Publications by authors named "Rory Wilson"

122 Publications

Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset.

Brain 2021 Sep 30. Epub 2021 Sep 30.

Institute of Neurogenomics (ING), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.

Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1x log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (p = 0.003) - being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.
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http://dx.doi.org/10.1093/brain/awab360DOI Listing
September 2021

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.

Nat Commun 2021 06 28;12(1):3987. Epub 2021 Jun 28.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.
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http://dx.doi.org/10.1038/s41467-021-23899-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238961PMC
June 2021

Animal tag technology keeps coming of age: an engineering perspective.

Philos Trans R Soc Lond B Biol Sci 2021 08 28;376(1831):20200229. Epub 2021 Jun 28.

Institute for Terrestrial and Aquatic Wildlife Research, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173 Hannover, Germany.

Animal-borne tags (biologgers) have now become extremely sophisticated, recording data from multiple sensors at high frequencies for long periods and, as such, have become a powerful tool for behavioural ecologists and physiologists studying wild animals. But the design and implementation of these tags is not trivial because engineers have to maximize performance and ability to function under onerous conditions while minimizing tag mass and volume (footprint) to maximize the wellbeing of the animal carriers. We present some of the major issues faced by tag engineers and show how tag designers must accept compromises while maintaining systems that can answer the questions being posed. We also argue that basic understanding of engineering issues in tag design by biologists will help feedback to engineers to better tag construction but also reduce the likelihood that tag-deploying biologists will misunderstand their own results. Finally, we suggest that proper consideration of conventional technology together with new approaches will lead to further step changes in our understanding of wild-animal biology using smart tags. This article is part of the theme issue 'Measuring physiology in free-living animals (Part II)'.
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http://dx.doi.org/10.1098/rstb.2020.0229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237169PMC
August 2021

Plasma Proteomics of Renal Function: A Trans-ethnic Meta-analysis and Mendelian Randomization Study.

J Am Soc Nephrol 2021 Jun 16. Epub 2021 Jun 16.

M Prunotto, School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.

Background: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed.

Methods: A cross-sectional study of 993 plasma proteins among 2,882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified trans-ethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR .

Results: Fifty-seven plasma proteins were associated with eGFR, including one novel protein. Twenty-three of these were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR.

Conclusions: In a discovery-replication setting, we identified 57 proteins trans-ethnically associated with eGFR. The revealed causal relationships are an important stepping-stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.
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http://dx.doi.org/10.1681/ASN.2020071070DOI Listing
June 2021

Limitations of using surrogates for behaviour classification of accelerometer data: refining methods using random forest models in Caprids.

Mov Ecol 2021 Jun 7;9(1):28. Epub 2021 Jun 7.

School of Biological Sciences, Institute for Global Food Security, Queen's University Belfast, 19 Chlorine Gardens, Belfast, BT9 5DL, Northern Ireland, UK.

Background: Animal-attached devices can be used on cryptic species to measure their movement and behaviour, enabling unprecedented insights into fundamental aspects of animal ecology and behaviour. However, direct observations of subjects are often still necessary to translate biologging data accurately into meaningful behaviours. As many elusive species cannot easily be observed in the wild, captive or domestic surrogates are typically used to calibrate data from devices. However, the utility of this approach remains equivocal.

Methods: Here, we assess the validity of using captive conspecifics, and phylogenetically-similar domesticated counterparts (surrogate species) for calibrating behaviour classification. Tri-axial accelerometers and tri-axial magnetometers were used with behavioural observations to build random forest models to predict the behaviours. We applied these methods using captive Alpine ibex (Capra ibex) and a domestic counterpart, pygmy goats (Capra aegagrus hircus), to predict the behaviour including terrain slope for locomotion behaviours of captive Alpine ibex.

Results: Behavioural classification of captive Alpine ibex and domestic pygmy goats was highly accurate (> 98%). Model performance was reduced when using data split per individual, i.e., classifying behaviour of individuals not used to train models (mean ± sd = 56.1 ± 11%). Behavioural classifications using domestic counterparts, i.e., pygmy goat observations to predict ibex behaviour, however, were not sufficient to predict all behaviours of a phylogenetically similar species accurately (> 55%).

