Maryam Oskoui

Screening for Developmental Delay in the Setting of a Community Pediatric Clinic: A Prospective Assessment of Parent-Report Questionnaires

OBJECTIVES. Our goal for this study was to prospectively test whether parent-completed questionnaires can be effectively used in the setting of a busy ambulatory pediatric clinic to accurately screen for developmental impairments. Specific objectives included (1) assessing the feasibility of using parent-report instruments in the setting of a community pediatric clinic, (2) evaluating the accuracy of 2 available screening tests (the Ages and Stages Questionnaire and Child Development Inventory), and (3) ascertaining if the pediatricians clinical judgment could be used as a potential modifier. METHODS. Subjects were recruited from the patient population of a community clinic providing primary ambulatory pediatric care. Subjects without previous developmental delay or concerns noted were contacted at the time of their routine 18-month-old visit. Those subjects who agreed to participate were randomly assigned to 1 of 2 groups and completed either the Ages and Stages Questionnaire or Child Development Inventory. The childs pediatrician also completed a brief questionnaire regarding his or her opinion of the childs development. Those children for whom concerns were identified by either questionnaire underwent additional detailed testing by the Battelle Development Inventory, the “gold standard” for the purposes of this study. An equal number of children scoring within the norms of the screening measures also underwent testing with the Battelle Development Inventory. RESULTS. Of the 356 parents contacted, 317 parents (90%) agreed to participate. Most parents correctly completed the Ages and Stages Questionnaire (81%) and the Child Development Inventory (75%). Predictive values were calculated for the Ages and Stages Questionnaire and the Child Development Inventory (sensitivity: 0.67 and 0.50; specificity: 0.39 and 0.86; positive predictive value: 34% and 50%; negative predictive value: 71% and 86%, respectively). Incorporating the physicians opinion regarding the developmental status of the child did not improve the accuracy of the screening questionnaires. CONCLUSIONS. Three important conclusions were reached: (1) parent-completed questionnaires can be feasibly used in the setting of a pediatric clinic; (2) the pediatricians opinion had little effect in ameliorating the accuracy of either questionnaire; and (3) single-point accuracy of these screening instruments in a community setting did not meet the requisite standard for development screening tests as set by current recommendations. This study raises important questions about how developmental screening can be performed, and we recommend additional research to elucidate a successful screening procedure.

Clinically relevant copy number variations detected in cerebral palsy

Cerebral palsy (CP) represents a group of non-progressive clinically heterogeneous disorders that are characterized by motor impairment and early age of onset, frequently accompanied by co-morbidities. The cause of CP has historically been attributed to environmental stressors resulting in brain damage. While genetic risk factors are also implicated, guidelines for diagnostic assessment of CP do not recommend for routine genetic testing. Given numerous reports of aetiologic copy number variations (CNVs) in other neurodevelopmental disorders, we used microarrays to genotype a population-based prospective cohort of children with CP and their parents. Here we identify de novo CNVs in 8/115 (7.0%) CP patients (∼1% rate in controls). In four children, large chromosomal abnormalities deemed likely pathogenic were found, and they were significantly more likely to have severe neuromotor impairments than those CP subjects without such alterations. Overall, the CNV data would have impacted our diagnosis or classification of CP in 11/115 (9.6%) families.

Prevalence of Cerebral Palsy in Quebec: Alternative Approaches

Aim: To provide an estimate of the period prevalence of cerebral palsy (CP) in the province of Quebec. Methods: Children with CP were identified from three consecutive birth cohorts (1999–2001) from the Quebec CP Registry, covering 6 of the 17 administrative health regions of the province. Two inferential approaches were applied for period prevalence estimation, frequentist and bayesian. Results: 228 children were identified with CP. Using a frequentist approach, the overall prevalence of CP was 1.84 per 1,000 children aged 9–11 years living in those areas in 2010 (95% CI 1.60–2.08). Using a bayesian approach taking into account the uncertainty about the registry’s sensitivity in capturing all cases, the overall prevalence is higher at 2.30 per 1,000 children with a 95% CI (1.99–2.65). Conclusion: Using a bayesian approach to adjust for the registry’s known high specificity and lower sensitivity, the prevalence estimate is in concordance with worldwide estimates and estimates using administrative databases in western Canadian provinces. Future studies are needed to validate the diagnosis of CP within administrative databases and to evaluate possible regional trends across Canada in both prevalence and health service utilization, which may highlight disparities in healthcare delivery.

Growing Up With Cerebral Palsy: Contemporary Challenges of Healthcare Transition

Cerebral palsy is traditionally known as a major cause of chronic disability in childhood. With advances in neonatal care and improved survival, the majority of adolescents with cerebral palsy require ongoing services into adulthood. This paper highlights some of the challenges in their transition from pediatric to adult healthcare and proposes key elements to ensure a smooth transition process.

