Displaying 1-10 letters out of 1308 published
Should we use linear splines to model complex growth processes?
We thank Dr. Johnson for his interest in our paper  and for the opportunity to discuss methods for modelling child growth. Many methods for modelling repeated measures data are available, and the strengths and limitations of each method will depend on many factors, including the specific research question of interest and the structure of the data being analysed. In our analysis, we used linear spline multilevel models. Such models divide age into separate 'pieces' joined with knot points, and model a different linear slope between each pair of knots. Individual- level random effects allow individuals to differ in both starting size (birth length or weight) and in their rate of growth in each period of childhood. Clearly, such a piecewise linear model is an approximation of the true complex underlying growth pattern. However, a key advantage of using linear splines to model infant and child growth is that they are easy to interpret. As well as being a useful way of creating interpretable summaries of growth trajectories, the linear spline approach provided good fit to our data, for all ethnic and sex groups, as seen in Supplementary web table 2 of our original paper.
Selection of knot points for linear spline models is an important issue. However, Dr. Johnson is incorrect when he states that we used the same knot points that had been derived from the Avon Longitudinal Study of Parents and Children (ALSPAC) data. As reported in the statistical analysis section of our paper,  we considered a series of models with knot points at different ages, and selected the best fitting models for the Born in Bradford data. These knot points were slightly different to those used in the ALSPAC study. However, it is interesting to note that this methodology has now been employed in several cohorts in varied geographical settings and with different ethnic and socioeconomic composition and that in each case, similar knot points that best fit the data in these different studies have been identified.[3-8] The fact that best-fitting models using data from very different populations have such similar knot points gives some biological credibility to the periods of growth identified by these models.
In the Born in Bradford cohort we had insufficient data in the first month of life to model neonatal weight loss. When these methods are applied to datasets with a greater number of measurements in early life, it is possible to model neonatal weight loss. For example in the Generation XXI cohort, based in Porto, Portugal, a median of ten growth measures are available for each child within the first few years of life, with almost all children having multiple growth measurements recorded in the first months of life. In this cohort, linear spline multilevel models with knot points at 10 days, 3 months and 1 year fit the data well.
Dr. Johnson suggests that individual knot points should have been used in our study. In contrast to our analyses, such models allow the age of change points within growth trajectories to vary between individuals. Allowing for individual-specific knot points may result in better fit of the statistical model to the data. But this increased model fit comes at the cost of complexity and interpretability. The timing of knot points is likely to be related to the rate of change before and after that knot point, and thus these quantities would need to be interpreted carefully. The potential added benefits of using this approach to address our question of ethnic differences in growth depend on two main factors: how variable knot points are likely to be between individuals, and whether the timing of individual-specific knot points is of interest in its own right. We do not feel that either of these actually support the use of this method to address the research question we were answering. Individual variation in, for example, the timing of puberty onset or the timing of cognitive decline in older age  is likely to be considerably greater than individual variation in the timing of changes in growth velocity in infancy and early childhood; therefore models incorporating individual- specific knot points may be more useful in the former situations than in the latter. Likewise, our research question concerned describing ethnic differences in rates of growth and was not concerned with ethnic differences in the timing of features of early growth. Such an approach would be useful when the research question centres on the timing of change and how this timing relates to earlier exposures or later outcomes, for example, when assessing whether age at puberty is associated with later cardiovascular health, one would need to estimate individual age at onset of puberty rather than assuming that this was constant across the population.
We once again thank Dr. Johnson for his interest in our paper. Whilst we recognise that linear spline models represent a simplification of the true underlying growth process, we feel that they are a suitable compromise between model fit, which was good in our study, and interpretability. Examination of growth using different models is important for triangulation, and different methods will be relevant for different research questions.
1. Fairley L, Petherick ES, Howe LD, Tilling K, Cameron N, Lawlor DA, et al. Describing differences in weight and length growth trajectories between white and Pakistani infants in the UK: analysis of the Born in Bradford birth cohort study using multilevel linear spline models. Arch Dis Child 2013,98:274-279.
