The impact of imprecisely measured covariates on estimating gene-environment interactions

BACKGROUND The effects of measurement error in epidemiological exposures and confounders on estimated effects of exposure are well described, but the effects on estimates for gene-environment interactions has received rather less attention. In particular, the effects of confounder measurement error on gene-environment interactions are unknown. METHODS We investigate these effects using simulated data and illustrate our results with a practical example in nutrition epidemiology. RESULTS We show that the interaction regression coefficient is unchanged by confounder measurement error under certain conditions, but biased by exposure measurement error. We also confirm that confounder measurement error can lead to estimated effects of exposure biased either towards or away from the null, depending on the correlation structure, with associated effects on type II errors. CONCLUSION Whilst measurement error in confounders does not lead to bias in interaction coefficients, it may still lead to bias in the estimated effects of exposure. There may still be cost implications for epidemiological studies that need to calibrate all error-prone covariates against a valid reference, in addition to the exposure, to reduce the effects of confounder measurement erro

Growth, current size and the role of the 'reversal paradox' in the foetal origins of adult disease: an illustration using vector geometry

BACKGROUND Numerous studies have reported inverse associations between birth weight and a range of diseases in later life. These have led to the development of the 'foetal origins of adult disease hypothesis'. However, many such studies have only been able to demonstrate a statistically significant association between birth weight and disease in later life by adjusting for current size. This has been interpreted as evidence that the impact of low birth weight on subsequent disease is somehow dependent on subsequent weight gain, and has led to a broadening of the hypothesis into the 'developmental origins of health and disease'. Unfortunately, much of the epidemiological evidence used for both of these interpretations is prone to a statistical artefact known as the 'reversal paradox'. The aim of this paper is to illustrate why, using vector geometry. MATERIALS AND METHODS This paper introduces the key concepts of vector geometry as applied to multiple regression analysis. This approach is then used to illustrate the similar statistical problems encountered when adjusting for current size or growth when exploring the association between birth weight and disease in later life. RESULTS Geometrically, the three covariates – birth size, growth, and current size – span only 2-dimensional space. Regressing disease in later life (i.e. the outcome variable) on any two of these covariates equates to projecting the disease variable onto the plane spanned by the three covariate vectors. The three possible regression models – where any two covariates are considered – are therefore equivalent and yield exactly the same model fit (R2). CONCLUSION Vector geometry illustrates why it is impossible to differentiate between the effects of growth from the effects of current size in studies exploring the relationship between size at birth and subsequent disease. For similar reasons, it is impossible to differentiate between the effects of growth and the effects of birth weight. Assessing the 'independent' impact of growth on later disease by adjusting for either birth weight or current size is therefore illusory

Joint disease mapping using six cancers in the Yorkshire region of England

OBJECTIVES: The aims of this study were to model jointly the incidence rates of six smoking related cancers in the Yorkshire region of England, to explore the patterns of spatial correlation amongst them, and to estimate the relative weight of smoking and other shared risk factors for the relevant disease sites, both before and after adjustment for socioeconomic background (SEB). METHODS: Data on the incidence of oesophagus, stomach, pancreas, lung, kidney, and bladder cancers between 1983 and 2003 were extracted from the Northern & Yorkshire Cancer Registry database for the 532 electoral wards in the Yorkshire region. Using postcode of residence, each case was assigned an area-based measure of SEB using the Townsend index. Standardised incidence ratios (SIRs) were calculated for each cancer site and their correlations investigated. The joint analysis of the spatial variation in incidence used a Bayesian shared-component model. Three components were included to represent differences in smoking (for all six sites), bodyweight/obesity (for oesophagus, pancreas and kidney cancers) and diet/alcohol consumption (for oesophagus and stomach cancers). RESULTS: The incidence of cancers of the oesophagus, pancreas, kidney, and bladder was relatively evenly distributed across the region. The incidence of stomach and lung cancers was more clustered around the urban areas in the south of the region, and these two cancers were significantly associated with higher levels of area deprivation. The incidence of lung cancer was most impacted by adjustment for SEB, with the rural/urban split becoming less apparent. The component representing smoking had a larger effect on cancer incidence in the eastern part of the region. The effects of the other two components were small and disappeared after adjustment for SEB. CONCLUSIONS: This study demonstrates the feasibility of joint disease modelling using data from six cancer sites. Incidence estimates are more precise than those obtained without smoothing. This methodology may be an important tool to help authorities evaluate healthcare system performance and the impact of policies