Conclusions: We demonstrate methods to refine the use of random forest models to classify behaviours of both captive and free-living animal species. We suggest there are two main reasons for reduced accuracy when using a domestic counterpart to predict the behaviour of a wild species in captivity; domestication leading to morphological differences and the terrain of the environment in which the animals were observed. We also identify limitations when behaviour is predicted in individuals that are not used to train models. Our results demonstrate that biologging device calibration needs to be conducted using: (i) with similar conspecifics, and (ii) in an area where they can perform behaviours on terrain that reflects that of species in the wild.
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http://dx.doi.org/10.1186/s40462-021-00265-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186069PMC
June 2021

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Eur J Epidemiol 2021 Jun 6. Epub 2021 Jun 6.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
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http://dx.doi.org/10.1007/s10654-021-00759-zDOI Listing
June 2021

DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function.

Clin Epigenetics 2021 Jun 2;13(1):121. Epub 2021 Jun 2.

Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Background: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.

Results: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β =  - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E-06). The "first-generation" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria.

Conclusion: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.
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http://dx.doi.org/10.1186/s13148-021-01082-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170969PMC
June 2021

Structural Evolution in BiNbO.

Inorg Chem 2021 Jun 1;60(12):8507-8518. Epub 2021 Jun 1.

School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom.

The sequence of transitions between different phases of BiNbO has been thoroughly investigated and clarified using thermal analysis, high-resolution neutron diffraction, and Raman spectroscopy. The theoretical optical phonon modes of the α-phase have been calculated. Based on thermoanalytical data supported by density functional theory (DFT) calculations, the β-phase is proposed to be metastable, while the α- and γ-phases are stable below and above 1040 °C, respectively. Accurate positional parameters for oxygen positions in the three main polymorphs (α, β, and γ) are presented and the structural relationships between these polymorphs are discussed. Even though no significant changes, only relaxation phenomena, are observed in the dielectric behavior of α-BiNbO below 1000 °C, evidence of two further subtle transitions at ∼350 and 600 °C is presented through careful analysis of structural parameters from variable temperature neutron diffraction measurements. Such phase variations are also evident in the phonon modes in Raman spectra and supported by changes in the thermoanalytical data. These subtle transitions may correspond to the previously proposed antiferroelectric to ferroelectric and ferroelectric to paraelectric phase transitions, respectively.
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http://dx.doi.org/10.1021/acs.inorgchem.1c00149DOI Listing
June 2021

Fine-scale changes in speed and altitude suggest protean movements in homing pigeon flights.

R Soc Open Sci 2021 May 19;8(5):210130. Epub 2021 May 19.

Biosciences, College of Science, Swansea University, Singleton Park, Swansea, UK.

The power curve provides a basis for predicting adjustments that animals make in flight speed, for example in relation to wind, distance, habitat foraging quality and objective. However, relatively few studies have examined how animals respond to the landscape below them, which could affect speed and power allocation through modifications in climb rate and perceived predation risk. We equipped homing pigeons () with high-frequency loggers to examine how flight speed, and hence effort, varies in relation to topography and land cover. Pigeons showed mixed evidence for an energy-saving strategy, as they minimized climb rates by starting their ascent ahead of hills, but selected rapid speeds in their ascents. Birds did not modify their speed substantially in relation to land cover, but used higher speeds during descending flight, highlighting the importance of considering the rate of change in altitude before estimating power use from speed. Finally, we document an unexpected variability in speed and altitude over fine scales; a source of substantial energetic inefficiency. We suggest this may be a form of protean behaviour adopted to reduce predation risk when flocking is not an option, and that such a strategy could be widespread.
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http://dx.doi.org/10.1098/rsos.210130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131938PMC
May 2021

Metabolic syndrome and the plasma proteome: from association to causation.

Cardiovasc Diabetol 2021 05 20;20(1):111. Epub 2021 May 20.

Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Background: The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering.

Methods: Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization.

Results: Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71-0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = - 0.12, Wald-p = 3.63e-13), apolipoprotein B (APOB) (Wald-Ratio = - 0.09, Wald-p = 2.54e-04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e-04).

Conclusions: Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy.
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http://dx.doi.org/10.1186/s12933-021-01299-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138979PMC
May 2021

The multiplicity of analysis strategies jeopardizes replicability: lessons learned across disciplines.