2. Hauspie R, Cameron N, Molinari L. Methods in Human Growth Research: Cambridge University Press; 2004.
3. Howe LD, Tilling K, Galobardes B, Smith GD, Gunnell D, Lawlor DA. Socioeconomic differences in childhood growth trajectories: at what age do height inequalities emerge? J.Epidemiol.Community Health 2012,66:143-148.
4. Paternoster L, Howe LD, Tilling K, Weedon MN, Freathy RM, Frayling TM, et al. Adult height variants affect birth length and growth rate in children. Hum.Mol.Genet. 2011,20:4069-4075.
5. Matijasevich A, Howe LD, Tilling K, Santos IS, Barros AJ, Lawlor DA. Maternal education inequalities in height growth rates in early childhood: 2004 Pelotas birth cohort study. Paediatr.Perinat.Epidemiol. 2012,26:236-249.
6. Tilling K, Davies N, Windmeijer F, Kramer MS, Bogdanovich N, Matush L, et al. Is infant weight associated with childhood blood pressure? Analysis of the Promotion of Breastfeeding Intervention Trial (PROBIT) cohort. Int.J.Epidemiol. 2011,40:1227-1237.
7. Tilling K, Davies NM, Nicoli E, Ben-Shlomo Y, Kramer MS, Patel R, et al. Associations of growth trajectories in infancy and early childhood with later childhood outcomes. Am.J.Clin.Nutr. 2011,94:1808S-1813S.
8. Howe LD. Individual trajectories of childhood growth in five cohorts: the application of linear spline multi-level models. In: EUCCONET/ Society for Longitudinal and Life Course Studies. Paris; 2012.
9. Bellera CA, Hanley JA, Joseph L, Albertsen PC. Hierarchical changepoint models for biochemical markers illustrated by tracking postradiotherapy prostate-specific antigen series in men with prostate cancer. Ann Epidemiol 2008,18:270-282.
10. van den Hout A, Muniz-Terrera G, Matthews FE. Change point models for cognitive tests using semi-parametric maximum likelihood. Comput Stat Data Anal 2013,57:684-698.
Conflict of Interest:
ADHD -Safeguarding responsibilities
Dr Webb's article highlights the fact that ADHD can be considered as a behavioural problem caused by many different aetiologies, including significan physical and emotional abuse. She identifies that the sort of abuse that triggers this behaviour is often longstanding and at a level that becomes tolerated by statutory services who are usually quick to intervene when there is physical harm, but allow emotional and social problems to fester.
It raises the question as to what is an appropriate safeguarding response to children presenting with ADHD? A child presenting with a subdural haemorrhage or unexplained fracture would have some level of safeguarding investigation performed - unless there was a clear non abusive history of trauma. Minimally this would be at a hospital level, but more likely escalated to police and social services.
Given the high incidence of disturbing and abusive behaviours in families with ADHD, it can be deduced that the child's condition is a result of this in much the same way that a subdural haemorrhage may be caused by shaking. Both conditions carry a guarded long term prognosis and are therefore manifestations of 'significant harm.'
It seems sensible to suggest that when making a diagnosis of ADHD in a child, serious consideration should be given to referring the family for a multiagency safeguarding assessment.
Conflict of Interest:
Yes, We Need to Change the Way We Deliver Unscheduled Care: and More.
Dear Ed Gill  and Powell  state there is little data on delivery of unscheduled care. We would like to share our learning.
To improve paediatric training in primary care one of us (SC) has worked with Advanced Life Support Group (ALSG) led by SW and piloted a, "Poorly Child Pathway Course." This one day course deals with the most common acute childhood presentations and uses a traffic light system (green, amber, red) to classify patients. It aims to improve the management of children presenting to Urgent Care and Out of Hours and communication between primary and secondary care.
