Paul H C Eilers

Wageningen UR, Wageningen, Gelderland, Netherlands

Are you Paul H C Eilers?

Claim your profile

Publications (183)563.76 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding the genetic basis of plant development in potato requires a proper characterization of plant morphology over time. Parameters related to different aging stages can be used to describe the developmental processes. It is attractive to map these traits simultaneously in a QTL analysis; because the power to detect a QTL will often be improved and it will be easier to identify pleiotropic QTLs. We included complex, agronomic traits together with plant development parameters in a multi-trait QTL analysis. First, the results of our analysis led to coherent insight into the genetic architecture of complex traits in potato. Secondly, QTL for parameters related to plant development were identified. Thirdly, pleiotropic regions for various types of traits were identified. Emergence, number of main stems, number of tubers and yield were explained by 9, 5, 4 and 6 QTL, respectively. These traits were measured once during the growing season. The genetic control of flowering, senescence and plant height, which were measured at regular time intervals, was explained by 9, 10 and 12 QTL, respectively. Genetic relationships between aboveground and belowground traits in potato were observed in 14 pleiotropic QTL. Some of our results suggest the presence of QTL-by-Environment interactions. Therefore, additional studies comparing development under different photoperiods are required to investigate the plasticity of the crop.
    Euphytica 07/2015; 204(1). DOI:10.1007/s10681-015-1431-2 · 1.69 Impact Factor
  • Silvia Rizzi, Jutta Gampe, Paul H C Eilers
    [Show abstract] [Hide abstract]
    ABSTRACT: Ungrouping binned data can be desirable for many reasons: Bins can be too coarse to allow for accurate analysis; comparisons can be hindered when different grouping approaches are used in different histograms; and the last interval is often wide and open-ended and, thus, covers a lot of information in the tail area. Age group-specific disease incidence rates and abridged life tables are examples of binned data. We propose a versatile method for ungrouping histograms that assumes that only the underlying distribution is smooth. Because of this modest assumption, the approach is suitable for most applications. The method is based on the composite link model, with a penalty added to ensure the smoothness of the target distribution. Estimates are obtained by maximizing a penalized likelihood. This maximization is performed efficiently by a version of the iteratively reweighted least-squares algorithm. Optimal values of the smoothing parameter are chosen by minimizing Akaike's Information Criterion. We demonstrate the performance of this method in a simulation study and provide several examples that illustrate the approach. Wide, open-ended intervals can be handled properly. The method can be extended to the estimation of rates when both the event counts and the exposures to risk are grouped. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.
    American journal of epidemiology 06/2015; DOI:10.1093/aje/kwv020 · 4.98 Impact Factor
  • Ron Wehrens, Tom Bloemberg, Paul Eilers
    [Show abstract] [Hide abstract]
    ABSTRACT: Alignment of peaks across samples is a difficult but unavoidable step in the data analysis for all analytical techniques containing a separation step like chromatography. Important application examples are the fields of metabolomics and proteomics. Parametric time warping (PTW) has already shown to be very useful in these fields because of the highly restricted form of the warping functions, avoiding overfitting. Here, we describe a new formulation of PTW, working on peak-picked features rather than on complete profiles. Not only does this allow for a much more smooth integration in existing pipelines, it also speeds up the (already among the fastest) algorithm by orders of magnitude. Using two publicly available data sets we show the potential of the new approach. The first set is a LC-DAD data set of grape samples, and the second an LC-MS data set of apple extracts. Parametric time warping of peak lists is implemented in the ptw package, version 1.9.1 and onwards, available from Github ( and CRAN ( The package also contains a vignette, providing more theoretical details and scripts to reproduce the results below. © The Author (2015). Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Bioinformatics 05/2015; DOI:10.1093/bioinformatics/btv299 · 4.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In many settings of empirical interest, time variation in the distribution parameters is important for capturing the dynamic behaviour of time series processes. Although the fitting of heavy tail distributions has become easier due to computational advances, the joint and explicit modelling of time-varying conditional skewness and kurtosis is a challenging task. We propose a class of parameter-driven time series models referred to as the generalized structural time series (GEST) model. The GEST model extends Gaussian structural time series models by a) allowing the distribution of the dependent variable to come from any parametric distribution, including highly skewed and kurtotic distributions (and mixed distributions) and b) expanding the systematic part of parameter-driven time series models to allow the joint and explicit modelling of all the distribution parameters as structural terms and (smoothed) functions of independent variables. The paper makes an applied contribution in the development of a fast local estimation algorithm for the evaluation of a penalised likelihood function to update the distribution parameters over time without the need for evaluation of a high-dimensional integral based on simulation methods.