and modified classical regulators of this pathway for the biogenesis of apical organelles

Estimation of health-related utility (EQ-5D index) in subjects with seasonal allergic rhinoconjunctivitis to evaluate health gain associated with sublingual grass allergen immunotherapy

Abstract Background: Grass allergen immunotherapy (AIT) reduces symptom severity in seasonal allergic rhinoconjunctivitis (ARC) but its impact on general health-related utility has not been characterised for the purposes of economic evaluation. The aim of this study was to model the preferred measure of utility, EQ-5D index, from symptom severity and estimate incremental quality adjusted life years (QALYs) associated with SQ-standardised grass immunotherapy tablet (GRAZAX®, 75,000 SQ-T/2,800 BAU, ALK, Denmark). Methods: Data were analysed from five consecutive pollen seasons in a randomised placebo controlled trial of GRAZAX®. Binomial and Gaussian mixed effects modelling related weekly EQ-5D index score to daily symptom and medication scores (DSS &amp; DMS respectively). In turn, daily EQ-5D index was estimated from ARC symptoms and medication use

Time to complete contemporary dental procedures – estimates from a cross-sectional survey of the dental team

Background: There are few contemporary studies on the time taken to complete dental procedures, those most heavily relied on in the United Kingdom date back to 1999. Objectives: This work aimed to establish how long members of the dental team took to complete specific dental procedures, relevant to their scope of practice. Methods: Data were collected via a purposive sample of 96 dentists, dental hygienists/therapists and dental nurses. Via an online survey, participants were asked to state the mean, minimum and maximum time they estimated that they took to complete individual dental procedures. Results: The mean time taken to complete procedures common to both dentists and dental hygienists/therapists ranged from 3.7 to 4 min respectively for clinical note reading prior to seeing patients to 30.1 and 28 min to undertake root surface debridement. There were no significant differences between the time taken by dentists and dental hygienists/therapists to treat adult patients. However, in all but one procedure, dental hygienists/therapists reported taking longer (p = 0.04) to treat child patients. Conclusions: The data provided here represent an up to date assessment of the time taken to complete specific tasks by different members of the dental team. These data will be of value to service planners and commissioners interested in evolving a dental care system that employs a greater degree of skill-mix and preventively oriented care