23 candidates were taught by 8 faculty. Candidate and Faculty feedback is ongoing, early results show: 80% agreed that a one day course worked well; confidence improved from 2.7/4 to 3.8/4. Primary Care facilities do not have the facility to review patients so hospitals see all amber patients
The second intervention was to pilot a, "Front of House," (FoH) model of care where children were seen and assessed by either a consultant paediatrician, paediatric middle grade or Advanced Nurse Practitioner Students (APNPs) prior to admission. There are two 24 hour paediatric units within CDDFT separated by 22 miles, University Hospital North Durham (UHND) and Darlington Memorial Hospital (DMH). The pilot ran at DMH over a 3 week period between 5th to 23rd November, 2013 on Mondays to Fridays 9:00 to 21:00. There was insufficient staff to run this model at weekends.
During November there were 391 admissions under 18 years of age compared to 406 in November 2012. The data is not scientific. Considering successive 8% annual increases in admissions it suggests a decrease in admissions.
We plan to perform a 6 month, "trial," at UHND using the system 7 days a week with consultants triaging calls.
1. Gill PJ, Goldacre MJ, Mant D et al. Increase in Emergency Admissions to Hospital for Children aged under 15 in Emgland, 199-2010: National Database Analysis. Arch. Dis Child 2013; 98: 328-334 2. Powell C Do we need to change the way we deliver unscheduled care? Arch. Dis Child 2013; 98: 319-320
With sincere thanks to the faculty of the pilot Poorly Child Pathway Course: Prof. Peter Driscoll (IDP) Dr. Martin Samuels (Stoke-on-Trent) Paul Lattimer (CDDFT) Dr Leigh Simmonds (CDDFT) Dr John Holmes (CDDFT) Dr Barbara Phillips (IDP) Dr David Ratcliffe (Manchster)
and to our APNPs: Lisa German-Phillips Amanda Dunn Susie Watson Shona Sangster Meg Davies Cheryl Peart
Conflict of Interest:
Light drinking in pregnancy and mid-childhood mental health and learning outcomes
We have read with interest the paper by Sayal et al. concerning a cohort of 11-year-old children prenatally exposed to alcohol and the major conclusion that light drinking in pregnancy does not appear to be associated with clinically important adverse effects for mental health and academic outcomes at the age of 11 years.
This broad epidemiological study has several problems related to the analysis of data and to the risk assumption. First of all, it has been demonstrated that questionnaires about the blame-attributing question of alcohol consumption during pregnancy are not reliable, because women do not tell the truth or because they are not aware about real alcohol consumption. (1) As a consequence, the division of the groups of women into various drinking levels cannot be considered reliable, which in turn, makes it impossible to draw conclusions from the outcomes of tests on the children. (1,2) Thus human observational studies must be based on objective measurements of prenatal alcohol exposure, that is, based on alcohol biomarkers in alternative matrices. (1,2)
There is clear evidence from animal studies and from human clinical observation that prenatal exposure to alcohol has deleterious effects, even in low doses, specifically on neurodevelopmental aspects. Clearer answers on the effects of alcohol on humans are to be expected from several currently on-going follow-up studies of newborns whose exposure was measured based on meconium alcohol biomarkers. (3,4)
However, the most important problem of this paper is the non acceptable risk assumption. It is not responsible to state that "occasional light drinking does not appear to be associated with adverse mental health or academic consequences at the age of 11 years". There HAVE TO be sure that there is no risk at all; if not, it is mandatory to recommend not to drink during pregnancy. Conversely to the authors' conclusion, the most "advanced" advice for women is not to drink alcohol during pregnancy. As everybody knows, lack of evidence is not the same as evidence of absence, and in this case, no evidence of harm does not mean evidence of no harm. (5)
Garcia-Algar O1,2, Diane Black2, Consuelo Guerri2,3, Simona Pichini2,4 1 URIE, Institut Hospital del Mar d'Investigacions M?diques (IMIM), Barcelona, Spain 2 European FASD Alliance, The Nederlands 3 Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanit?, Rome, Italy 4 Centro de Investigaci?n Pr?ncipe Felipe, Valencia, Spain
1. Manich A, Velasco M, Joya X, Garc?a-Lara NR, Pichini S, Vall O, Garc?a-Algar O. [Validity of a maternal alcohol consumption questionnaire in detecting prenatal exposure]. An Pediatr (Barc) 2012;76:324-328. 2. Pichini S, Marchei E, Vagnarelli F, Tarani L, Raimondi F, Maffucci R, et al. Assessment of prenatal exposure to ethanol by meconium analysis: results of an Italian multicenter study. Alcohol Clin Exp Res 2012;36:417- 424. 3. Garcia-Algar O, Kulaga V, Gareri J, Koren G, Vall O, Zuccaro P, Pacifici R, Pichini S. Alarming prevalence of fetal alcohol exposure in a Mediterranean city. Ther Drug Monit 2008;30:249-254. 4. Valenzuela CF, Morton RA, Diaz MR, Topper L. Does moderate drinking harm the fetal brain? Insights from animal models. Trends Neurosci 2012;35:284-92. 5. Garcia-Algar O, Black D, Guerri C, Pichini S. The effect of different alcohol drinking patterns in early to mid-pregnancy. BJOG 2012;119:1670-1.
