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1. Empirically assessing the plausibility of unconfoundedness in observational studies

Author

Hartwig, Fernando Pires, Tilling, Kate, and Smith, George Davey

Subjects
Statistics - Methodology
Abstract

The possibility of unmeasured confounding is one of the main limitations for causal inference from observational studies. There are different methods for partially empirically assessing the plausibility of unconfoundedness. However, most currently available methods require (at least partial) assumptions about the confounding structure, which may be difficult to know in practice. In this paper we describe a simple strategy for empirically assessing the plausibility of conditional unconfoundedness (i.e., whether the candidate set of covariates suffices for confounding adjustment) which does not require any assumptions about the confounding structure, requiring instead assumptions related to temporal ordering between covariates, exposure and outcome (which can be guaranteed by design), measurement error and selection into the study. The proposed method essentially relies on testing the association between a subset of covariates (those associated with the exposure given all other covariates) and the outcome conditional on the remaining covariates and the exposure. We describe the assumptions underlying the method, provide proofs, use simulations to corroborate the theory and illustrate the method with an applied example assessing the causal effect of length-for-age measured in childhood and intelligence quotient measured in adulthood using data from the 1982 Pelotas (Brazil) birth cohort. We also discuss the implications of measurement error and some important limitations.

Published
2024

2. Relationship between Collider Bias and Interactions on the Log-Additive Scale

Author

Gkatzionis, Apostolos, Seaman, Shaun R., Hughes, Rachael A., and Tilling, Kate

Subjects
Statistics - Methodology
Abstract

Collider bias occurs when conditioning on a common effect (collider) of two variables $X, Y$. In this manuscript, we quantify the collider bias in the estimated association between exposure $X$ and outcome $Y$ induced by selecting on one value of a binary collider $S$ of the exposure and the outcome. In the case of logistic regression, it is known that the magnitude of the collider bias in the exposure-outcome regression coefficient is proportional to the strength of interaction $\delta_3$ between $X$ and $Y$ in a log-additive model for the collider: $\mathbb{P} (S = 1 | X, Y) = \exp \left\{ \delta_0 + \delta_1 X + \delta_2 Y + \delta_3 X Y \right\}$. We show that this result also holds under a linear or Poisson regression model for the exposure-outcome association. We then illustrate by simulation that even if a log-additive model with interactions is not the true model for the collider, the interaction term in such a model is still informative about the magnitude of collider bias. Finally, we discuss the implications of these findings for methods that attempt to adjust for collider bias, such as inverse probability weighting which is often implemented without including interactions between variables in the weighting model., Comment: Main Part: 19 pages, 5 figures, 3 tables. Supplement: 16 pages, 3 figures, 5 tables

Published
2023

9. Using Instruments for Selection to Adjust for Selection Bias in Mendelian Randomization

Author

Gkatzionis, Apostolos, Tchetgen, Eric J. Tchetgen, Heron, Jon, Northstone, Kate, and Tilling, Kate

Subjects
Statistics - Methodology, Quantitative Biology - Quantitative Methods
Abstract

Selection bias is a common concern in epidemiologic studies. In the literature, selection bias is often viewed as a missing data problem. Popular approaches to adjust for bias due to missing data, such as inverse probability weighting, rely on the assumption that data are missing at random and can yield biased results if this assumption is violated. In observational studies with outcome data missing not at random, Heckman's sample selection model can be used to adjust for bias due to missing data. In this paper, we review Heckman's method and a similar approach proposed by Tchetgen Tchetgen and Wirth (2017). We then discuss how to apply these methods to Mendelian randomization analyses using individual-level data, with missing data for either the exposure or outcome or both. We explore whether genetic variants associated with participation can be used as instruments for selection. We then describe how to obtain missingness-adjusted Wald ratio, two-stage least squares and inverse variance weighted estimates. The two methods are evaluated and compared in simulations, with results suggesting that they can both mitigate selection bias but may yield parameter estimates with large standard errors in some settings. In an illustrative real-data application, we investigate the effects of body mass index on smoking using data from the Avon Longitudinal Study of Parents and Children., Comment: Main part: 28 pages, 3 figures, 4 tables. Supplement: 24 pages, 8 figures, 10 tables. Paper currently under review

Published
2022

10. Mixed-effects location scale models for joint modelling school value-added effects on the mean and variance of student achievement

Author

Leckie, George, Parker, Richard, Goldstein, Harvey, and Tilling, Kate

Subjects
Statistics - Applications
Abstract

School value-added models are widely applied to study, monitor, and hold schools to account for school differences in student learning. The traditional model is a mixed-effects linear regression of student current achievement on student prior achievement, background characteristics, and a school random intercept effect. The latter is referred to as the school value-added score and measures the mean student covariate-adjusted achievement in each school. In this article, we argue that further insights may be gained by additionally studying the variance in this quantity in each school. These include the ability to identify both individual schools and school types that exhibit unusually high or low variability in student achievement, even after accounting for differences in student intakes. We explore and illustrate how this can be done via fitting mixed-effects location scale versions of the traditional school value-added model. We discuss the implications of our work for research and school accountability systems.