R Soc Open Sci 2021 Apr 21;8(4):201925. Epub 2021 Apr 21.

LMU Open Science Center, Ludwig-Maximilians-Universität München, Munich, Germany.

For a given research question, there are usually a large variety of possible analysis strategies acceptable according to the scientific standards of the field, and there are concerns that this multiplicity of analysis strategies plays an important role in the non-replicability of research findings. Here, we define a general framework on common sources of uncertainty arising in computational analyses that lead to this multiplicity, and apply this framework within an overview of approaches proposed across disciplines to address the issue. Armed with this framework, and a set of recommendations derived therefrom, researchers will be able to recognize strategies applicable to their field and use them to generate findings more likely to be replicated in future studies, ultimately improving the credibility of the scientific process.
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http://dx.doi.org/10.1098/rsos.201925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059606PMC
April 2021

On the optimistic performance evaluation of newly introduced bioinformatic methods.

Genome Biol 2021 05 11;22(1):152. Epub 2021 May 11.

Institute for Medical Information Processing, Biometry and Epidemiology, LMU, Munich, Germany.

Most research articles presenting new data analysis methods claim that "the new method performs better than existing methods," but the veracity of such statements is questionable. Our manuscript discusses and illustrates consequences of the optimistic bias occurring during the evaluation of novel data analysis methods, that is, all biases resulting from, for example, selection of datasets or competing methods, better ability to fix bugs in a preferred method, and selective reporting of method variants. We quantitatively investigate this bias using an example from epigenetic analysis: normalization methods for data generated by the Illumina HumanMethylation450K BeadChip microarray.
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http://dx.doi.org/10.1186/s13059-021-02365-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111726PMC
May 2021

Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases.

Clin Epigenetics 2021 03 22;13(1):60. Epub 2021 Mar 22.

The Framingham Heart Study, 73 Mt. Wayte Avenue, Framingham, MA, 01702, USA.

Background: DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases.

Results: We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data.

Conclusions: Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.
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http://dx.doi.org/10.1186/s13148-021-01041-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986283PMC
March 2021

Accidents alter animal fitness landscapes.

Ecol Lett 2021 May 9;24(5):920-934. Epub 2021 Mar 9.

Department of Biosciences, Swansea University, Swansea, UK.

Animals alter their habitat use in response to the energetic demands of movement ('energy landscapes') and the risk of predation ('the landscape of fear'). Recent research suggests that animals also select habitats and move in ways that minimise their chance of temporarily losing control of movement and thereby suffering slips, falls, collisions or other accidents, particularly when the consequences are likely to be severe (resulting in injury or death). We propose that animals respond to the costs of an 'accident landscape' in conjunction with predation risk and energetic costs when deciding when, where, and how to move in their daily lives. We develop a novel theoretical framework describing how features of physical landscapes interact with animal size, morphology, and behaviour to affect the risk and severity of accidents, and predict how accident risk might interact with predation risk and energetic costs to dictate movement decisions across the physical landscape. Future research should focus on testing the hypotheses presented here for different real-world systems to gain insight into the relative importance of theorised effects in the field.
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http://dx.doi.org/10.1111/ele.13705DOI Listing
May 2021

DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures.

Clin Epigenetics 2021 01 7;13(1). Epub 2021 Jan 7.

Center for Life Course Health Research, University of Oulu, Oulu University Hospital, Oulu, Finland.

Background: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances.

Results: We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations.

Conclusion: Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
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http://dx.doi.org/10.1186/s13148-020-00957-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789600PMC
January 2021

Genetic divergence and evidence of human-mediated translocation of two-fingered sloths (C) in Costa Rica.

Evol Appl 2020 Oct 26;13(9):2439-2448. Epub 2020 Jun 26.

Biosciences, College of Science Swansea University Wales UK.

