The impact of study design and diagnostic approach in a large multi-centre ADHD study: Part 2: Dimensional measures of psychopathology and intelligence

Background

The International Multi-centre ADHD Genetics (IMAGE) project with 11 participating centres from 7 European countries and Israel has collected a large behavioural and genetic database for present and future research. Behavioural data were collected from 1068 probands with ADHD and 1446 unselected siblings. The aim was to describe and analyse questionnaire data and IQ measures from all probands and siblings. In particular, to investigate the influence of age, gender, family status (proband vs. sibling), informant, and centres on sample homogeneity in psychopathological measures.

Methods

Conners' Questionnaires, Strengths and Difficulties Questionnaires, and Wechsler Intelligence Scores were used to describe the phenotype of the sample. Data were analysed by use of robust statistical multi-way procedures.

Results

Besides main effects of age, gender, informant, and centre, there were considerable interaction effects on questionnaire data. The larger differences between probands and siblings at home than at school may reflect contrast effects in the parents. Furthermore, there were marked gender by status effects on the ADHD symptom ratings with girls scoring one standard deviation higher than boys in the proband sample but lower than boys in the siblings sample. The multi-centre design is another important source of heterogeneity, particularly in the interaction with the family status. To a large extent the centres differed from each other with regard to differences between proband and sibling scores.

Conclusions

When ADHD probands are diagnosed by use of fixed symptom counts, the severity of the disorder in the proband sample may markedly differ between boys and girls and across age, particularly in samples with a large age range. A multi-centre design carries the risk of considerable phenotypic differences between centres and, consequently, of additional heterogeneity of the sample even if standardized diagnostic procedures are used. These possible sources of variance should be counteracted in genetic analyses either by using age and gender adjusted diagnostic procedures and regional normative data or by adjusting for design artefacts by use of covariate statistics, by eliminating outliers, or by other methods suitable for reducing heterogeneity.     

Secondary thrombocytosis

To estimate the incidence and causes of secondary thrombocytosis in children, a 12 month study of all patients attending a children's hospital and discovered to have a platelet count over two times the upper normal limit (> 800 x 10(9)/l) was undertaken. Data so obtained were analysed both separately and together with those from two previous studies to gain as broad a perspective as possible. Of 7916 children who had platelet counts during the study period, 36 (0.5%) produced a value > 800 x 10(9)/l; there were 19 boys and 17 girls. There was a preponderance of young infants (median age 13 months). Twenty seven of the 36 had some sort of associated infection, bacterial in 18 and viral in nine. The other nine were either recovering from anti-neoplastic chemotherapy (n = 6), were post-operative (n = 2), or simply iron deficient (n = 1). Combining these patients with those described in previous studies allowed a review of 139 unselected children with very high platelet counts. Fifty three (38%) had infections, 29 (20%) had traumatic or surgical tissue damage, 16 (11%) had malignant disease undergoing chemotherapy or surgery, and 13 (9%) had connective tissue or autoimmune disorders. Secondary thrombocytosis is not rare and is most frequently seen in very young infants after infection. It can arise in a wide variety of other circumstances including rebound from myelosuppression, iron lack, or as part of an acute phase response. It is clinically unimportant in terms of morbidity and requires no treatment other than that for the primary condition.     

Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia

Two children with acute lymphoblastic leukaemia (ALL) taking daily 6-mercaptopurine as part of a national UK therapeutic trial repeatedly developed profound myelosuppression on 25% of the standard protocol dose. Both were found to have undetectable intracellular activity of thiopurine methyltransferase (TPMT), an enzyme controlling one of the major alternative catabolic pathways of 6-mercaptopurine, and both produced higher concentrations of cytotoxic drug metabolites at 10-25% of the protocol dose than other patients taking 100%. It is supposed that these patients represent the 0.33% of the normal population constitutionally lacking TPMT. It is important to recognise such individuals both to avoid fatal bone marrow failure through inadvertent overdosage, and to be reassured that an adequate drug effect can be achieved at around 10% of the standard dose.     