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Bayesian approach has become increasingly popular because it allows to model quite complex models via Markov chain Monte Carlo (MCMC) sampling. However, it is also recognized nowadays that MCMC sampling can become computationally prohibitive when a complex model needs to be fit to a large data set. To overcome this problem, we applied and extended a recently proposed two-stage approach to model a complex hierarchical data structure of glaucoma patients who participate in an ongoing Dutch study. Glaucoma is one of the leading causes of blindness in the world. In order to detect deterioration at an early stage, a model for predicting visual fields (VF) in time is needed. Hence, the true underlying VF progression can be determined, and treatment strategies can then be optimized to prevent further VF loss. Since we were unable to fit these data with the classical one-stage approach upon which the current popular Bayesian software is based, we made use of the two-stage Bayesian approach. The considered hierarchical longitudinal model involves estimating a large number of random effects and deals with censoring and high measurement variability. In addition, we extended the approach with tools for model evaluation
  • [Show abstract] [Hide abstract]
    ABSTRACT: Most longitudinal growth curve models evaluate the evolution of each of the anthropometric measurements separately. When applied to a 'reference population', this exercise leads to univariate reference curves against which new individuals can be evaluated. However, growth should be evaluated in totality, that is, by evaluating all body characteristics jointly. Recently, Cole et al. suggested the Superimposition by Translation and Rotation (SITAR) model, which expresses individual growth curves by three subject-specific parameters indicating their deviation from a flexible overall growth curve. This model allows the characterization of normal growth in a flexible though compact manner. In this paper, we generalize the SITAR model in a Bayesian way to multiple dimensions. The multivariate SITAR model allows us to create multivariate reference regions, which is advantageous for prediction. The usefulness of the model is illustrated on longitudinal measurements of embryonic growth obtained in the first semester of pregnancy, collected in the ongoing Rotterdam Predict study. Further, we demonstrate how the model can be used to find determinants of embryonic growth. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Statistics in Medicine 01/2015; 34(8). DOI:10.1002/sim.6411 · 2.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The beneficial health effects of fruits and vegetables have been attributed to their polyphenol content. These compounds undergo many bioconversions in the body. Modeling polyphenol exposure of humans upon intake is a prerequisite for understanding the modulating effect of the food matrix and the colonic microbiome. This modeling is not a trivial task and requires a careful integration of measuring techniques, modeling methods and experimental design. Moreover, both at the population level as well as the individual level polyphenol exposure has to be quantified and assessed. We developed a strategy to quantify polyphenol exposure based on the concept of nutrikinetics in combination with population-based modeling. The key idea of the strategy is to derive nutrikinetic model parameters that summarize all information of the polyphenol exposure at both individual and population level. This is illustrated by a placebo-controlled crossover study in which an extract of wine/grapes and black tea solids was administered to twenty subjects. We show that urinary and plasma nutrikinetic time-response curves can be used for phenotyping the gut microbial bioconversion capacity of individuals. Each individual harbours an intrinsic microbiota composition converting similar polyphenols from both test products in the same manner and stable over time. We demonstrate that this is a novel approach for associating the production of two gut-mediated γ-valerolactones to specific gut phylotypes. The large inter-individual variation in nutrikinetics and γ-valerolactones production indicated that gut microbial metabolism is an essential factor in polyphenol exposure and related potential health benefits.
    Metabolomics 12/2014; 10(6). DOI:10.1007/s11306-014-0645-y · 3.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Maternal one-carbon (1-C) metabolism provides methylgroups for fetal development and programing by DNA methylation as one of the underlying epigenetic mechanisms. We aimed to investigate maternal 1-C biomarkers, folic acid supplement use, and MTHFR C677T genotype as determinants of 1-C metabolism in early pregnancy in association with newborn DNA methylation levels of fetal growth and neurodevelopment candidate genes. The participants were 463 mother-child pairs of Dutch national origin from a large population-based birth cohort in Rotterdam, The Netherlands. In early pregnancy (median 13.0 weeks, 90% range 10.4-17.1), we assessed the maternal folate and homocysteine blood concentrations, folic acid supplement use, and the MTHFR C677T genotype in mothers and newborns. In newborns, DNA methylation was measured in umbilical cord blood white blood cells at 11 regions of the seven genes: NR3C1, DRD4, 5-HTT, IGF2DMR, H19, KCNQ1OT1, and MTHFR. The associations between the 1-C determinants and DNA methylation were examined using linear mixed models. An association was observed between maternal folate deficiency and lower newborn DNA methylation, which attenuated after adjustment for potential confounders. The maternal MTHFR TT genotype was significantly associated with lower DNA methylation. However, maternal homocysteine and folate concentrations, folic acid supplement use, and the MTHFR genotype in the newborn were not associated with newborn DNA methylation. The maternal MTHFR C677T genotype, as a determinant of folate status and 1-C metabolism, is associated with variations in the epigenome of a selection of genes in newborns. Research on the implications of these variations in methylation on gene expression and health is recommended.