Sloths are notoriously slow and consequently have limited dispersal ability, which makes them particularly vulnerable to the effects of habitat fragmentation and degradation. Sloths in Costa Rica are considered of conservation concern due to habitat loss, livestock production and increasing urbanization. Reintroductions from rescue centres are commonplace across the country, yet their genetic diversity and population structure are unknown, and there is currently little consideration of the genetic background prior to intervention or releases. We used microsatellite analysis to undertake the first exploratory investigation into sloth population genetics in Costa Rica. Using data from 98 two-fingered sloths () from four different geographic regions, we determined the presence of four potential genetic groups, three of them with minimal population structuring despite the limited dispersal ability and presence of physical barriers. Sloths from the North appear to represent a highly distinct population that we propose may require management as a discrete unit for conservation. We stress the need for additional analyses to better understand the genetic structure and diversity of North andWest regions and suggest that rescue facilities in Costa Rica should consider the genetic background of rehabilitated sloths when planning future reintroductions. Our results also highlight the threat posed by physical isolation due to widespread urbanization and agriculture expansion for a species with a weak dispersal ability.
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http://dx.doi.org/10.1111/eva.13036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513709PMC
October 2020

Deciphering the Plasma Proteome of Type 2 Diabetes.

Diabetes 2020 12 14;69(12):2766-2778. Epub 2020 Sep 14.

Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

With an estimated prevalence of 463 million affected, type 2 diabetes represents a major challenge to health care systems worldwide. Analyzing the plasma proteomes of individuals with type 2 diabetes may illuminate hitherto unknown functional mechanisms underlying disease pathology. We assessed the associations between type 2 diabetes and >1,000 plasma proteins in the Cooperative Health Research in the Region of Augsburg (KORA) F4 cohort ( = 993, 110 cases), with subsequent replication in the third wave of the Nord-Trøndelag Health Study (HUNT3) cohort ( = 940, 149 cases). We computed logistic regression models adjusted for age, sex, BMI, smoking status, and hypertension. Additionally, we investigated associations with incident type 2 diabetes and performed two-sample bidirectional Mendelian randomization (MR) analysis to prioritize our results. Association analysis of prevalent type 2 diabetes revealed 24 replicated proteins, of which 8 are novel. Proteins showing association with incident type 2 diabetes were aminoacylase-1, growth hormone receptor, and insulin-like growth factor-binding protein 2. Aminoacylase-1 was associated with both prevalent and incident type 2 diabetes. MR analysis yielded nominally significant causal effects of type 2 diabetes on cathepsin Z and rennin, both known to have roles in the pathophysiological pathways of cardiovascular disease, and of sex hormone-binding globulin on type 2 diabetes. In conclusion, our high-throughput proteomics study replicated previously reported type 2 diabetes-protein associations and identified new candidate proteins possibly involved in the pathogenesis of type 2 diabetes.
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http://dx.doi.org/10.2337/db20-0296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679779PMC
December 2020

A new direction for differentiating animal activity based on measuring angular velocity about the yaw axis.

Ecol Evol 2020 Jul 6;10(14):7872-7886. Epub 2020 Jul 6.

Red Sea Research Centre King Abdullah University of Science and Technology Thuwal Saudi Arabia.

The use of animal-attached data loggers to quantify animal movement has increased in popularity and application in recent years. High-resolution tri-axial acceleration and magnetometry measurements have been fundamental in elucidating fine-scale animal movements, providing information on posture, traveling speed, energy expenditure, and associated behavioral patterns. Heading is a key variable obtained from the tandem use of magnetometers and accelerometers, although few field investigations have explored fine-scale changes in heading to elucidate differences in animal activity (beyond the notable exceptions of dead-reckoning).This paper provides an overview of the value and use of animal heading and a prime derivative, angular velocity about the yaw axis, as an important element for assessing activity extent with potential to allude to behaviors, using "free-ranging" Loggerhead turtles () as a model species.We also demonstrate the value of yaw rotation for assessing activity extent, which varies over the time scales considered and show that various scales of body rotation, particularly rate of change of yaw, can help resolve differences between fine-scale behavior-specific movements. For example, oscillating yaw movements about a central point of the body's arc implies bouts of foraging, while unusual circling behavior, indicative of conspecific interactions, could be identified from complete revolutions of the longitudinal axis.We believe this approach should help identification of behaviors and "space-state" approaches to enhance our interpretation of behavior-based movements, particularly in scenarios where acceleration metrics have limited value, such as for slow-moving animals.
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http://dx.doi.org/10.1002/ece3.6515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391348PMC
July 2020

Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.