Prevalence Estimate of Cerebral Palsy in Northern Alberta: Births, 2008-2010

OBJECTIVES The objectives of this study were to determine prevalence estimates of cerebral palsy (CP) among 5-year-old children in northern Alberta; to provide congenital, gestational age- and birth weight-specific, and postneonatal CP rates; and to describe motor subtypes and function. METHODS This population-based prevalence estimate study, part of the Canadian Cerebral Palsy Registry, reports confirmed CP diagnoses at age 5 years made by pediatric rehabilitation and child neurology specialists. Prevalence rates with 95% confidence intervals (CIs) used Alberta government denominators of same-age children and live births. RESULTS The Northern Alberta CP rate (birth years, 2008-2010) for 173 5-year-old children is 2.22 (95% CI 2.12, 2.32) per 1000 5-year-old children. The congenital CP rate is 1.99 (95% CI, 1.89-2.09) per 1000 live births; unilateral congenital CP, 1.0 (95% CI, 0.64-1.36) per 1000 live births; and postneonatal CP, 0.12 (95% CI, 0.1-0.14) per 1000 live births. Gestational age-specific rates are similar: age <28 weeks, 27.2 (95% CI, 23.05-31.35) and 28 to 31 weeks, 29.5 (95% CI, 25.78-33.22). Motor subtypes for 169 children (data missing, 4; male, 97; postnatal, 9) are: spastic, 148 (87.6%) including 31 (20.9%) with diplegia, 10 (6.8%) triplegia, 33 (22.2%) quadriplegia, 74 (50%) hemiplegia/monoplegia); and dyskinetic, 18 (10.6%) and ataxic, 3 (1.8%). A total of 107 (63.3%) ambulate without assistive devices and 111(65.7%) handle most objects with their hands independently. CONCLUSIONS This is the fourth Canadian CP prevalence study; one from Quebec used a similar case ascertainment approach and two 1980s studies from Alberta and British Columbia used administrative databases. Northern Alberta CP rates are comparable with other developed countries. The hemiplegic subtype is the most common. Rates among preterm children have declined but are similar for the <28 and 28 to 31 gestation-week groups.

Cerebral palsy after neonatal encephalopathy: do neonates with suspected asphyxia have worse outcomes?

We sought to investigate how brain injury and severity, and neurological subtype of cerebral palsy (CP) differed in term‐born children with CP after neonatal encephalopathy, between those with suspected birth asphyxia and those without.

Disentangling racial and ethnic disparities in cerebral palsy.

Durkin et al. examine racial and ethnic disparities in the risk of developing cerebral palsy (CP) in a population-based cohort of 8-year-old children in the USA. They show that black children have a 52% higher risk of spastic CP than white children, and identify socioeconomic status (SES) and perinatal factors as mediators of this association between race and CP risk. Based on their adjusted odds ratios when SES and perinatal factors are included in their model, there is no additional risk for black children, who, paradoxically, appear to have a reduced risk of developing CP. A similar conclusion was reached in a study in California, which reported that the risk of developing CP was increased in black children overall, but was protective among infants of low birthweight (LBW) or born preterm. In their discussion, Durkin et al. mention the ‘birth weight paradox’. A 1971 study provides a classic example of this paradox, reporting that maternal smoking is protective against infant mortality among LBW infants. This apparent paradox of a protective effect of a known risk factor in higher-risk subgroups has been replicated not just by smoking-related studies, but also by studies of other prenatal exposures that affect infant mortality, such as race and ethnic group. In studies of CP epidemiology, it is common practice to examine gestational ageand birthweight-specific associations with prenatal exposures, presumably to control for the effects of early delivery and fetal growth restriction on CP risk. Under certain conditions, this may lead to biased and paradoxical results. Black children are at an increased risk of preterm birth and LBW, both known to be strong predictors of the development of CP. Conditioning on these intermediates using conventional mediation analysis, such as multivariable logistic regression or stratification, in an attempt to estimate the ‘direct’ causal effect of race on the risk of developing CP, can lead to biased effect estimates and even reverse the direction of effects through collider-stratification bias. To demonstrate this point, consider a simplified causal network where black children are at increased risk of CP only through preterm birth. The crude risk ratio of CP among black children would be greater than 1, but the adjusted or stratum-specific risk ratio is expected to be 1. This would mean that race confers a risk of CP only through preterm birth and not through any other mechanism. Now consider a slightly more complex causal network in which an unmeasured factor unrelated to black children (e.g. a congenital malformation) is another underlying cause of preterm birth (the mediator) and CP (the outcome). In this scenario, preterm birth becomes a collider, creating a statistical relationship between otherwise independent factors (race and congenital malformation). If preterm birth resulting from a congenital malformation is associated with a greater risk of CP than preterm birth among black children, then black children would appear to be protected from CP in the preterm group. The crude risk ratio of CP among black children would again be greater than 1, but the adjusted or stratum-specific risk ratio would be less than 1, appearing protective, thus being biased. The controlled direct effect of race on CP risk, which is independent of mediation by preterm birth and LBW, could be estimated using marginal structural models. ‘Fetuses-at-risk’ denominators were introduced in research on preterm stillbirth and are gaining application when analysing overall infant mortality and other outcomes associated with preterm birth. The premise is that, at every gestational age, the denominator should not be restricted to births at that gestational age, but rather should include all fetuses at risk – whether born at that gestational age or at a later gestational age. By using this approach, the paradoxical protective effect of known risk factors for preterm birth could be abolished by removing the conditioning on preterm birth, a selection bias that can be seen even in the absence of unmeasured confounding. Racial and ethnic disparities in the risk of developing CP exist, and are likely to be mediated by SES, preterm birth, and associated perinatal factors, as suggested by Durkin et al. The question of whether the effect of race