    Reproduction (Cambridge, England) 12/2014; 148(6):581-92. DOI:10.1530/REP-14-0260 · 3.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The superficial branch of the radial nerve (SBRN) is known for developing neuropathic pain syndromes after trauma. These pain syndromes can be hard to treat due to the involvement of other nerves in the forearm. When a nerve is cut, the Schwann cells, and also other cells in the distal segment of the transected nerve, produce the nerve growth factor (NGF) in the entire distal segment. If two nerves overlap anatomically, similar to the lateral antebrachial cutaneous nerve (LACN) and SBRN, the increase in secretion of NGF, which is mediated by the injured nerve, results in binding to the high-affinity NGF receptor, tyrosine kinase A (TrkA). This in turn leads to possible sprouting and morphological changes of uninjured fibers, which ultimately causes neuropathic pain. The aim of this study was to map the level of overlap between the SBRN and LACN. Twenty arms (five left and 15 right) were thoroughly dissected. Using a new analysis tool called CASAM (Computer Assisted Surgical Anatomy Mapping), the course of the SBRN and LACN could be compared visually. The distance between both nerves was measured at 5-mm increments, and the number of times they intersected was documented. In 81% of measurements, the distance between the nerves was >10 mm, and in 49% the distance was even <5 mm. In 95% of the dissected arms, the SBRN and LACN intersected. On average, they intersected 2.25 times. The close (anatomical) relationship between the LACN and the SBRN can be seen as a factor in the explanation of persistent neuropathic pain in patients with traumatic or iatrogenic lesion of the SBRN or the LACN. Copyright © 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
    Journal of Plastic Reconstructive & Aesthetic Surgery 10/2014; 68(2). DOI:10.1016/j.bjps.2014.10.010 · 1.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Is in vitro fertilization treatment with or without intracytoplasmatic sperm injection (IVF/ICSI) associated with changes in first and second trimester embryonic and fetal growth trajectories and birthweight in singleton pregnancies?
    Human Reproduction 10/2014; 29(12). DOI:10.1093/humrep/deu271 · 4.59 Impact Factor
  • J. De Rooi, C. Ruckebusch, M. Sliwa, P.H.C. Eilers
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Many studies have established dental age standards for different populations; however, very few studies have investigated whether dental development is stable over time on a population level. Therefore, the aim of this study was to analyze changes in dental maturity in Dutch children born between 1961 and 2004. We used 2,655 dental panoramic radiographs of 2- to 16-year-old Dutch children from studies performed in three major cities in the Netherlands. Based on a trend in children born between 1961 and 1994, we predicted that a child of a certain age and gender born in 1963 achieved the same dental maturity on average, 1.5 years later than a child of the same age born 40 years later. After adjusting for the birth year of a child in the analysis, the regression coefficient of the city variable was reduced by 56.6% and it remained statistically significant. The observed trend from 1961 to 1994 was extrapolated to 9- to 10-year-old children born in 2002-2004, and validation with the other samples of children with the same characteristics showed that 95.9%-96.8% of the children had dental maturity within the 95% of the predicted range. Dental maturity score was significantly and positively associated with the year of birth, gender, and age in Dutch children, indicating a trend in earlier dental development during the observation period, 1961-2004. These findings highlight the necessity of taking the year of birth into account when assessing dental development within a population with a wider time span. Am J Phys Anthropol, 2014. © 2014 Wiley Periodicals, Inc.
    American Journal of Physical Anthropology 09/2014; 155(1). DOI:10.1002/ajpa.22556 · 2.51 Impact Factor
  • Johan J De Rooi, Cyril Ruckebusch, Paul H C Eilers
    [Show abstract] [Hide abstract]
    ABSTRACT: Deconvolution of noisy signals and images is an important task in various areas, examples are: chemometrics, biology and imaging. When the solution is required to be sparse, desirable results are obtained using penalized estimation techniques. Sparseness is realized by shrinking coefficients to zero. We use penalized regression with a penalty based on the L0 norm, as presented, for one dimensional data, in earlier work. Several extensions to this approach are presented. In case of blind deconvolution, a smoother is applied to improve the estimated impulse response, which is applicable to any unimodal response function. Results are demonstrated on pulse identification in endocrine data where it is aimed to model secretion pattern as a sparse series of spikes. Application to single-molecule fluorescence imaging is also demonstrated for functional superresolution in cell biology.