Conflict of Interest:
Re: The importance of a preschool booster for children born to hepatitis B-positive mothers
We read Ladhani and Ramsay's editorial with great interest. Whilst we agree on the need for the delivery of a completed course of Hepatitis B vaccinations in infants of high-risk mothers where the fourth vaccination is administration by their first birthday, in order to improve uptake of vaccines it is essential to recognise factors preventing this occurring.
Firstly, Hepatitis B positive mothers diagnosed in antenatal services may give birth in a labour unit outside of their local area due to bed pressures and newborns may not receive their first vaccination. This should, however, be limited by the use of patient-held maternity records.
The initial Hepatitis B vaccination is often administered by maternity or neonatal paediatric staff under a hospital doctor prescription. Subsequent vaccines are currently offered by a variety of healthcare professionals such as general practitioners (GP) or community paediatricians. Yates et al showed a high level of participation at the first vaccination but large numbers of infants did not have follow-up vaccines. Reasons for this may include poor transfer of information and clinical records between providers. Also, the administration of infant Hepatitis B vaccinations does not result in item of service payments for GPs and as such GP may be less likely to offer follow up vaccinations. Similarly, acquisition of vaccines, blood test sampling, sample handling practices and pathology systems may vary among GP practices, thus posing additional barriers to the completion of vaccination schedules and serological testing.
In the North London Borough of Enfield, a number of children under the age of 2 years old move in and out of area making follow-up more challenging. However, in 2004 in this borough, 80% of all high-risk neonates of Hepatitis B positive mothers registered at Chase Farm Hospital during antenatal testing received the full vaccination course and serology. This success has been attributed to the use of a named clinical lead conducting an integrated immunisation clinic with a clinic nurse. The team would recall and follow up patients to offer immunisation and serological testing while considering migration, language and access barriers. In a resource-limited health system such immunisation clinics may not be feasible. Universal vaccination of children with Hepatitis B vaccines is not practical or more effective than a targeted approach. Therefore, we would recommend that follow-up Hepatitis B vaccinations and serology are performed by incentivised GPs as a new 'item of service' payment.
1. Yates TA, Paranthaman K, Yu L-M, et al. UK vaccination schedule: persistence of immunity to hepatitis B in children vaccinated after perinatal exposure. Arch Dis Child 2013;98:429-33. 2. Giroudon I. Immunization Coverage in Infants at Risk of Perinatal Transmission of Hepatitis B: A London Study (LANSSG). HPA London Regional Epidemiology Unit. 2008. 3. Balogum MA, Parry JV, Mutton K, et al. Hepatitis B virus transmission in pre-adolescent schoolchildren in four multi-ethnic areas of England. Epidemiol Infect 2013; 141(5):916-25
Conflict of Interest:
Response to: "Capillary refill time: Time to fill the gaps!"