Published
2021

13. A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E)

Author

Higgins, Julian P.T., Morgan, Rebecca L., Rooney, Andrew A., Taylor, Kyla W., Thayer, Kristina A., Silva, Raquel A., Lemeris, Courtney, Akl, Elie A., Bateson, Thomas F., Berkman, Nancy D., Glenn, Barbara S., Hróbjartsson, Asbjørn, LaKind, Judy S., McAleenan, Alexandra, Meerpohl, Joerg J., Nachman, Rebecca M., Obbagy, Julie E., O'Connor, Annette, Radke, Elizabeth G., Savović, Jelena, Schünemann, Holger J., Shea, Beverley, Tilling, Kate, Verbeek, Jos, Viswanathan, Meera, and Sterne, Jonathan A.C.

Published
2024
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14. Conceptualising Natural and Quasi Experiments in Public Health

Author

de Vocht, Frank, Katikireddi, Srinivasa Vittal, McQuire, Cheryl, Tilling, Kate, Hickman, Matthew, and Craig, Peter

Subjects
Statistics - Methodology
Abstract

Background: Natural or quasi experiments are appealing for public health research because they enable the evaluation of events or interventions that are difficult or impossible to manipulate experimentally, such as many policy and health system reforms. However, there remains ambiguity in the literature about their definition and how they differ from randomised controlled experiments and from other observational designs. Methods: We conceptualise natural experiments in in the context of public health evaluations, align the study design to the Target Trial Framework, and provide recommendation for improvement of their design and reporting. Results: Natural experiment studies combine features of experiments and non-experiments. They differ from RCTs in that exposure allocation is not controlled by researchers while they differ from other observational designs in that they evaluate the impact of event or exposure changes. As a result they are, in theory, less susceptible to bias than other observational study designs. Importantly, the strength of causal inferences relies on the plausibility that the exposure allocation can be considered "as-if randomised". The target trial framework provides a systematic basis for assessing the plausibility of such claims, and enables a structured method for assessing other design elements. Conclusions: Natural experiment studies should be considered a distinct study design rather than a set of tools for analyses of non-randomised interventions. Alignment of natural experiments to the Target Trial framework will clarify the strength of evidence underpinning claims about the effectiveness of public health interventions., Comment: 28 pages, 1 figure, 1 table, 1 supplementary table

Published
2020
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15. Framework for the Treatment And Reporting of Missing data in Observational Studies: The TARMOS framework

Author

Lee, Katherine J, Tilling, Kate, Cornish, Rosie P, Little, Roderick JA, Bell, Melanie L, Goetghebeur, Els, Hogan, Joseph W, and Carpenter, James R

Subjects
Statistics - Methodology, 6207
Abstract

Missing data are ubiquitous in medical research. Although there is increasing guidance on how to handle missing data, practice is changing slowly and misapprehensions abound, particularly in observational research. We present a practical framework for handling and reporting the analysis of incomplete data in observational studies, which we illustrate using a case study from the Avon Longitudinal Study of Parents and Children. The framework consists of three steps: 1) Develop an analysis plan specifying the analysis model and how missing data are going to be addressed. An important consideration is whether a complete records analysis is likely to be valid, whether multiple imputation or an alternative approach is likely to offer benefits, and whether a sensitivity analysis regarding the missingness mechanism is required. 2) Explore the data, checking the methods outlined in the analysis plan are appropriate, and conduct the pre-planned analysis. 3) Report the results, including a description of the missing data, details on how the missing data were addressed, and the results from all analyses, interpreted in light of the missing data and the clinical relevance. This framework seeks to support researchers in thinking systematically about missing data, and transparently reporting the potential effect on the study results., Comment: 37 pages, including 3 Figures, 1 table and supplementary material

Published
2020

17. Sample-constrained partial identification with application to selection bias

Author

Tudball, Matthew, Hughes, Rachael, Tilling, Kate, Bowden, Jack, and Zhao, Qingyuan

Subjects
Statistics - Methodology
Abstract

Many partial identification problems can be characterized by the optimal value of a function over a set where both the function and set need to be estimated by empirical data. Despite some progress for convex problems, statistical inference in this general setting remains to be developed. To address this, we derive an asymptotically valid confidence interval for the optimal value through an appropriate relaxation of the estimated set. We then apply this general result to the problem of selection bias in population-based cohort studies. We show that existing sensitivity analyses, which are often conservative and difficult to implement, can be formulated in our framework and made significantly more informative via auxiliary information on the population. We conduct a simulation study to evaluate the finite sample performance of our inference procedure and conclude with a substantive motivating example on the causal effect of education on income in the highly-selected UK Biobank cohort. We demonstrate that our method can produce informative bounds using plausible population-level auxiliary constraints. We implement this method in the R package selectioninterval., Comment: 23 pages, 6 figures