    Analytical Chemistry 06/2014; 86(13). DOI:10.1021/ac500260h · 5.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: X-ray diffraction scans consist of series of counts; these numbers obey Poisson distributions with varying expected values. These scans are often smoothed and the Kα2 component is removed. This article proposes a framework in which both issues are treated. Penalized likelihood estimation is used to smooth the data. The penalty combines the Poisson log-likelihood and a measure for roughness based on ideas from generalized linear models. To remove the Kα doublet the model is extended using the composite link model. As a result the data are decomposed into two smooth components: a Kα1 and a Kα2 part. For both smoothing and Kα2 removal, the weight of the applied penalty is optimized automatically. The proposed methods are applied to experimental data and compared with the Savitzky–Golay algorithm for smoothing and the Rachinger method for Kα2 stripping. The new method shows better results with less local distortion. Freely available software in MATLAB and R has been developed.
    Journal of Applied Crystallography 06/2014; 47(3). DOI:10.1107/S1600576714005809 · 3.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A new computational algorithm for estimating the smoothing parameters of a multidimensional penalized spline generalized linear model with anisotropic penalty is presented. This new proposal is based on the mixed model representation of a multidimensional P-spline, in which the smoothing parameter for each covariate is expressed in terms of variance components. On the basis of penalized quasi-likelihood methods, closed-form expressions for the estimates of the variance components are obtained. This formulation leads to an efficient implementation that considerably reduces the computational burden. The proposed algorithm can be seen as a generalization of the algorithm by Schall (1991)—for variance components estimation—to deal with non-standard structures of the covariance matrix of the random effects. The practical performance of the proposed algorithm is evaluated by means of simulations, and comparisons with alternative methods are made on the basis of the mean square error criterion and the computing time. Finally, we illustrate our proposal with the analysis of two real datasets: a two dimensional example of historical records of monthly precipitation data in USA and a three dimensional one of mortality data from respiratory disease according to the age at death, the year of death and the month of death.
    Statistics and Computing 04/2014; DOI:10.1007/s11222-014-9464-2 · 1.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: To introduce a method to optimize structural retinal nerve fiber layer (RNFL) models based on glaucomatous visual field data and to show how such an optimized model can be used to reduce noise in visual fields while preserving clinically important features. Methods: Correlation coefficients between age-adjusted deviation values of pairs of visual field test locations were calculated from 104 visual fields of moderately glaucomatous eyes. Distances between those test locations were defined for various parameters of a mathematical RNFL model. Then, the correspondence between the structural and functional data was defined by the spread, or variance, of the correlation coefficients for all distances. The model parameters that minimized this spread constituted the optimized model. To reduce noise in visual fields, the optimized model was used to smooth visual field data according to the RNFL's structure. The resulting fields were compared to visual fields that were smoothed based on the regular testing grid. Results: The optimal parameters for the RNFL model reduced the variance of the correlation coefficients by 85% and were well within the range of parameters previously determined from fundus photographs. Smoothing the visual fields based on the optimized RNFL-model strongly reduced noise while keeping important features. Conclusions: Mathematical RNFL models can be optimized based on visual field data, resulting in a strong structure-function relationship. Taking the RNFL's shape, as defined by such an optimized model, into account when smoothing visual fields results in better noise reduction while preserving important details.
    Investigative ophthalmology & visual science 03/2014; 55(4). DOI:10.1167/iovs.13-12492 · 3.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 17ß-Estradiol, an epigenetic modulator, is involved in the increased prevalence of migraine in women. Together with the prophylactic efficacy of valproate, which influences DNA methylation and histone modification, this points to the involvement of epigenetic mechanisms. Epigenetic studies are often performed on leukocytes, but it is unclear to what extent methylation is similar in other tissues. Therefore, we investigated methylation of migraine-related genes that might be epigenetically regulated (CGRP-ergic pathway, estrogen receptors, endothelial NOS, as well as MTHFR) in different migraine-related tissues and compared this to methylation in rat as well as human leukocytes. Further, we studied whether 17ß-estradiol has a prominent role in methylation of these genes. Female rats (n = 35) were ovariectomized or sham-operated and treated with 17β-estradiol or placebo. DNA was isolated and methylation was assessed through bisulphite treatment and mass spectrometry. Human methylation data were obtained using the Illumina 450k genome-wide methylation array in 395 female subjects from a population-based cohort study. We showed that methylation of the Crcp, Calcrl, Esr1 and Nos3 genes is tissue-specific and that methylation in leukocytes was not correlated to that in other tissues. Interestingly, the interindividual variation in methylation differed considerably between genes and tissues. Furthermore we showed that methylation in human leukocytes was similar to that in rat leukocytes in our genes of interest, suggesting that rat may be a good model to study human DNA methylation in tissues that are difficult to obtain. In none of the genes a significant effect of estradiol treatment was observed.