Thank you for your response to our research 'The agreement of fingertip and sternum capillary refill time (CRT) in children'
We agree that there is a lack of gold standard for assessing tissue perfusion in a simple and timely manner and continue to extrapolate that in shock, blood is usually diverted from the skin in an attempt to perfuse vital organs. Current practice and guidance assumes that CRT is a reflection of this (1-7). We were not expecting to find fingertip CRT to be faster than sternum CRT, although we did not find it strange. We agree and also suspect that different sites have different refill times because of the complex and intricate relationships involved, which are not practical or possible to record prior to carrying out the CRT (such as arteriolar resistance, venular resistance etc. as discussed in Carcillo (1)). There is a substantial amount of research in CRT in vascular medicine which we decided not to include in our literature review prior to this study, although our findings might indicate it would be more appropriate to examine this area in more detail. We do know that the fingertip pulp is rich in arterio-venous anastomoses which may explain why it had the quickest CRT and that vascular resistance is increased in peripheral beds and this may explain why it also had the slowest CRT.
We agree that there needs to be standardisation of the technique, greater awareness of CRT limitations and it should be analysed in conjunction with other haemodynamic markers. We suggested that guidance provided by the Resuscitation Council (RC) (2-4), amongst others, be reviewed for exactly these reasons. The RC highlight CRT as one of the five parameters to observe when examining circulation, giving it equal weighting to heart rate, pulse volume, blood pressure and end organ perfusion status. The RC guidance does advise to consider CRT with other cardiovascular signs but importantly does not consider the fingertip site or variables such as inter and intra observer reliability and skin colour.
Carcillo's editorial is interesting; however this purposive review is not balanced or systematic and does not provide a comprehensive overview of the literature relating to CRT. Interestingly although Carcillo is discussing sick children we are informed that CRT is age dependant and rightly references the study that discovered this in 1988, there is no evidence that tells us otherwise, yet we can find no guidance by the RC or other group that utilises an age dependant model, why is that?
Our study did not set out to examine the usefulness of the test, but led us to question the way CRT is conducted in current clinical practice. In an era where we try to practice evidence based medicine, if this test is recommended for use in practice (something our research cannot answer) then we have a duty to generate the evidence to support the way in which it is conduced.
1. Carcillo JA. Capillary refill time is a very useful clinical signin early recognition and treatment of very sick children. Editorial on Pediatr Crit Care Med 2012; 13:136 -140
2. Resuscitation Council. Medical Emergencies and Resucitation-- Standards for clinical practice and training for dental practitioners and dental care professionals in general dental practice. http://www.resus.org.uk/pages/MEdental.pdf (accessed May 2013):24.
3. Resuscitation Council. European paediatric life support (EPLS). 3rd edn. London:
4. Resuscitation Council 2011:12. Resuscitation Council. A systematic approach to the acutely ill patient, adapted from the ALERTTM. http://www.resus.org.uk/pages/alsABCDE.htm (accessed May 2013).
5. Jevon P. Measuring capillary refill time. Nurs Times 2007;103:26- 7.
6. Lima A, Jansen TC, Van Bommel J, et al. The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients. Crit Care Med 2009;37:934-8.
7. Graham C, Parke T. Critical care in the emergency department: shock and circulatory support. Emerg Med J 2005;22:17-21.
Conflict of Interest:
Re: The importance of a preschool booster for children born to hepatitis B-positive mothers
We are grateful to Dr Ladhani and Dr Ramsay  for their thoughtful editorial that accompanied the publication of our paper . We would agree that, despite discrepant observational data in the UK regarding the waning of antibody titres [2, 3], there is now a large body of evidence  demonstrating that, even where antibody titres have waned, booster doses are not required if an adequate primary schedule has been completed.
As discussed in the editorial, the pragmatic priority is to ensure that all children complete the course and receive at least one further dose after their initial (accelerated) schedule at 0, 1, 2 months.
Routine immunisation visits are a convenient time to do this, and the pre-school booster presents one such opportunity. However, as Dr Ladhani and Dr Ramsay have noted elsewhere, almost all UK children diagnosed with chronic hepatitis B infection acquire this through vertical transmission . Having a named clinician responsible for delivery of the 0, 1, 2 month schedule can improve its delivery , and the 12 month routine vaccine visit is more timely than the pre-school booster for ensuring its completion.