Aging (Albany NY) 2020 07 22;12(14):14092-14124. Epub 2020 Jul 22.

Section General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02215, USA.

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality ( < 9.3x10) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to , and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to , and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes () linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.
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http://dx.doi.org/10.18632/aging.103408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425458PMC
July 2020

An "orientation sphere" visualization for examining animal head movements.

Ecol Evol 2020 May 24;10(10):4291-4302. Epub 2020 Mar 24.

School of Biological Sciences Queen's University Belfast Belfast UK.

Animal behavior is elicited, in part, in response to external conditions, but understanding how animals perceive the environment and make the decisions that bring about these behavioral responses is challenging.Animal heads often move during specific behaviors and, additionally, typically have sensory systems (notably vision, smell, and hearing) sampling in defined arcs (normally to the front of their heads). As such, head-mounted electronic sensors consisting of accelerometers and magnetometers, which can be used to determine the movement and directionality of animal heads (where head "movement" is defined here as changes in heading [azimuth] and/or pitch [elevation angle]), can potentially provide information both on behaviors in general and also clarify which parts of the environment the animals might be prioritizing ("environmental framing").We propose a new approach to visualize the data of such head-mounted tags that combines the instantaneous outputs of head heading and pitch in a single intuitive spherical plot. This sphere has magnetic heading denoted by "longitude" position and head pitch by "latitude" on this "orientation sphere" (O-sphere).We construct the O-sphere for the head rotations of a number of vertebrates with contrasting body shape and ecology (oryx, sheep, tortoises, and turtles), illustrating various behaviors, including foraging, walking, and environmental scanning. We also propose correcting head orientations for body orientations to highlight specific heading-independent head rotation, and propose the derivation of O-sphere-metrics, such as angular speed across the sphere. This should help identify the functions of various head behaviors.Visualizations of the O-sphere provide an intuitive representation of animal behavior manifest head orientation and rotation. This has ramifications for quantifying and understanding behaviors ranging from navigation through vigilance to feeding and, when used in tandem with body movement, should provide an important link between perception of the environment and response to it in free-ranging animals.
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http://dx.doi.org/10.1002/ece3.6197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246194PMC
May 2020

A genome-wide analysis of DNA methylation identifies a novel association signal for Lp(a) concentrations in the LPA promoter.

PLoS One 2020 28;15(4):e0232073. Epub 2020 Apr 28.

Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.

Lipoprotein(a) [Lp(a)] is a major cardiovascular risk factor, which is largely genetically determined by one major gene locus, the LPA gene. Many aspects of the transcriptional regulation of LPA are poorly understood and the role of epigenetics has not been addressed yet. Therefore, we conducted an epigenome-wide analysis of DNA methylation on Lp(a) levels in two population-based studies (total n = 2208). We identified a CpG site in the LPA promoter which was significantly associated with Lp(a) concentrations. Surprisingly, the identified CpG site was found to overlap the SNP rs76735376. We genotyped this SNP de-novo in three studies (total n = 7512). The minor allele of rs76735376 (1.1% minor allele frequency) was associated with increased Lp(a) values (p = 1.01e-59) and explained 3.5% of the variation of Lp(a). Statistical mediation analysis showed that the effect on Lp(a) is rather originating from the base change itself and is not mediated by DNA methylation levels. This finding is supported by eQTL data from 208 liver tissue samples from the GTEx project, which shows a significant association of the rs76735376 minor allele with increased LPA expression. To evaluate, whether the association signal at rs76735376 may actually be derived from a stronger eQTL signal in LD with this SNP, eQTL association results of all correlated SNPs (r2≥0.1) were integrated with genetic association results. This analysis pinpointed to rs10455872 as the potential trigger of the effect of rs76735376. Furthermore, both SNPs coincide with short apo(a) isoforms. Adjusting for both, rs10455872 and the apo(a) isoforms diminished the effect size of rs76735376 to 5.38 mg/dL (p = 0.0463). This indicates that the effect of rs76735376 can be explained by both an independent effect of the SNP and a strong correlation with rs10455872 and apo(a) isoforms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232073PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188291PMC
July 2020

Epigenetic Link Between Statin Therapy and Type 2 Diabetes.

Diabetes Care 2020 04 7;43(4):875-884. Epub 2020 Feb 7.

Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.

Objective: To investigate the role of epigenetics in statins' diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood.

Research Design And Methods: Five cohort studies' participants ( = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated.

Results: Discovery ( = 6,820) and replication ( = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 × 10 []), cg10177197 (3.94 × 10 []), cg06500161 (2.67 × 10 []), cg27243685 (6.01 × 10 []), and cg05119988 (7.26 × 10 []). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and methylation were associated with downregulation, suggesting epigenetic regulation of expression. Further, outcomes insulin and HOMA-IR were significantly associated with expression.

Conclusions: This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins' effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to epigenetic regulation.
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http://dx.doi.org/10.2337/dc19-1828DOI Listing
April 2020

Impact of long-term storage and freeze-thawing on eight circulating microRNAs in plasma samples.

PLoS One 2020 14;15(1):e0227648. Epub 2020 Jan 14.

Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Center for Environmental Health, Neuherberg, Germany.

Sample collection, processing, storage and isolation methods constitute pre-analytic factors that can influence the quality of samples used in research and clinical practice. With regard to biobanking practices, a critical point in the sample's life chain is storage, particularly long-term storage. Since most studies examine the influence of different temperatures (4°C, room temperature) or delays in sample processing on sample quality, there is only little information on the effects of long-term storage at ultra-low (vapor phase of liquid nitrogen) temperatures on biomarker levels. Among these biomarkers, circulating miRNAs hold great potential for diagnosis or prognosis for a variety of diseases, like cancer, infections and chronic diseases, and are thus of high interest in several scientific questions. We therefore investigated the influence of long-term storage on levels of eight circulating miRNAs (miR-103a-3p, miR-191-5p, miR-124-3p, miR-30c-5p, miR-451a, miR-23a-3p, miR-93-5p, miR-24-3p, and miR-33b-5p) from 10 participants from the population-based cohort study KORA. Sample collection took place during the baseline survey S4 and the follow-up surveys F4 and FF4, over a time period spanning from 1999 to 2014. The influence of freeze-thaw (f/t) cycles on miRNA stability was also investigated using samples from volunteers (n = 6). Obtained plasma samples were profiled using Exiqon's miRCURYTM real-time PCR profiling system, and repeated measures ANOVA was used to check for storage or f/t effects. Our results show that detected levels of most of the studied miRNAs showed no statistically significant changes due to storage at ultra-low temperatures for up to 17 years; miR-451a levels were altered due to contamination during sampling. Freeze-thawing of one to four cycles showed an effect only on miR-30c-5p. Our results highlight the robustness of this set of circulating miRNAs for decades of storage at ultra-low temperatures and several freeze-thaw cycles, which makes our findings increasingly relevant for research conducted with biobanked samples.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227648PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959605PMC
April 2020

Epigenetics meets proteomics in an epigenome-wide association study with circulating blood plasma protein traits.

Nat Commun 2020 01 3;11(1):15. Epub 2020 Jan 3.

Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar.

DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation.
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http://dx.doi.org/10.1038/s41467-019-13831-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941977PMC
January 2020

Alcohol consumption is associated with widespread changes in blood DNA methylation: Analysis of cross-sectional and longitudinal data.

Addict Biol 2021 01 2;26(1):e12855. Epub 2019 Dec 2.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.

DNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart. Using the Illumina HumanMethylation450 BeadChip, DNA methylation was measured in blood samples from 5606 Melbourne Collaborative Cohort Study (MCCS) participants. For 1088 of them, these measures were repeated using blood samples collected a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models. Independent data from the London Life Sciences Prospective Population (LOLIPOP) (N = 4042) and Cooperative Health Research in the Augsburg Region (KORA) (N = 1662) cohorts were used to replicate associations discovered in the MCCS. Cross-sectional analyses identified 1414 CpGs associated with alcohol intake at P < 10 , 1243 of which had not been reported previously. Of these novel associations, 1078 were replicated (P < .05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated 403 of 518 previously reported associations. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1414 CpGs, 530 were differentially methylated (P < .05) in former compared with current drinkers. Longitudinal associations between the change in alcohol intake and the change in methylation were observed for 513 of the 1414 cross-sectional associations. Our study indicates that alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with alcohol consumption changes in adulthood.
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http://dx.doi.org/10.1111/adb.12855DOI Listing
January 2021

X-ray total scattering study of magic-size clusters and quantum dots of cadmium sulphide.

Nanoscale 2019 Nov;11(45):21900-21908

School of Physics and Astronomy, Queen Mary University of London, Mile End Road, London, E1 4NS, UK.

Four types of magic-size CdS clusters and three different CdS quantum dots have been studied using the technique of X-ray total scattering and pair distribution function analysis. We found that the CdS quantum dots could be modelled as a mixed phase of atomic structures based on the two bulk crystalline phases, which is interpreted as representing the effects of random stacking of layers. However, the results for the magic-size clusters are significantly different. On one hand, the short-range features in the pair distribution function reflect the bulk, indicating that these structures are based on the same tetrahedral coordination found in the bulk phases (and therefore excluding new types of structures such as cage-like arrangements of atoms). But on the other hand, the longer-range atomic structure clearly does not reflect the layer structures found in the bulk and the quantum dots. We compare the effect of two ligands, phenylacetic acid and oleic acid, showing that in one case the ligand has little effect on the atomic structure of the magic-size nanocluster, and in another it has a significant effect.
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http://dx.doi.org/10.1039/c9nr06355bDOI Listing
November 2019

Can Fish and Cell Phones Teach Us about Our Health?

ACS Sens 2019 10 2;4(10):2566-2570. Epub 2019 Oct 2.

Department of Biosciences, College of Science , Swansea University , Swansea , Wales , SA2 8PP , United Kingdom.

Biologging is a scientific endeavor that studies the environment and animals within it by outfitting the latter with sensors of their dynamics as they roam freely in their natural habitats. As wearable technologies advance for the monitoring of human health, it may be instructive to reflect on the successes and failures of biologging in field biology over the past few decades. Several lessons may be of value. Physiological sensors can "encode" for a wider number of states than the one explicitly targeted, although the limits of this are debatable. The combination of orthogonal sensors turns out to be critical to delivering a high value data set. Sensor fusion and engineering for longevity are also important for success. This Perspective highlights successful strategies for biologging that hold promise for human health monitoring.
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http://dx.doi.org/10.1021/acssensors.9b00947DOI Listing
October 2019

Validated inference of smoking habits from blood with a finite DNA methylation marker set.

Eur J Epidemiol 2019 Nov 7;34(11):1055-1074. Epub 2019 Sep 7.

Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUC 0.925 ± 0.021, AUC0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.
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http://dx.doi.org/10.1007/s10654-019-00555-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861351PMC
November 2019

Optimizing the use of biologgers for movement ecology research.

J Anim Ecol 2020 01 1;89(1):186-206. Epub 2019 Oct 1.

Department of Biosciences, College of Science, Swansea University, Swansea, UK.

The paradigm-changing opportunities of biologging sensors for ecological research, especially movement ecology, are vast, but the crucial questions of how best to match the most appropriate sensors and sensor combinations to specific biological questions and how to analyse complex biologging data, are mostly ignored. Here, we fill this gap by reviewing how to optimize the use of biologging techniques to answer questions in movement ecology and synthesize this into an Integrated Biologging Framework (IBF). We highlight that multisensor approaches are a new frontier in biologging, while identifying current limitations and avenues for future development in sensor technology. We focus on the importance of efficient data exploration, and more advanced multidimensional visualization methods, combined with appropriate archiving and sharing approaches, to tackle the big data issues presented by biologging. We also discuss the challenges and opportunities in matching the peculiarities of specific sensor data to the statistical models used, highlighting at the same time the large advances which will be required in the latter to properly analyse biologging data. Taking advantage of the biologging revolution will require a large improvement in the theoretical and mathematical foundations of movement ecology, to include the rich set of high-frequency multivariate data, which greatly expand the fundamentally limited and coarse data that could be collected using location-only technology such as GPS. Equally important will be the establishment of multidisciplinary collaborations to catalyse the opportunities offered by current and future biologging technology. If this is achieved, clear potential exists for developing a vastly improved mechanistic understanding of animal movements and their roles in ecological processes and for building realistic predictive models.
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http://dx.doi.org/10.1111/1365-2656.13094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041970PMC
January 2020
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