Resonance studies of artificial earth satellites

Orbit determination from artificial satellite observations is a key process in obtaining information about the Earth and its environment. A study of the perturbations experienced by these satellites enables knowledge to be gained of the upper atmosphere, the gravity field, ocean tides, solid-Earth tides and solar radiation. The gravity field is expressed as a double infinite series of associated Legendre functions (tesseral harmonics). In contemporary global gravity field models the overall geoid is well determined. An independent check on these gravity field harmonics of a particular order may be made by analysis of satellites that pass through resonance of that order. For such satellites the perturbations of the orbital elements close to resonance are analysed to derive lumped harmonic coefficients. The orbital parameters of 1984-106A have been determined at 43 epochs, during which time the satellite was close to 14th order resonance. Analysis of the inclination and eccentricity yielded 6 lumped harmonic coefficients of order 14 whilst analysis of the mean motion yielded additional pairs of lumped harmonics of orders 14, 28 and 42, with the 14th order harmonics superseding those obtained from analysis of the inclination. This thesis concentrates in detail on the theoretical changes of a near-circular satellite orbit perturbed by the Earth's gravity field under the influence of minimal air-drag whilst in resonance with the Earth. The satellite 1984-106A experienced the interesting property of being temporarily trapped with respect to a secondary resonance parameter due to the low air-drag in 1987. This prompted the theoretical investigation of such a phenomenon. Expressions obtained for the resonance parameter led to the determination of 8 lumped harmonic coefficients, coincidental to those already obtained. All the derived lumped harmonic values arc used to test the accuracy of contemporary gravity field models and the underlying theory in this thesis

Response to: Simpson’s Paradox is suppression, but Lord’s Paradox is neither: clarification of and correction to Tu, Gunnell, and Gilthorpe (2008) by Nickerson CA & Brown NJL (https://doi.org/10.1186/1742-7622-5-2)

We commend Nickerson and Brown on their insightful exposition of the mathematical algebra behind Simpson’s paradox, suppression and Lord’s paradox; we also acknowledge there can be differences in how Lord’s paradox is approached analytically, compared to Simpson’s paradox and suppression, though not in every example of Lord’s paradox. Furthermore, Simpson’s paradox, suppression and Lord’s paradox ask the same contextual questions, seeking to understand if statistical adjustment is valid and meaningful, identifying which analytical option is correct. In our exposition of this, we focus on the perspective of context, which must invoke causal thinking. From a causal thinking perspective, Simpson’s paradox, suppression and Lord’s paradox present very similar analytical challenges

A randomized-controlled trial of low-dose doxycycline for periodontitis in smokers

Background/Aim : Tobacco use reduces the effect of non-surgical periodontal therapy. Host-modulation with low-dose doxycycline (LDD) might favour repair and promote an improved treatment response. The aim of this study was to investigate the effect of LDD in smokers on non-surgical periodontal therapy. Material and Methods : This was a parallel arm, randomized, identical placebo-controlled trial with masking of examiner, care-giver, participant and statistician and 6 months of follow-up. Patients received non-surgical therapy and 3 months of test or control drug. Statistical analysis used both conventional methods and multilevel modelling. Results : Eighteen control and 16 test patients completed the study. The velocity of change was statistically greater for the test group for clinical attachment level −0.19 mm/month (95% CI=−0.34, 0.04; p =0.012) and probing depth 0.30 mm/month (95% CI=−0.42, −0.17; p <0.001). However, no differences were observed for absolute change in clinical or biochemical markers at 6 months. Conclusions : This study does not provide evidence of a benefit of using LDD as an adjunct to non-surgical periodontal therapy in smokers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74791/1/j.1600-051X.2007.01058.x.pd