Accuracy of administrative claims data for cerebral palsy diagnosis: a retrospective cohort study

BACKGROUND Cerebral palsy is the most common cause of childhood physical disability, with multiple associated comorbidities. Administrative claims data provide population-level prevalence estimates for cerebral palsy surveillance; however, their diagnostic accuracy has never been validated in Quebec. This study aimed to assess the accuracy of administrative claims data for the diagnosis of cerebral palsy. METHODS We conducted a retrospective cohort study of children with cerebral palsy born between 1999 and 2002 within 6 health administrative regions of Quebec. Provincial cerebral palsy registry data (reference standard) and administrative physician claims were linked. We explored differences between true-positive and false-negative cases using subgroup sensitivity analysis. RESULTS A total of 301 children were identified with confirmed cerebral palsy from the provincial registry, for an estimated prevalence of 1.8 (95% confidence interval [CI] 1.6-2.1) per 1000 children 5 years of age. The sensitivity and specificity of administrative claims data for cerebral palsy were 65.5% (95% CI 59.8%-70.8%) and 99.9% (95% CI 99.9%-99.9%), respectively, yielding a prevalence of 2.0 (95% CI 1.9-2.3) per 1000 children 5 years of age. The positive and negative predictive values were 58.8% (95% CI 53.3%-64.1%) and 99.9% (95% CI 99.9%-99.9%), respectively. The κ value was 0.62 (95% CI 0.57-0.67). Administrative claims data were more sensitive for children from rural regions, born preterm, with spastic quadriparesis and with higher levels of motor impairment. INTERPRETATION Administrative claims data do not capture the full spectrum of children with cerebral palsy. This suggests the need for a more sensitive case definition and caution when using such data without validation.

Response to the Canadian Agency for Drugs and Technologies in Health and Institut national d’excellence en santé et en services sociaux decision regarding nusinersen for Spinal Muscular Atrophy

As Canadian neuromuscular specialists caring for children and adults with spinal muscular atrophy (SMA), we write to express our disappointment with the recent decision to largely reject access for SMA patients to the anti-sense oligonucleotide drug nusinersen (Spinraza) by Canadian Agency for Drugs and Technologies in Health (CADTH) and Institut national d’excellence en santé et en services sociaux (INESSS). After the initial positive decision by Health Canada, and the wide access to nusinersen for a broad range of SMA patients in a number of regions, including the United States and Europe, this decision is very difficult for the SMA community in Canada. With an estimated incidence of 1 in 11,000 births, SMA is the leading genetic cause of death in infants; without supportive care, children with the most severe form, SMA type I, rarely live to see their second birthday, and those who do, have significant disability. Nusinersen is the first, and currently only, approved treatment for 5q SMA, with high-level evidence to change the course of the disease. It has the potential to make a difference in the lives of all individuals with SMA types I to III and of all ages. In accordance with this view, after reviewing all available data, Health Canada—in July 2017— provided broad approval of nusinersen for all SMA patients. This contrasts with the opinion from Quebec’s INESSS, which, while ostensibly recognizing the therapeutic value for type I, asserted that the data from well-designed nusinersen clinical trials are insufficient for SMA types with later age of diagnosis, and the resulting gaps in knowledge are sufficient to not recommend listing the drug for the treatment of all SMA types. On the other hand, the Canadian CADTH recognized the therapeutic value in the most severely affected individuals, but only if started early in their disease course, while rejecting this prescription to all SMA types of varying ages of diagnosis and clinical severity and evolution—in other words, excluding a large part of the SMA community from access to this genetically based treatment. CADTH made their limited approval to type 1 SMA conditional on SMA specialist care, a substantial reduction in price, and the “collection of real-world evidence on the use of nusinersen for the treatment of SMA”. Althoughwe view the first two conditions as appropriate, we strongly believe that the third condition is not appropriate; therefore, while the SMAcommunity is actively collecting further data on a broader range of affected individuals, the totality of the data supports broader access than the INESSS and CADTH decisions reflect.