1. Ladhani SN, Ramsay ME. The importance of a preschool booster for children born to hepatitis B-positive mothers. Arch Dis Child. 2013; 98: 395-396. 2. Yates TA, Paranthaman K, Yu LM, et al. UK vaccination schedule: persistence of immunity to hepatitis B in children vaccinated after perinatal exposure. Arch Dis Child. 2013; 98: 429-433. 3. Boxall EH, A Sira J, El-Shuhkri N, et al. Long-term persistence of immunity to hepatitis B after vaccination during infancy in a country where endemicity is low. J Infect Dis. 2004; 190(7): 1264-9. 4. Leuridan E, Van Damme P. Hepatitis B and the need for a booster dose. Clin Infect Dis. 2011; 53(1): 68-75. 5. Flood J, Amirthalingam G, Ramsay ME, et al. The diagnosis of chronic Hepatitis B infection among children born in England after introduction of universal antenatal HBV screening programme. Poster presented at the European Society of Paediatric Infectious Disease Meeting, The Hague, June 2011. http://www.kenes.com/ espid2011/cd/pdf/P774.pdf.
Conflict of Interest:
Our study was supported by the NIHR Oxford Biomedical Research Centre and GlaxoSmithKline Biologicals. SL has undertaken paid work for vaccine manufacturers for provision of travel health training and attendance at advisory group meetings. AJP and MDS have conducted clinical trials on behalf of Oxford University sponsored by manufacturers of vaccines. AJP and MDS do not accept any personal payments from vaccine manufacturers: grants for support of educational activities are paid to an educational/administrative fund held by the Department of Paediatrics, Oxford University. MDS has received support from vaccine manufacturers to attend academic conferences. ED, SBW, SJH, KP and TAY declare no conflicts of interest besides funding received for the study.
Capillary refill time:Time to fill the gaps!
We read with great interest the article on capillary refill time (CRT) in children. Crook J and Taylor RM have carried out a simple and yet very relevant study on CRT in children.CRT is almost universally checked by child care providers particularly in emergency room or intensive care setting and is taken as a surrogate of the perfusion status. However, two issues have plagued this simple bedside test:
(i) There seems to be no uniformity in the way this test is carried out across the world. We recently published a letter to editor (1) describing the variations in eliciting CRT amongst the various standard texts and references. After analysis of all the references, it seemed prudent to follow the Pediatric advanced life support(PALS )guideline for CRT in children (finger tip) and the WHO guideline for CRT in young infants (finger tip and sternum) with a pressure application of at least 3 seconds. There continue to be issues with eliciting CRT from the peripheries in neonates (2).In the current article ,the authors have rightly suggested a uniform practice for assessing CRT though it wasn't in the purview of their study.
(ii) There have been various studies questioning the utility of CRT .Even the APLS manual suggests use of caution in interpreting CRT as a standalone measure of shock. Another recent article suggests poor inter- rater reliability and poor correlation with cardiac output in non-acutely ill children (3).The confusion with respect to studies on CRT perhaps stems from the lack of a simple gold standard for assessing perfusion status of the tissues. It could be the pulse pressure, skin temperature gradient, central venous oxygen saturations (ScVO2), lactate , near infra red spectroscopy (NIRS) etc or a mixture of such variables. It is also important to remember that in an attempt to perfuse the vital organs in shock , the blood is usually diverted from the skin and hence the delay in CRT is supposed to reflect the degree of shock. As pointed out by Carcillo JA in an excellent editorial(4) ,there are numerous studies supporting the use of CRT and hence it is a useful tool for evaluation of the hemodynamic status in children.