A Model for the Analysis of Caries Occurrence in Primary Molar Tooth Surfaces

Recently methods of caries quantification in the primary dentition have moved away from summary ‘whole mouth’ measures at the individual level to methods based on generalised linear modelling (GLM) approaches or survival analysis approaches. However, GLM approaches based on logistic transformation fail to take into account the time-dependent process of tooth/surface survival to caries. There may also be practical difficulties associated with casting parametric survival-based approaches in a complex multilevel hierarchy and the selection of an optimal survival distribution, while non-parametric survival methods are not generally suitable for the assessment of supplementary information recorded on study participants. In the current investigation, a hybrid semi-parametric approach comprising elements of survival-based and GLM methodologies suitable for modelling of caries occurrence within fixed time periods is assessed, using an illustrative multilevel data set of caries occurrence in primary molars from a cohort study, with clustering of data assumed to occur at surface and tooth levels. Inferences of parameter significance were found to be consistent with previous parametric survival-based analyses of the same data set, with gender, socio-economic status, fluoridation status, tooth location, surface type and fluoridation status-surface type interaction significantly associated with caries occurrence. The appropriateness of the hierarchical structure facilitated by the hybrid approach was also confirmed. Hence the hybrid approach is proposed as a more appropriate alternative to primary caries modelling than non-parametric survival methods or other GLM-based models, and as a practical alternative to more rigorous survival-based methods unlikely to be fully accessible to most researchers

Chick Lrrn2, a novel downstream effector of Hoxb1 and Shh, functions in the selective targeting of rhombomere 4 motor neurons

<p>Abstract</p> <p>Background</p> <p>Capricious is a <it>Drosophila </it>adhesion molecule that regulates specific targeting of a subset of motor neurons to their muscle target. We set out to identify whether one of its vertebrate homologues, Lrrn2, might play an analogous role in the chick.</p> <p>Results</p> <p>We have shown that <it>Lrrn2 </it>is expressed from early development in the prospective rhombomere 4 (r4) of the chick hindbrain. Subsequently, its expression in the hindbrain becomes restricted to a specific group of motor neurons, the branchiomotor neurons of r4, and their pre-muscle target, the second branchial arch (BA2), along with other sites outside the hindbrain. Misexpression of the signalling molecule Sonic hedgehog (Shh) via <it>in ovo </it>electroporation results in upregulation of <it>Lrrn2 </it>exclusively in r4, while the combined expression of Hoxb1 and Shh is sufficient to induce ectopic <it>Lrrn2 </it>in r1/2. Misexpression of Lrrn2 in r2/3 results in axonal rerouting from the r2 exit point to the r4 exit point and BA2, suggesting a direct role in motor axon guidance.</p> <p>Conclusion</p> <p>Lrrn2 acts downstream of Hoxb1 and plays a role in the selective targeting of r4 motor neurons to BA2.</p

Intervention differential effects and regression to the mean in studies where sample selection is based on the initial value of the outcome variable: an evaluation of methods illustrated in weight-management studies

© 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Background: Intervention differential effects (IDEs) occur where changes in an outcome depend upon the initial values of that outcome. Although methods to identify IDEs are well documented, there remains a lack of understanding about the circumstances under which these methods are robust. One context that has not been explored is the identification of intervention differential effect in studies where sample selection is based on the initial value of the outcome being evaluated. We hypothesise that, in such settings, established methods for detecting IDEs will struggle to discriminate these from regression to the mean. Methods: Using simulated datasets of weight-loss intervention programmes that recruit according to initial body mass index, we explore the reliability of Oldham's method and multilevel modelling (MLM) to detect IDEs. Results: In datasets simulated with no IDE, Oldham's method and MLM yield Type I error rates >90%, confirming that threshold selection/truncation leads to bias due to regression to the mean. Type I error rates return close to 5% for both methods when a control group is introduced. Conclusions: Oldham's method and MLM can robustly detect IDEs in this setting, but only if analyses incorporate a control group for comparison

Placental blood transfusion in newborn babies reaches a plateau after 140 s: Further analysis of longitudinal survey of weight change

Objective: With the introduction of active management of the third stage of labour in the 1960s, it became usual practice to clamp and cut the umbilical cord immediately following birth. The timing of this cord clamping is controversial, as blood may beneficially be transferred to the baby if clamping of the cord is delayed slightly. There is no agreement, however, on how long the delay should be before clamping the cord. This study aimed to establish when blood ceased to flow in the umbilical cord to determine how long to delay clamping of the umbilical cord following delivery of the term newborn to maximise placental transfusion. Methods: This observational study collected longitudinal weight measurements set in a hospital labour ward. A total of 26 mothers at term and their singleton babies participated in the study. In this reanalysis, the velocity of weight change over the first minutes of life determined by functional data analysis was estimated. Results: We found that the flow velocity in the umbilical cord was on average 0 at 125 s after placing the baby on the scales, which was typically 140 s after birth. Conclusions: To maximise placental transfusion, cord clamping should be delayed for at least 140 s following birth of the baby