Dr John Watkins

Publication

• Date
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Research

Introduction

Most though not all of my research has involved various elements of infant and child wellbeing and a number of pieces of work with their associated publications are summarised below. 

Effects of prematurity and low birth weight on Spirometry

Investigations of effects of being born at term with IntraUterine Growth Retardation (IUGR), i.e. in the lightest 10% for gestational age when compare to appropriately weighted controls showed that IUGR born children from the ALSPAC cohort had significantly lower lung function measures (FEV1, FVC and FEF2575) at school age than the controls. Looking just at the IGUR children we also showed that those who “caught up”, i.e. became weight appropriate for age by 8-9 years had higher – although not significantly - lung function measures than those that didn’t. These two groups could represent those children who are genetically small and those that were small at birth due to some adverse reason i.e. maternal smoking.

Kotecha SJ, Watkins WJ, Heron J, Henderson J, Dunstan FD, Kotecha S. Spirometric lung function in school-age children: effect of intrauterine growth retardation and catch-up growth. American journal of respiratory and critical care medicine. 2010;181(9):969-74. https://doi.org/10.1164/rccm.200906-0897OC

 To investigate prematurity, we compared the lung function at 8-9 and 14-17 years for children born late preterm (33-34 and 35-36 weeks gestation) with children of similar age born at term (>=37 weeks gestation). We also compared these with very preterm children born at 25-32 weeks gestation. The results showed that the children born at 33-34 weeks had similarly to the 25-32 weekers, significantly poorer lung function at 8-9 years than the term children however the 35-36 weekers did not. These detriments at 8-9 were somewhat mitigated by 14-17 years.

Kotecha SJ, Watkins WJ, Paranjothy S, Dunstan FD, Henderson AJ, Kotecha S. Effect of late preterm birth on longitudinal lung spirometry in school age children and adolescents. Thorax. 2012;67(1):54-61. http://dx.doi.org/10.1136/thoraxjnl-2011-200329

The effect of low birth weight of term children at 8-9 years and again at 14-17 years was assessed again using the ALSPAC cohort. Standardised lung function measures, adjusted for sex, height, and age, were modeled in terms of birth weight z-score and adjusted for sex as well as gestation and head circumference and other potential confounders. The lung function measures (FEV1, FVC and FEF2575) were significantly associated at 8-9 years with birth weight and these relationships largely continued after the models were fully adjusted. However by 14-17 years the relationships were largely non-significant again demonstrating the mitigation of detriments at birth by 14-17 years of age, i.e. post puberty.

Kotecha SJ, Watkins WJ, Henderson AJ, Kotecha S. The Effect of Birth Weight on Lung Spirometry in White, School-Aged Children and Adolescents Born at Term: A Longitudinal Population Based Observational Cohort Study. The Journal of pediatrics. 2015;166(5):1163-7.  https://doi.org/10.1016/j.jpeds.2015.01.002

The differences between early term (i.e. 37-38 weeks) and full term (39+ weeks) was also assessed. Those born early term had lower spirometry measures than those born at full term, although they were within the normal range. Again by 14-17 years the differences had largely vanished.

Kotecha, S. J., Watkins, W. J., Lowe, J., Henderson, A. J., & Kotecha, S. (2016). Effect of early‐term birth on respiratory symptoms and lung function in childhood and adolescence.Pediatric pulmonology, 51(11), 1212-1221. https://doi.org/10.1002/ppul.23448

Fetal growth and rapid postnatal weight gain are associated with adverse respiratory outcomes in childhood. We investigated if these changes had additional adverse effects in preterm children when compared to term.  From a cohort of preterm‐ and term‐born (n = 4284 and 2865) children, aged 1‐10 years, outcomes obtained from a respiratory questionnaire were investigated using adjusted regression models. We found that accelerated fetal growth during both the 1st and 2nd trimesters was associated with increased wheeze‐ever in preterm‐born children. Also rapid infant weight gain was associated with increased wheeze‐ever with children born ≤32 weeks’ gestation exhibiting rapid weight gain having a fivefold higher risk of wheeze‐ever compared to term‐born without weight gain.

John Lowe, Sarah J. Kotecha, William John Watkins, Sailesh Kotecha (2017). Effect of fetal and infant growth on respiratory symptoms in preterm‐born children November 2017 Pediatric Pulmonology 53(2). https://doi.org/10.1002/ppul.23920

Helping Identify Child abuse.

 Investigation of bruising on young children plays an important part in determining if the child could have been subject to abuse or not. A factor might be the quantity of non-child DNA found within the area of a bruise. In order for this to be useful, normal or background levels of DNA found on parts of the childs body where bruises have previously been shown to suggest abuse have to be determined. I compiled the data and conducted the primary statistical analysis of the first quantification of levels of background DNA, both the childs and non- childs,  found on the skin of infants and very young children. We showed that despite intimate contact with carers and siblings, levels of non-child DNA found are extremely low through normal non-abusive contact.

Graham EAM, Watkins WJ, Dunstan F, Maguire S, Nuttall D, Swinfield CE, et al. Defining background DNA levels found on the skin of children aged 0–5 years. International journal of legal medicine. 2013:1-8. https://doi.org/10.1007/s00414-013-0906-8

Another mechanism for investigating bruises as potential indicators of abuse is the determination of the plausibility of the bruise given the carers explanation as to the cause. Eight accidental situations – eg.  falls, sports injuries, motor vehicle incidents etc - that could lead to bruising were investigated and the frequency of resulting bruising at various body locations measured. We found that some areas of the childs body rarely if ever showed bruising and so bruises here could be treated as indicators in investigation of possible abuse.

Hibberd, O., Nuttall, D., Watson, R.E., Watkins, W.J., Kemp, A.M., Maguire, S. (2017). Childhood bruising distribution observed from eight mechanisms of unintentional injury. Archives of Disease in Childhood – August 2017 102(12):archdischild-2017-312847 http://dx.doi.org/10.1136/archdischild-2017-312847

Population studies – Low birth weight and pollution

 Low birthweight (LBW) is associated with increased mortality in infancy, but its association with mortality in later childhood and adolescence is less clear.  We conducted a population study of all live births occurring in England and Wales from 1993 for to 2011 (12,355,251 live births), looking at mortality and its primary causes for different birthweight groups upto the age 18 years. We showed through Cox regression that both extreme and moderate low birth weight were associated with increased mortality at all points upto 18 years of age and we were also able to use ICD9/10 codes to see the variation in causes of death with the birth weight bands.

Watkins, W. J., Kotecha, S. J., & Kotecha, S. (2016). All-cause mortality of low birthweight infants in infancy, childhood, and adolescence: population study of England and Wales.PLoS Med, 13(5), e1002018.  https://doi.org/10.1371/journal.pmed.1002018

We investigated whether pollution exposure (PM10, SO2 and NO2) is differentially associated with all-cause infant, neonatal or postneonatal mortality and within these, specific causes of infant mortality for 7,984,366 live births between 2001 and 2012 in England and Wales. The 36,485 infant deaths (25,110 neonatal and 11,375 postneonatal) were modeled with adjustments for the following major confounders: deprivation, birthweight, maternal age, sex, and multiple birth. We found infant deaths were significantly increased with NO2, PM10, and SO2 when highest and lowest pollutant quintiles were compared; however, neonatal mortality was significantly associated with SO2 but not significantly associated with NO2 and PM10. Postneonatal mortality was significantly associated with all pollutants. For specific causes, all pollutants were similarly associated with endocrine causes of infant deaths, however otherwise they were differentially associated with other specific causes: NO2 and PM10 were associated with an increase in infant deaths from congenital malformations of the nervous and gastrointestinal systems whereas SO2 was associated with an increase in infant deaths from perinatal causes and from malformations of the circulatory system.

Kotecha SJ*, Watkins WJ*, Lowe J, Kotecha S, Differential association of air pollution exposure on neonatal and post-neonatal mortality in England and Wales: a cohort study. PLOS Medicine, Oct 2020 *Joint first authors. https://doi.org/10.1371/journal.pmed.1003400

Novel methodology – Growth charts

 The current growth charts work on the premise that growth in utero occurs in the same way as post natal growth so effectively for premature children the "lost" growth in utero is modeled the same way as post natal growth. This is not the case and so we included two terms in our model, one representing weight increase from birth but the other representing weight increase from conception. When our new predicted growth charts were tested with actual growth data for children born up to 31 weeks gestation, they were found to be considerable more representative than the existing charts.

Modelling predictive gender- and gestation-specific weight reference centiles for preterm infants using a population-based cohort study. Nature Scientific Reports, Feb 2020. W. John Watkins, Daniel Farewell, Sujoy Banerjee, Hesham Nasef, Anitha James, Mallinath Chakraborty. https://doi.org/10.1038/s41598-020-60895-6

Novel methodology – Re-intubation prediction

 In a paper of 2018, we utilized regression methods to test the hypothesis that in neonates on mechanical ventilation, heart rate characteristics index (HRCi) can be combined with a clinical model for predicting extubation (or re-intubation) outcomes in neonates. We showed that multivariable linear mixed-effects models used to create prediction models, using relevant variables, significantly improved the understanding of the chances of extubation success.

Nitin Goel, Mallinath Chakraborty, William John Watkins and Sujoy Banerjee (2018). Predicting Extubation Outcomes — A Model Incorporating Heart Rate Characteristics Index. The Journal of Pediatrics. Jan 2018 https://doi.org/10.1016/j.jpeds.2017.11.037

In a follow up paper in 2020, we extended this work to the development of a prototype decision support tool for clinicians that might be used prior to extubation to estimate the chances of re-intubation. An additional prototype tool was produced that used a survival model to estimate the probability of re-intubation in the period after extubation. The graphical interface provided an updateable estimate of the hazard curve (instantaneous likelihood of re-intubation).

Chakraborty, M.*, Watkins, W. J.*, Tansey, K., King, W. E., & Banerjee, S. (2020). Predicting extubation outcomes using Heart Rate Characteristics Index in Preterm Infants: A cohort study. European Respiratory Journal. *Joint first authors https://doi.org/10.1183/13993003.01755-2019

Wheezing

 The negative effect of prematurity on respiratory function throughout childhood is understood but the effects of being born Early Term (37-38 weeks) were unclear. As part of a questionnaire study of term born 1-10 year olds, we were able to compare 545 early term–births with 2,300 were full term births. Early term–born children had significantly higher rates of hospital admission during their first year of life. When grouped into less than 5 years old and greater than 5 years old we found that early term–born children in both groups reported both significantly more wheeze and more recent wheezing although the differences were more pronounced in the younger group. These differences persisted  when family history of atopy and delivery by means of cesarean sections were included in logistic regression models used..

Edwards MO, Kotecha SJ, Lowe J, Richards L, Watkins WJ, Kotecha S. Early-term birth is a risk factor for wheezing in childhood: A cross-sectional population study. Journal of Allergy and Clinical Immunology. 2015. https://doi.org/10.1016/j.jaci.2015.05.005

In the same study as above we investigated the role of gestation in the extent to which a family history of Atopy affects the prevalence of wheezing in childhood. Both the under 5’s and the over 5’s showed a significantly increased chance of wheezing with prematurity and that worsened with increased prematurity. No relation with family atopy was observed.

Edwards, M. O., Kotecha, S. J., Lowe, J., Richards, L., Watkins, W. J., & Kotecha, S. (2016). Management of prematurity-associated wheeze and its association with atopy. PloS one, 11(5), e0155695.   https://10.1371/journal.pone.0155695

Two subsequent papers looked at the relationship between early life factors and childhood wheezing phenotypes defined as no wheeze, early wheeze, late wheeze and persistent wheeze which were determined by wheeze at 3, 5, 7 and 11 years of age for children from the Millennium Cohort Study who were born between 2000 and 2002. The first paper looked at preterm and term children with other factors like smoking, atopy and gender adjusted for. Preterm-born children had similar wheeze phenotypes to term-born children although we did see higher rates of early and persistent wheeze on the preterm group.

Sarah J Kotecha, W John Watkins, John Lowe, Raquel Granell, A John Henderson, Sailesh Kotecha; (2019) Comparison of the Associations of Early-Life Factors on Wheezing Phenotypes in Preterm-Born Children and Term-Born Children, American Journal of Epidemiology, , kwy268, https://doi.org/10.1093/aje/kwy268

The second paper looked at the effect of catchup growth in term births from the same data set. We showed that catchup growth – defined as a change in age and gender standardized z-score of 0.67 - might be related to increased chance of early wheeze although this might be mitigated by long term improvements.

Kotecha SJ, Lowe J, Granell R, W. John Watkins, et al. The effect of catch-up growth in the first year of life on later wheezing phenotypes. Eur Respir J 2020; 56: 2000884 https://doi.org/10.1183/13993003.00884-2020

Teaching

Biography

Career overview

• 2022 – Now:  Senior Lecturer, School of Medicine, Cardiff University
• 2016 – 2022: Senior Medical Statistician and Lecturer, School of Medicine, Cardiff University
• 2008 – 2016: Medical Statistician, Cardiff University
• 2002 – 2008: Senior Systems Engineer, General Dynamics UK
• 1999 – 2002: Senior Software Engineer and Team leader, Ascom Telecommunications, Cardiff
• 1997 – 1999: Research Associate, Radiocommunications Agency/Cardiff University
• 1996 – 1997: IT and Software Support, Cardiff University
• 1992 – 1996: Research Associate, School of Engineering, Cardiff University
• 1987 – 1992: Part time Lecturer/Tutor, Cardiff University

 Education and qualifications

• 2006: Diploma in Statistics, Open University
• 1991: PhD (Astrophysics, Applied Mathematics, Computing), Cardiff University
• 1987: BSc (Mathematics), Cardiff University

Engagement

I am the external statistical advisor to the Paediatric Medicines Expert Advisory Group (PMEAG). We sit monthly, examining medical trials and publications with a view to advising the UK government of the quality of the trial and the efficacy of the medication. Significantly, recent efforts have included evaluation of clinical trials of Covid vaccines for young children, with immediate consequences in rapid development of national guidelines.