Published
2019
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18. Ethnic differences in the indirect effects of the COVID-19 pandemic on clinical monitoring and hospitalisations for non-COVID conditions in England: a population-based, observational cohort study using the OpenSAFELY platform

Author

Chaturvedi, Nishi, Park, Chloe, Carnemolla, Alisia, Williams, Dylan, Knueppel, Anika, Boyd, Andy, Turner, Emma L., Evans, Katharine M., Thomas, Richard, Berman, Samantha, McLachlan, Stela, Crane, Matthew, Whitehorn, Rebecca, Oakley, Jacqui, Foster, Diane, Woodward, Hannah, Campbell, Kirsteen C., Timpson, Nicholas, Kwong, Alex, Soares, Ana Goncalves, Griffith, Gareth, Toms, Renin, Jones, Louise, Annie, Herbert, Mitchell, Ruth, Palmer, Tom, Sterne, Jonathan, Walker, Venexia, Huntley, Lizzie, Fox, Laura, Denholm, Rachel, Knight, Rochelle, Northstone, Kate, Kanagaratnam, Arun, Horne, Elsie, Forbes, Harriet, North, Teri, Taylor, Kurt, Arab, Marwa A.L., Walker, Scott, Coronado, Jose I.C., Karthikeyan, Arun S., Ploubidis, George, Moltrecht, Bettina, Booth, Charlotte, Parsons, Sam, Wielgoszewska, Bozena, Bridger-Staatz, Charis, Steves, Claire, Thompson, Ellen, Garcia, Paz, Cheetham, Nathan, Bowyer, Ruth, Freydin, Maxim, Roberts, Amy, Goldacre, Ben, Walker, Alex, Morley, Jess, Hulme, William, Nab, Linda, Fisher, Louis, MacKenna, Brian, Andrews, Colm, Curtis, Helen, Hopcroft, Lisa, Green, Amelia, Patalay, Praveetha, Maddock, Jane, Patel, Kishan, Stafford, Jean, Jacques, Wels, Tilling, Kate, Macleod, John, McElroy, Eoin, Shah, Anoop, Silverwood, Richard, Denaxas, Spiros, Flaig, Robin, McCartney, Daniel, Campbell, Archie, Tomlinson, Laurie, Tazare, John, Zheng, Bang, Smeeth, Liam, Herrett, Emily, Cowling, Thomas, Mansfield, Kate, Costello, Ruth E., Wang, Kevin, Mansfield, Kathryn, Mahalingasivam, Viyaasan, Douglas, Ian, Langan, Sinead, Brophy, Sinead, Parker, Michael, Kennedy, Jonathan, McEachan, Rosie, Wright, John, Willan, Kathryn, Badrick, Ellena, Santorelli, Gillian, Yang, Tiffany, Hou, Bo, Steptoe, Andrew, Giorgio, Di Gessa, Zhu, Jingmin, Zaninotto, Paola, Wood, Angela, Cezard, Genevieve, Ip, Samantha, Bolton, Tom, Sampri, Alexia, Rafeti, Elena, Almaghrabi, Fatima, Sheikh, Aziz, Shah, Syed A., Katikireddi, Vittal, Shaw, Richard, Hamilton, Olivia, Green, Michael, Kromydas, Theocharis, Kopasker, Daniel, Greaves, Felix, Willans, Robert, Glen, Fiona, Sharp, Steve, Hughes, Alun, Wong, Andrew, Howes, Lee Hamill, Rapala, Alicja, Nigrelli, Lidia, McArdle, Fintan, Beckford, Chelsea, Raman, Betty, Dobson, Richard, Folarin, Amos, Stewart, Callum, Ranjan, Yatharth, Carpentieri, Jd, Sheard, Laura, Fang, Chao, Baz, Sarah, Gibson, Andy, Kellas, John, Neubauer, Stefan, Piechnik, Stefan, Lukaschuk, Elena, Saunders, Laura C., Wild, James M., Smith, Stephen, Jezzard, Peter, Tunnicliffe, Elizabeth, Sanders, Zeena-Britt, Finnigan, Lucy, Ferreira, Vanessa, Green, Mark, Rhead, Rebecca, Kibble, Milla, Wei, Yinghui, Lemanska, Agnieszka, Perez-Reche, Francisco, Piehlmaier, Dominik, Teece, Lucy, Parker, Edward, Walker, Alex J., Inglesby, Peter, Curtis, Helen J., Morton, Caroline E., Morley, Jessica, Mehrkar, Amir, Bacon, Sebastian C.J., Hickman, George, Croker, Richard, Evans, David, Ward, Tom, DeVito, Nicholas J., Green, Amelia C.A., Massey, Jon, Smith, Rebecca M., Hulme, William J., Davy, Simon, Andrews, Colm D., Hopcroft, Lisa E.M., Drysdale, Henry, Dillingham, Iain, Park, Robin Y., Higgins, Rose, Cunningham, Christine, Wiedemann, Milan, Maude, Steven, Macdonald, Orla, Butler-Cole, Ben F.C., O'Dwyer, Thomas, Stables, Catherine L., Wood, Christopher, Brown, Andrew D., Speed, Victoria, Bridges, Lucy, Schaffer, Andrea L., Walters, Caroline E., Rentsch, Christopher T., Bhaskaran, Krishnan, Schultze, Anna, Williamson, Elizabeth J., McDonald, Helen I., Tomlinson, Laurie A., Mathur, Rohini, Eggo, Rosalind M., Wing, Kevin, Wong, Angel Y.S., Grieve, Richard, Grint, Daniel J., Mansfield, Kathryn E., Douglas, Ian J., Evans, Stephen J.W., Walker, Jemma L., Cowling, Thomas E., Herrett, Emily L., Parker, Edward P.K., Bates, Christopher, Cockburn, Jonathan, Parry, John, Hester, Frank, Harper, Sam, O'Hanlon, Shaun, Eavis, Alex, Jarvis, Richard, Avramov, Dima, Griffiths, Paul, Fowles, Aaron, Parkes, Nasreen, Nicholson, Brian, Perera, Rafael, Harrison, David, Khunti, Kamlesh, Sterne, Jonathan AC., Quint, Jennifer, Henderson, Alasdair D., Carreira, Helena, Bidulka, Patrick, Warren-Gash, Charlotte, Hayes, Joseph F., Quint, Jennifer K., Katikireddi, Srinivasa Vittal, and Langan, Sinéad M.