The authors of this current study have carried out both sternal and finger tip CRT in normal children and found that there was a poor correlation between the two. Another interesting finding was that the finger tip CRT was faster than the sternal CRT.This finding is rather strange and seems difficult to fit in despite the complex and intricate relationship between arteriolar resistance, venular resistance, viscosity, microvessel patency, polycythemia etc involved in the capillary refill. It was also premature on part of the authors to consider resuscitation council(RC) to re-evaluate their recommendations on CRT.
It is important for us to ensure that the CRT is carried out with some uniform method by all child care providers and that studies on CRT should consider assessing its utility against a set of surrogate variables of perfusion in the normal and sick children. One must be aware of the limitations of CRT and analyse it in conjunction with the other markers of hemodynamic status. A normal CRT in a sick child except perhaps in warm shock has a good negative predictive value. One could consider inventing a simple device akin to a ball point pen with a stopwatch which delivers a standard pressure for appropriate time on the skin surface so as to make the process of eliciting CRT more uniform. It would be even better if the refill measurement could be digitized to avoid any subjective error. Irrespective of the technique used, a resource limited country is likely to use only clinical signs or low cost devices for assessment of perfusion in sick children with shock.
1. Pandey A,John BM.Capillary refill time:Is it time to fill the gaps.Medical Journal Armed Forces India 2013;69:97-98.
2. Gale C.Is capillary refill time a useful marker of hemodynamic status in neonates? Arch Dis Child 2010; 95:395-397
3. Lobos A,Lee S,Menon K. Capillary refill time and cardiac output in children undergoing cardiac catheterization. Pediatr Crit Care Med 2012; 13:136 -140
4. Carcillo JA. Capillary refill time is a very useful clinical sign in early recognition and treatment of very sick children. Editorial on Pediatr Crit Care Med 2012; 13:136 -140
Conflict of Interest:
Should we use linear splines to model complex growth processes?
Fairley et al(1) describe differences in growth between White and Pakistani infants in the BiB study using mixed effects linear splines, an approach becoming popular in the analysis of serial anthropometry. Linear splines were used because they summarize noisy data in meaningful parameters: an intercept and linear slope terms (connected by knots) governing different age sections. Adding an exposure obtained estimates of differences between ethnicities in size at the intercept and in rate of change for each age section. Linear splines are an appealing analytical choice, but their biological and statistical limitations are often overlooked.
Growth follows a complex pattern of age related change and linear splines (by their very nature) have limited ability to describe this process. A traditional structural growth model (e.g., Berkey-Reed 1st order(2)) may be a better choice to "describe the growth pattern". Careful selection of knots might have improved matters (e.g., given neonatal weight loss, a knot at age two weeks would make sense). Instead, knots developed in the ALSPAC study were used, thereby assuming that the growth process was the same for BiB infants (with different defining characteristics) compared to ALSPAC infants. Further, when investigating the effects of an exposure on growth, does it make sense to impose the same inflection points (i.e., knots) on each response of that exposure? A major assumption of the mixed effects linear splines used by Fairley et al(1) was that all individuals shared the same inflection points. Applying conventional regression to hierarchical data produces incorrect standard errors(3) and linear spline specification that does not account for between individual variation may have similar consequences.
Methods in other disciplines(4) have extended the flexibility of linear splines to incorporate individual level inflection points at knots that do not need to be specified a priori, but instead are data driven. A promising avenue of research is to extend mixed effects linear splines for growth modelling to include individual level inflection points; this could be done in existing Bayesian modelling framework software(5).
1. Fairley L, Petherick ES, Howe LD, Tilling K, Cameron N, Lawlor DA, et al. Describing differences in weight and length growth trajectories between white and Pakistani infants in the UK: analysis of the Born in Bradford birth cohort study using multilevel linear spline models. Archives of Disease in Childhood 2013;98:274-9. 2. Berkey CS, Reed RB. A model for describing normal and abnormal growth in early childhood. Human Biology 1987;59:973-87. 3. Goldstein H. Efficient statistical modelling of longitudinal data. Annals of Human Biology 1986;13:129-41. 4. van den Hout A, Muniz-Terrera G, Matthews FE. Change point models for cognitive tests using semi-parametric maximum likelihood. Computational Statistics & Data Analysis 2013;57:684-98. 5. Lunn DJT, A. Best, N. Spiegelhalter, D. WinBUGS - a Bayesian modelling framework: concepts, structure, and extensibility. Statistics and Computing 2000;10:325-37.