    PLoS ONE 03/2014; 9(3):e87616. DOI:10.1371/journal.pone.0087616 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine sociodemographic and life style-related risk factors and trimester specific maternal, placental, and fetal consequences of maternal anaemia and elevated haemoglobin levels in pregnancy. In a population-based prospective cohort study of 7317 mothers, we measured haemoglobin levels in early pregnancy [gestational age median 14.4 weeks (inter-quartile-range 12.5-17.5)]. Anaemia (haemoglobin ≤11 g/dl) and elevated haemoglobin levels (haemoglobin ≥13.2 g/dl) were defined according to the WHO criteria. Maternal blood pressure, placental function and fetal growth were measured in each trimester. Data on gestational hypertensive disorders and birth outcomes was collected from hospitals. Older maternal age, higher body mass index, primiparity and European descent were associated with higher haemoglobin levels (P < 0.05). Elevated haemoglobin levels were associated with increased systolic and diastolic blood pressure throughout pregnancy (mean differences 5.1 mmHg, 95% confidence interval [CI] 3.8, 6.5 and 4.1 mmHg, 95% CI 3.0, 5.2, respectively) and with a higher risk of third trimester uterine artery notching (RR 1.3, 95% CI 1.0, 1.7). As compared with maternal normal haemoglobin levels, not anaemia, but elevated haemoglobin levels were associated with fetal head circumference, length, and weight growth restriction from third trimester onwards (P < 0.05). Elevated haemoglobin levels were associated with increased risks of gestational hypertensive disorders (RR 1.4, 95% CI 1.1, 1.8) and adverse birth outcomes (RR 1.4, 95% CI 1.1, 1.7). In a low-risk population, various sociodemographic and life style factors affect haemoglobin levels during pregnancy. Elevated haemoglobin levels are associated with increased risks of maternal, placental, and fetal complications.
    Paediatric and Perinatal Epidemiology 02/2014; DOI:10.1111/ppe.12112 · 2.81 Impact Factor
  • Paul H. C. Eilers, Pieter M. Kroonenberg
    [Show abstract] [Hide abstract]
    ABSTRACT: Rayleigh and Raman scatter in fluorescence (excitation–emission) landscapes are a nuisance in two-way and three-way data modeling. We provide a method to clean individual emission spectra. The scatter can be represented accurately by Gaussian peaks, characterized by location, width and height. The analytic signal of interest effectively acts as a background to the scatter peaks. Modeling it locally as a smooth curve, using penalized least squares, allows accurate estimation of the parameters of scatter peaks. Once the peaks are modeled, they can be subtracted from the spectrum, almost completely removing the artifacts. Apart from local smoothness, no assumptions are made about the fluorescence spectra.
    Chemometrics and Intelligent Laboratory Systems 01/2014; 130:1–5. DOI:10.1016/j.chemolab.2013.09.002 · 2.38 Impact Factor

Publication Stats

5k Citations
563.76 Total Impact Points


  • 2015
    • Wageningen UR
      Wageningen, Gelderland, Netherlands
  • 2009–2015
    • Erasmus MC
      • Department of Biostatistics
      Rotterdam, South Holland, Netherlands
  • 2009–2014
    • Erasmus Universiteit Rotterdam
      • Department of Internal Medicine
      Rotterdam, South Holland, Netherlands
  • 2011–2012
    • Wageningen University
      Wageningen, Gelderland, Netherlands
  • 2008–2011
    • Universiteit Utrecht
      • • Faculty of Social and Behavioural Sciences
      • • Department of Methodology and Statistics
      Utrecht, Utrecht, Netherlands
  • 2005–2009
    • Leiden University
      Leyden, South Holland, Netherlands
  • 2000–2007
    • Leiden University Medical Centre
      • • Department of Parasitology
      • • Department of Molecular Cell Biology
      • • Department of Obstetrics
      Leyden, South Holland, Netherlands
  • 2006
    • Louisiana State University
      • Department of Experimental Statistics
      Baton Rouge, Louisiana, United States
  • 2004
    • Heriot-Watt University
      • Department of Actuarial Mathematics and Statistics
      Edinburgh, Scotland, United Kingdom