Published
2023
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20. Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records

Author

Thompson, Ellen J., Williams, Dylan M., Walker, Alex J., Mitchell, Ruth E., Niedzwiedz, Claire L., Yang, Tiffany C., Huggins, Charlotte F., Kwong, Alex S. F., Silverwood, Richard J., Di Gessa, Giorgio, Bowyer, Ruth C. E., Northstone, Kate, Hou, Bo, Green, Michael J., Dodgeon, Brian, Doores, Katie J., Duncan, Emma L., Williams, Frances M. K., Steptoe, Andrew, Porteous, David J., McEachan, Rosemary R. C., Tomlinson, Laurie, Goldacre, Ben, Patalay, Praveetha, Ploubidis, George B., Katikireddi, Srinivasa Vittal, Tilling, Kate, Rentsch, Christopher T., Timpson, Nicholas J., Chaturvedi, Nishi, and Steves, Claire J.

Published
2022
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25. Prenatal and early life influences on epigenetic age in children: a study of mother–offspring pairs from two cohort studies

Author

Simpkin, Andrew J, Hemani, Gibran, Suderman, Matthew, Gaunt, Tom R, Lyttleton, Oliver, Mcardle, Wendy L, Ring, Susan M, Sharp, Gemma C, Tilling, Kate, Horvath, Steve, Kunze, Sonja, Peters, Annette, Waldenberger, Melanie, Ward-Caviness, Cavin, Nohr, Ellen A, Sørensen, Thorkild IA, Relton, Caroline L, and Smith, George Davey

Subjects
Aging, Pediatric Research Initiative, Pediatric, Clinical Research, Genetics, Perinatal Period - Conditions Originating in Perinatal Period, Prevention, 2.2 Factors relating to the physical environment, Aetiology, Generic health relevance, Good Health and Well Being, Birth Weight, Child, Cohort Studies, DNA Methylation, Epigenesis, Genetic, Humans, Longitudinal Studies, Mothers, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time-points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. AA was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging.

Published
2016

30. Associations between insomnia and pregnancy and perinatal outcomes: Evidence from mendelian randomization and multivariable regression analyses

Author

Yang, Qian, Borges, Maria Carolina, Sanderson, Eleanor, Magnus, Maria C., Kilpi, Fanny, Collings, Paul J., Soares, Ana Luiza, West, Jane, Magnus, Per, Wright, John, Håberg, Siri E., Tilling, Kate, and Lawlor, Deborah A.

Subjects
Miscarriage -- Risk factors, Insomnia -- Complications and side effects, Birth weight, Low -- Risk factors, Multivariate analysis -- Methods, Biological sciences
Abstract

Background Insomnia is common and associated with adverse pregnancy and perinatal outcomes in observational studies. However, those associations could be vulnerable to residual confounding or reverse causality. Our aim was to estimate the association of insomnia with stillbirth, miscarriage, gestational diabetes (GD), hypertensive disorders of pregnancy (HDP), perinatal depression, preterm birth (PTB), and low/high offspring birthweight (LBW/HBW). Methods and findings We used 2-sample mendelian randomization (MR) with 81 single-nucleotide polymorphisms (SNPs) instrumenting for a lifelong predisposition to insomnia. Our outcomes included ever experiencing stillbirth, ever experiencing miscarriage, GD, HDP, perinatal depression, PTB (gestational age Conclusions In this study, we observed some evidence in support of a possible causal relationship between genetically predicted insomnia and miscarriage, perinatal depression, and LBW. Our study also found observational evidence in support of an association between insomnia in pregnancy and perinatal depression, with no clear multivariable evidence of an association with LBW. Our findings highlight the importance of healthy sleep in women of reproductive age, though replication in larger studies, including with genetic instruments specific to insomnia in pregnancy are important., Author(s): Qian Yang 1,2,*, Maria Carolina Borges 1,2, Eleanor Sanderson 1,2, Maria C. Magnus 1,2,3, Fanny Kilpi 1,2, Paul J. Collings 4, Ana Luiza Soares 1,2, Jane West 4, Per [...]

Published
2022
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37. Association between perinatal mortality and morbidity and customised and non-customised birthweight centiles in Denmark, Finland, Norway, Wales, and England: comparative, population based, record linkage study

Author

Kilpi, Fanny, primary, Jones, Hayley E, additional, Magnus, Maria Christine, additional, Santorelli, Gillian, additional, Højsgaard Schmidt, Lise Kristine, additional, Urhoj, Stine Kjaer, additional, Nelson, Scott M, additional, Tuffnell, Derek, additional, French, Robert, additional, Magnus, Per Minor, additional, Nybo Andersen, Anne-Marie, additional, Martikainen, Pekka, additional, Tilling, Kate, additional, and Lawlor, Deborah A, additional

Published
2023
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39. Ethnic differences in the indirect effects of the COVID-19 pandemic on clinical monitoring and hospitalisations for non-COVID conditions in England: a population-based, observational cohort study using the OpenSAFELY platform

Author

Costello, Ruth E., primary, Tazare, John, additional, Piehlmaier, Dominik, additional, Herrett, Emily, additional, Parker, Edward P.K., additional, Zheng, Bang, additional, Mansfield, Kathryn E., additional, Henderson, Alasdair D., additional, Carreira, Helena, additional, Bidulka, Patrick, additional, Wong, Angel Y.S., additional, Warren-Gash, Charlotte, additional, Hayes, Joseph F., additional, Quint, Jennifer K., additional, MacKenna, Brian, additional, Mehrkar, Amir, additional, Eggo, Rosalind M., additional, Katikireddi, Srinivasa Vittal, additional, Tomlinson, Laurie, additional, Langan, Sinéad M., additional, Mathur, Rohini, additional, Chaturvedi, Nishi, additional, Park, Chloe, additional, Carnemolla, Alisia, additional, Williams, Dylan, additional, Knueppel, Anika, additional, Boyd, Andy, additional, Turner, Emma L., additional, Evans, Katharine M., additional, Thomas, Richard, additional, Berman, Samantha, additional, McLachlan, Stela, additional, Crane, Matthew, additional, Whitehorn, Rebecca, additional, Oakley, Jacqui, additional, Foster, Diane, additional, Woodward, Hannah, additional, Campbell, Kirsteen C., additional, Timpson, Nicholas, additional, Kwong, Alex, additional, Soares, Ana Goncalves, additional, Griffith, Gareth, additional, Toms, Renin, additional, Jones, Louise, additional, Annie, Herbert, additional, Mitchell, Ruth, additional, Palmer, Tom, additional, Sterne, Jonathan, additional, Walker, Venexia, additional, Huntley, Lizzie, additional, Fox, Laura, additional, Denholm, Rachel, additional, Knight, Rochelle, additional, Northstone, Kate, additional, Kanagaratnam, Arun, additional, Horne, Elsie, additional, Forbes, Harriet, additional, North, Teri, additional, Taylor, Kurt, additional, Arab, Marwa A.L., additional, Walker, Scott, additional, Coronado, Jose I.C., additional, Karthikeyan, Arun S., additional, Ploubidis, George, additional, Moltrecht, Bettina, additional, Booth, Charlotte, additional, Parsons, Sam, additional, Wielgoszewska, Bozena, additional, Bridger-Staatz, Charis, additional, Steves, Claire, additional, Thompson, Ellen, additional, Garcia, Paz, additional, Cheetham, Nathan, additional, Bowyer, Ruth, additional, Freydin, Maxim, additional, Roberts, Amy, additional, Goldacre, Ben, additional, Walker, Alex, additional, Morley, Jess, additional, Hulme, William, additional, Nab, Linda, additional, Fisher, Louis, additional, Andrews, Colm, additional, Curtis, Helen, additional, Hopcroft, Lisa, additional, Green, Amelia, additional, Patalay, Praveetha, additional, Maddock, Jane, additional, Patel, Kishan, additional, Stafford, Jean, additional, Jacques, Wels, additional, Tilling, Kate, additional, Macleod, John, additional, McElroy, Eoin, additional, Shah, Anoop, additional, Silverwood, Richard, additional, Denaxas, Spiros, additional, Flaig, Robin, additional, McCartney, Daniel, additional, Campbell, Archie, additional, Smeeth, Liam, additional, Cowling, Thomas, additional, Mansfield, Kate, additional, Costello, Ruth E., additional, Wang, Kevin, additional, Mansfield, Kathryn, additional, Mahalingasivam, Viyaasan, additional, Douglas, Ian, additional, Langan, Sinead, additional, Brophy, Sinead, additional, Parker, Michael, additional, Kennedy, Jonathan, additional, McEachan, Rosie, additional, Wright, John, additional, Willan, Kathryn, additional, Badrick, Ellena, additional, Santorelli, Gillian, additional, Yang, Tiffany, additional, Hou, Bo, additional, Steptoe, Andrew, additional, Giorgio, Di Gessa, additional, Zhu, Jingmin, additional, Zaninotto, Paola, additional, Wood, Angela, additional, Cezard, Genevieve, additional, Ip, Samantha, additional, Bolton, Tom, additional, Sampri, Alexia, additional, Rafeti, Elena, additional, Almaghrabi, Fatima, additional, Sheikh, Aziz, additional, Shah, Syed A., additional, Katikireddi, Vittal, additional, Shaw, Richard, additional, Hamilton, Olivia, additional, Green, Michael, additional, Kromydas, Theocharis, additional, Kopasker, Daniel, additional, Greaves, Felix, additional, Willans, Robert, additional, Glen, Fiona, additional, Sharp, Steve, additional, Hughes, Alun, additional, Wong, Andrew, additional, Howes, Lee Hamill, additional, Rapala, Alicja, additional, Nigrelli, Lidia, additional, McArdle, Fintan, additional, Beckford, Chelsea, additional, Raman, Betty, additional, Dobson, Richard, additional, Folarin, Amos, additional, Stewart, Callum, additional, Ranjan, Yatharth, additional, Carpentieri, Jd, additional, Sheard, Laura, additional, Fang, Chao, additional, Baz, Sarah, additional, Gibson, Andy, additional, Kellas, John, additional, Neubauer, Stefan, additional, Piechnik, Stefan, additional, Lukaschuk, Elena, additional, Saunders, Laura C., additional, Wild, James M., additional, Smith, Stephen, additional, Jezzard, Peter, additional, Tunnicliffe, Elizabeth, additional, Sanders, Zeena-Britt, additional, Finnigan, Lucy, additional, Ferreira, Vanessa, additional, Green, Mark, additional, Rhead, Rebecca, additional, Kibble, Milla, additional, Wei, Yinghui, additional, Lemanska, Agnieszka, additional, Perez-Reche, Francisco, additional, Teece, Lucy, additional, Parker, Edward, additional, Walker, Alex J., additional, Inglesby, Peter, additional, Curtis, Helen J., additional, Morton, Caroline E., additional, Morley, Jessica, additional, Bacon, Sebastian C.J., additional, Hickman, George, additional, Croker, Richard, additional, Evans, David, additional, Ward, Tom, additional, DeVito, Nicholas J., additional, Green, Amelia C.A., additional, Massey, Jon, additional, Smith, Rebecca M., additional, Hulme, William J., additional, Davy, Simon, additional, Andrews, Colm D., additional, Hopcroft, Lisa E.M., additional, Drysdale, Henry, additional, Dillingham, Iain, additional, Park, Robin Y., additional, Higgins, Rose, additional, Cunningham, Christine, additional, Wiedemann, Milan, additional, Maude, Steven, additional, Macdonald, Orla, additional, Butler-Cole, Ben F.C., additional, O'Dwyer, Thomas, additional, Stables, Catherine L., additional, Wood, Christopher, additional, Brown, Andrew D., additional, Speed, Victoria, additional, Bridges, Lucy, additional, Schaffer, Andrea L., additional, Walters, Caroline E., additional, Rentsch, Christopher T., additional, Bhaskaran, Krishnan, additional, Schultze, Anna, additional, Williamson, Elizabeth J., additional, McDonald, Helen I., additional, Tomlinson, Laurie A., additional, Wing, Kevin, additional, Grieve, Richard, additional, Grint, Daniel J., additional, Douglas, Ian J., additional, Evans, Stephen J.W., additional, Walker, Jemma L., additional, Cowling, Thomas E., additional, Herrett, Emily L., additional, Bates, Christopher, additional, Cockburn, Jonathan, additional, Parry, John, additional, Hester, Frank, additional, Harper, Sam, additional, O'Hanlon, Shaun, additional, Eavis, Alex, additional, Jarvis, Richard, additional, Avramov, Dima, additional, Griffiths, Paul, additional, Fowles, Aaron, additional, Parkes, Nasreen, additional, Nicholson, Brian, additional, Perera, Rafael, additional, Harrison, David, additional, Khunti, Kamlesh, additional, Sterne, Jonathan AC., additional, and Quint, Jennifer, additional

Published
2023
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40. Natural experiments for the evaluation of place-based public health interventions: a methodology scoping review

Author

Albers, Patricia N., primary, Rinaldi, Chiara, additional, Brown, Heather, additional, Mason, Kate E., additional, d'Apice, Katrina, additional, McGill, Elizabeth, additional, McQuire, Cheryl, additional, Craig, Peter, additional, Laverty, Anthony A., additional, Beeson, Morgan, additional, Campbell, Mhairi, additional, Egan, Matt, additional, Gibson, Marcia, additional, Fuller, Maxwell, additional, Dillon, Amy, additional, Taylor-Robinson, David, additional, Jago, Russell, additional, Tilling, Kate, additional, Barr, Benjamin, additional, Sniehotta, Falko F., additional, Hickman, Matthew, additional, Millett, Christopher J., additional, and de Vocht, Frank, additional

Published
2023
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44. Association of physical activity intensity and bout length with mortality: An observational study of 79,503 UK Biobank participants

Author

Millard, Louise A. C., Tilling, Kate, Gaunt, Tom R., Carslake, David, and Lawlor, Deborah A.

Subjects
Exercise -- Health aspects -- Physiological aspects, Medical research, Medicine, Experimental, Mortality -- Health aspects -- Physiological aspects -- United Kingdom, Sedentary behavior -- Research, Health behavior -- Research, Biological sciences
Abstract

Background Spending more time active (and less sedentary) is associated with health benefits such as improved cardiovascular health and lower risk of all-cause mortality. It is unclear whether these associations differ depending on whether time spent sedentary or in moderate-vigorous physical activity (MVPA) is accumulated in long or short bouts. In this study, we used a novel method that accounts for substitution (i.e., more time in MVPA means less time sleeping, in light activity or sedentary) to examine whether length of sedentary and MVPA bouts associates with all-cause mortality. Methods and findings We used data on 79,503 adult participants from the population-based UK Biobank cohort, which recruited participants between 2006 and 2010 (mean age at accelerometer wear 62.1 years [SD = 7.9], 54.5% women; mean length of follow-up 5.1 years [SD = 0.73]). We derived (1) the total time participants spent in activity categories-sleep, sedentary, light activity, and MVPA-on average per day; (2) time spent in sedentary bouts of short (1 to 15 minutes), medium (16 to 40 minutes), and long (41+ minutes) duration; and (3) MVPA bouts of very short (1 to 9 minutes), short (10 to 15 minutes), medium (16 to 40 minutes), and long (41+ minutes) duration. We used Cox proportion hazards regression to estimate the association of spending 10 minutes more average daily time in one activity or bout length category, coupled with 10 minutes less time in another, with all-cause mortality. Those spending more time in MVPA had lower mortality risk, irrespective of whether this replaced time spent sleeping, sedentary, or in light activity, and these associations were of similar magnitude (e.g., hazard ratio [HR] 0.96 [95% CI: 0.94, 0.97; P < 0.001] per 10 minutes more MVPA, coupled with 10 minutes less light activity per day). Those spending more time sedentary had higher mortality risk if this replaced light activity (HR 1.02 [95% CI: 1.01, 1.02; P < 0.001] per 10 minutes more sedentary time, with 10 minutes less light activity per day) and an even higher risk if this replaced MVPA (HR 1.06 [95% CI: 1.05, 1.08; P < 0.001] per 10 minutes more sedentary time, with 10 minutes less MVPA per day). We found little evidence that mortality risk differed depending on the length of sedentary or MVPA bouts. Key limitations of our study are potential residual confounding, the limited length of follow-up, and use of a select sample of the United Kingdom population. Conclusions We have shown that time spent in MVPA was associated with lower mortality, irrespective of whether it replaced time spent sleeping, sedentary, or in light activity. Time spent sedentary was associated with higher mortality risk, particularly if it replaced MVPA. This emphasises the specific importance of MVPA. Our findings suggest that the impact of MVPA does not differ depending on whether it is obtained from several short bouts or fewer longer bouts, supporting the recent removal of the requirement that MVPA should be accumulated in bouts of 10 minutes or more from the UK and the United States policy. Further studies are needed to investigate causality and explore health outcomes beyond mortality., Author(s): Louise A. C. Millard 1,2,*, Kate Tilling 1,2, Tom R. Gaunt 1,2, David Carslake 1,2, Deborah A. Lawlor 1,2 Introduction Physical activity is associated with many health benefits such [...]

Published
2021
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46. The effect of a lifestyle intervention in obese pregnant women on gestational metabolic profiles: findings from the UK Pregnancies Better Eating and Activity Trial (UPBEAT) randomised controlled trial

Author

Mills, Harriet L., Patel, Nashita, White, Sara L., Pasupathy, Dharmintra, Briley, Annette L., Santos Ferreira, Diana L., Seed, Paul T., Nelson, Scott M., Sattar, Naveed, Tilling, Kate, Poston, Lucilla, Lawlor, Deborah A., and On behalf of the UPBEAT Consortium

Published
2019
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47. Natural experiments for the evaluation of place-based public health interventions: a methodology scoping review

Author

Albers, Patricia N., Rinaldi, Chiara, Brown, Heather, Mason, Kate E., dApice, Katrina, McGill, Elizabeth, McQuire, Cheryl, Craig, Peter, Laverty, Anthony A., Beeson, Morgan, Campbell, Mhairi, Egan, Matt, Gibson, Marcia, Fuller, Maxwell, Dillon, Amy, Taylor-Robinson, David, Jago, Russell, Tilling, Kate, Barr, Benjamin, Sniehotta, Falko F., Hickman, Matthew, Millett, Christopher J., and de Vocht, Frank

Subjects
Public Health, Environmental and Occupational Health
Abstract

Introduction: Place-based public health evaluations are increasingly making use of natural experiments. This scoping review aimed to provide an overview of the design and use of natural experiment evaluations (NEEs), and an assessment of the plausibility of the as-if randomization assumption.Methods: A systematic search of three bibliographic databases (Pubmed, Web of Science and Ovid-Medline) was conducted in January 2020 to capture publications that reported a natural experiment of a place-based public health intervention or outcome. For each, study design elements were extracted. An additional evaluation of as-if randomization was conducted by 12 of this paper's authors who evaluated the same set of 20 randomly selected studies and assessed ‘as-if ' randomization for each.Results: 366 NEE studies of place-based public health interventions were identified. The most commonly used NEE approach was a Difference-in-Differences study design (25%), followed by before-after studies (23%) and regression analysis studies. 42% of NEEs had likely or probable as-if randomization of exposure (the intervention), while for 25% this was implausible. An inter-rater agreement exercise indicated poor reliability of as-if randomization assignment. Only about half of NEEs reported some form of sensitivity or falsification analysis to support inferences.Conclusion: NEEs are conducted using many different designs and statistical methods and encompass various definitions of a natural experiment, while it is questionable whether all evaluations reported as natural experiments should be considered as such. The likelihood of as-if randomization should be specifically reported, and primary analyses should be supported by sensitivity analyses and/or falsification tests. Transparent reporting of NEE designs and evaluation methods will contribute to the optimum use of place-based NEEs.

Published
2023

48. Evaluating causal associations of chronotype with pregnancy and perinatal outcomes and its interactions with insomnia and sleep duration: a Mendelian randomization study

Author

Yang, Qian, Magnus, Maria C, Kilpi, Fanny, Santorelli, Gillian, Soares, Ana Goncalves, West, Jane, Magnus, Per, Håberg, Siri E., Tilling, Kate, Lawlor, Deborah A, Borges, M Carolina, and Sanderson, Eleanor

Subjects
Article
Abstract

IMPORTANCE: Observational studies suggest that chronotype is associated with pregnancy and perinatal outcomes. Whether these associations are causal is unclear. OBJECTIVE: To explore associations of a lifetime genetic predisposition to an evening preference chronotype with pregnancy and perinatal outcomes, and explore differences in associations of insomnia and sleep duration with those outcomes between chronotype. DESIGN, SETTING, AND PARTICIPANTS: We conducted two-sample Mendelian randomization (MR) using 105 genetic variants reported in a genome-wide association study (N=248 100) to instrument for lifelong predisposition to evening-versus morning-preference chronotypes. We generated variant-outcome associations in European ancestry women from UK Biobank (UKB, N=176 897), Avon Longitudinal Study of Parents and Children (ALSPAC, N=6826), Born in Bradford (BiB, N=2940) and Norwegian Mother, Father and Child Cohort Study (MoBa, with linked data from the Medical Birth Registry of Norway (MBRN), N=57 430), and extracted equivalent associations from FinnGen (N=190 879). We used inverse variance weighted (IVW) as main analysis, with weighted median and MR-Egger as sensitivity analyses. We also conducted IVW analyses of insomnia and sleep duration on the outcomes stratified by genetically predicted chronotype. EXPOSURES: Self-reported and genetically predicted chronotype, insomnia and sleep duration. MAIN OUTCOMES AND MEASURES: Stillbirth, miscarriage, preterm birth, gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, low birthweight and macrosomia. RESULTS: In IVW and sensitivity analyses we did not find robust evidence of effects of chronotype on the outcomes. Insomnia was associated with a higher risk of preterm birth among evening preference women (odds ratio 1.61, 95% confidence interval: 1.17, 2.21), but not among morning preference women (odds ratio 0.87, 95% confidence interval: 0.64, 1.18), with an interaction P-value=0.01. There was no evidence of interactions between insomnia and chronotype on other outcomes, or between sleep duration and chronotype on any outcomes. CONCLUSIONS AND RELEVANCE: This study raises the possibility of a higher risk of preterm birth among women with insomnia who also have an evening preference chronotype. Our findings warrant replications due to imprecision of the estimates. KEY POINTS: QUESTION: Does an evening preference chronotype adversely affect pregnancy and perinatal outcomes? Is there an interaction between chronotype and either insomnia or sleep duration in relation to those outcomes? FINDINGS: There was no evidence that evening preference was associated with pregnancy or perinatal outcomes. Women with a genetically predicted insomnia had a higher risk of preterm birth, if they also had a genetically predicted preference for evening chronotype. MEANING: The suggestive interaction between insomnia and evening preference on preterm birth, if replicated, supports targeting insomnia prevention in women of reproductive age with an evening chronotype.

Published
2023

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