Management of intracranial dural arteriovenous shunts in adults

Dural arteriovenous shunts are abnormal arteriovenous communications within the dura. They are thought to be an acquired condition in adults and can present with a variety of clinical features, ranging from benign bruits to intracranial hemorrhage and neurological deficits. The presentation and natural history of these shunts is largely determined by the pattern of venous drainage. Knowledge of natural history and careful study of the angioarchitexture by angiography is therefore mandatory for correct management of these lesions. In this review, principles of management in adults and the various factors that influence treatment decisions are discussed, with a focus on endovascular therapy. Retrograde leptomeningeal or cortical venous drainage has a strong correlation with adverse clinical events and the requirement for aggressive management in this situation is highlighted. Indications for endovascular treatment, therapeutic goals, approaches and techniques are reviewed. The role of surgical treatment is also briefly discussed.     

Intraventricular haemorrhage in the preterm infant without hyaline membrane disease

The clinicopathological associations of 33 singleton infants who died with intraventricular haemorrhage (IVH) without hyaline membrane disease (HMD) ('IVH only') were compared with those of 39 infants who died with IVH+HMD over the same gestation range in order to determine what factors other than those related to HMD may contribute to the pathogenesis of IVH. The incidence of 'IVH only' was inversely related to gestational age in the Hammersmith birth population, whereas the incidence of IVH+HMD rose to a peak at 28-29 weeks' gestation. Infants with 'IVH only' lived longer on average than those with IVH+HMD despite a lower birthweight and shorter gestation. Infants who died in the first 12 hours from 'IVH only' had suffered severe birth asphyxia but in those who died later the main symptom was recurrent apnoea. Fewer infants with asphyxia but in those who died later the main symptom was.recurrent apnoea. Fewer infants with 'IVH only' were given alkali therapy or were connected to the ventilator as compared to those with IVH+HMD, but there were no differences in alkali therapy in those who lived for 12 hours or more. In the 'IVH only' group there was a high incidence of haemorrhage from other sites and of bacterial infections. It is suggested that, in the absence of HMD, extreme immaturity is the main factor determining the occurrence of IVH. Birth asphyxia, apnoeic attacks, haemorrhage, and infections may play subsidiary roles, possibly through development of metabolic acidosis.     

Challenges of Conducting Community-Based Participatory Research in Boston’s Neighborhoods to Reduce Disparities in Asthma

Boston is one of the preeminent health care and research centers in the world, but for much of its urban core, these resources are largely out of reach. Community Based Participatory Research (CBPR) provides a model with the potential to bridge the gaps between its research prominence and the health of its residents. We report here two case studies of major research projects that were partnerships between universities in Boston and community based organizations and city agencies. The Healthy Public Housing Initiative (HPHI) and the Asthma Center on Community Environment and Social Stress (ACCESS) are projects that provide numerous lessons about the potential and challenges of conducting CBPR. Ensuring that the projects were true partnerships emerged as key issues in both, especially with respect to funding mechanisms and distribution of resources, although the nature of the challenges differed substantially in the two projects. We note that both academic and community partners may harbor stereotypes about the other and that generalizations about broad populations, academics or community members, may not apply well to everyone. Aligning objectives and expectations emerged as another key lesson. In HPHI, tension between service delivery and research was both a source of conflict and a source of creative development that led to divergent but interesting outcomes. In ACCESS, the tensions revolved more around community capacity building while attempting to build and maintain a large cohort for epidemiological investigations. We conclude that open and frank discussion and a transparent process upfront about project direction, finances, expectations, and other dimensions are necessary but not sufficient to address the inherent challenges in CBPR, and that even so, there are likely to be differences in perspective in such partnerships that require honest negotiation throughout the process of the project.     

Sternocostoclavicular hyperostosis: a review and report of 11 cases

Sternocostoclavicular hyperostosis is a benign ossifying diathesis of unknown etiology characterized by hyperostosis and soft-tissue ossification between the clavicles, anterior portion of the upper ribs, and manubrium, with variable hyperostosis or ankylosis in the spine and sacroiliac joints. Our cumulative experience with 11 cases is reported, with emphasis on radiographic features of the condition. Scintigraphic results in five patients and computed tomographic findings in one patient are presented. A review of the literature and our own material indicates that sternocostoclavicular hyperostosis may be more common than has been previously recognized.