Conflict of Interest:
Issues relating to basilar artery strokes in children
The timely commentary on basilar artery stroke(1) serves as an opportunity to highlight the importance of a high index of suspicion for posterior circulation transient neurological episodes(TNAs)(2), especially in the presence of risk factors for vertebral artery dissection(3). It is also a reminder of the underuse of magnetic resonance imaging(utilised in only 44.3% of 97 children in one review)(4), notwithstanding the fact that it is the modality of choice for distinguishing between transient ischaemic attack(including TNAs) and iscahemic stroke, the distinguishing characteristic of the latter being its assocation with infarction of brain tissue(5). The recognition of the diagnostic and prognostic import of TNAs leaves considerable room for improvement, not only in adults(2), but also in children(4).In the former age group one study reported that 45 out of 275 patients(ie 16%) with brainstem strokes had experienced antecedent TNAs, and that only ten of those patients with TNAs had sought medical attention at the time. More to the point, a vascular cause was suspected by the doctor in only one of those cases(2). Given the higher prevalence of brainstem TNAs among children(43% of 97 patients with eventual basilar artery strokes in one study)(4), even greater use should be made of MRI to establish the distinction between TNA and brainstem stroke. The index of suspicion for attributing brainstem TNA to vertebral artery dissection should also be high if there is an antecedent history of trauma to the neck or head region, as was the case in 50% of 68 childhood instances of vertebral artery dissection reviewed in one publication(3).Although MRI does establish the distinction between TNA and stroke within the therapeutic time window for thrombolysis it is still uncertain whether or not children with stroke should receive thrombolytic therapy(6)(7). Good outcomes were reported in 24 children with basilar artery stroke who did not receive thrombolysis(6), and it has been argued that the benefit vs risk profile of thrombolysis(for basilar artery occlusion) might be different in children as opposed to adults(7). Nevertheless, in one review, 17 of the 97 children with basilar strokes received thrombolysis. One criticism that has been levelled is that, in the rare event of administration of thrombolytic therapy to children to with stroke, dose regimens vary widely, and treatment is often given outside the time intervals recommended for adults(8). These observations reinforce the view that clinical trials to evaluate dose and safety of thrombolytic therapy are needed in childhood stroke(8). References
(1) Archivist Basilar artery stroke Arch Dis Child 2013;98:334 (2)Paul N., Simani M., Rothwell PM Transient isolated brainstem symptoms preceding posterior circulation stroke; a population-based study Lancet Neurology 2013;12:65-71 (3) Hasan I., Wapnick S., Tenner MS.,Couldwell WT Vertebral artery dissection in children: A compreshensive review Pediatric Neurosurgery 2002;37:168-177 (4)Simonetti BG., Ritter B., Gautschi M et al Basilar artery stroke in childhood Developmental Medicine and Child Neurology 2013;55:65-70 (5)Easton JD., Saver JL., Albers GW et al Definition and evaluation of transient ischemic attack. A scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Council; Council on Cradiovascular surgery and anesthesia;Council on cardiovascular radiology and intervention;Council on cardiovascular nursing; and Interdisciplinary council on peripheral vascular disease Stroke 2009;40:2276-2293 (6)Langman-Bartolome M., Pontigon A-M., Moharir M et al Basilar artery strokes in children: good outcomes with conservative medical treatment Develomental Medicine doi: 10.1111/dmen.12092 (7)Deveber G Childhood basilar artery thrombosis: reassuring outcomes in younger patients Developmental Medicine and Child Neurology 2013;55:7-14 (8) Amlie-Lefond C., deVeber G., Chan AK Use of alteplase in childhood artrial ischaemic stroke; a multicentre observational cohort study Lancet 2009;8:530-536
Conflict of Interest: