Evaluation of risk assessment questions used to target blood lead screening in Illinois

OBJECTIVE: Beginning in 1995, Illinois law permitted targeted-as opposed to universal-blood lead screening in low-risk areas, which were defined by ZIP code characteristics. State guidelines recommended specific lead risk assessment questions to use when targeting screening. This study was designed to evaluate the sensitivity and specificity of Illinois lead risk assessment questions. DESIGN: Parents bringing their 9- or 10- or 12-month and 24-month-old children for health supervision visits at 13 pediatric practices and parents of children (aged 6 through 25 months and who needed a blood lead test) receiving care at 5 local health departments completed a lead risk assessment questionnaire concerning their child. Children had venous or capillary blood lead testing. Venous confirmation results of children with a capillary level >/=10 micrograms/dL were used in analyses. CHILDREN: There were 460 children with both blood and questionnaire data recruited at the pediatric practices (58% of eligible) and 285 children (51% of eligible) recruited at local health departments. Of the 745 children studied, 738 provided a ZIP code that allowed their residence to be categorized as in a low-risk (n = 456) or high-risk (n = 282) area. RESULTS: Sixteen children (3.5%) living in low-risk areas versus 34 children (12.1%) living in high-risk areas had a venous blood lead level (BLL) >/=10 micrograms/dL; 1.8% and 5.3%, respectively, had a venous BLL >/=15 micrograms/dL. For children living in low-risk areas, Illinois mandated risk assessment questions (concerning ever resided in home built before 1960, exposure to renovation, and exposure to adult with a job or hobby involving lead) had a combined sensitivity of.75 for levels >/=10 micrograms/dL and.88 for levels >/=15 micrograms/dL; specificity was.39 and.39, respectively. The sensitivity of these questions was similar among children from high-risk areas; specificity decreased to.27 and.28, for BLLs >/=10 micrograms/dL and >/=15 micrograms/dL, respectively. The combination of items requiring respondents to list house age (built before 1950 considered high risk) and indicate exposure to renovation had a sensitivity among children from low-risk areas of.62 for BLLs >/=10 micrograms/dL with specificity of.57; sensitivity and specificity among high-risk area children were.82 and.36, respectively. For this strategy, similar sensitivities and specificities for low and high-risk areas were found for BLLs >/=15 micrograms/dL. CONCLUSIONS: The Illinois lead risk assessment questions identified most children with an elevated BLL. Using these questions, the majority of Illinois children in low-risk areas will continue to need a blood lead test. This first example of a statewide screening strategy using ZIP code risk designation and risk assessment questions will need further refinement to limit numbers of children tested. In the interim, this strategy is a logical next step after universal screening.     

Limited motor performance and minor neurological dysfunction at school age

Aim: To investigate the relationship between motor performance and minor neurological dysfunction (MND) at school age. Methods: Two hundred and fifty‐three children (158 boys, 95 girls; mean age 8 years and 7 months) of whom 167 children received mainstream education and 86 children special education were neurologically examined according to Touwen. Special attention was paid to the severity of MND (simple or complex form) and type of dysfunction. Motor performance was assessed with the Movement Assessment Battery for Children (MABC), a parental questionnaire (Developmental Coordination Disorder Questionnaire; DCD‐Q) and a teacher’s questionnaire (Motor Observation Questionnaire for Teachers; MOQ‐T). Results: Total scores of MABC, DCD‐Q and MOQ‐T were strongly related to the severity of MND and to dysfunctional coordination and fine manipulation. Mild dysfunction in posture and muscle tone was only weakly related to limited motor performance. Children with a MABC score < 5th percentile showed significantly more often complex MND than children with scores between the 5th and 15th percentile or >15th percentile (54% vs 17% and 10%). Conclusion: Limited motor performance is related to the severity and type of MND. Coordination problems and fine manipulative disability are strongly related to poor motor performance, mild dysfunctions of posture and muscle tone to a lesser extent.     

Whole exome sequencing combined with linkage analysis identifies a novel 3?bp deletion in NR5A1

Disorders of sex development (DSDs) encompass a broad spectrum of conditions affecting the development of the gonads and genitalia. The underlying causes for DSDs include gain or loss of function variants in genes responsible for gonad development or steroidogenesis. Most patients with DSD have an unknown genetic etiology and cannot be given an accurate diagnosis. We used whole exome capture and massively parallel sequencing to analyse a large family with 46,XY DSD and 46,XX premature ovarian insufficiency. In addition, we used a recently developed method for linkage analysis using genotypes extracted from the MPS data. This approach identified a unique linkage peak on chromosome 9 and a novel, 3 bp, in-frame deletion in exon six of NR5A1 (steroidogenic factor-1 or SF1) in all affected individuals. We confirmed that the variant disrupts the SF1 protein and its ability to bind and regulate downstream genes. NR5A1 has key roles at multiple points in gonad development and steroidogenic pathways. The variant described here affects the function of SF1 in early testis development and later ovarian function, ultimately leading to the 46,XY DSD and 46,XX premature ovarian insufficiency phenotypes, respectively. This study shows that even at low coverage, whole exome sequencing, when combined with linkage analysis, can be a powerful tool to identify rapidly the disease-causing variant in large pedigrees.     

Peptide selectivity discriminates NK cells from KIR2DL2‐ and KIR2DL3‐positive individuals

Natural killer cells are controlled by peptide selective inhibitory receptors for MHC class I, including the killer cell immunoglobulin‐like receptors (KIRs). Despite having similar ligands, KIR2DL2 and KIR2DL3 confer different levels of protection to infectious disease. To investigate how changes in peptide repertoire may differentially affect NK cell reactivity, NK cells from KIR2DL2 and KIR2DL3 homozygous donors were tested for activity against different combinations of strong inhibitory (VAPWNSFAL), weak inhibitory (VAPWNSRAL), and antagonist peptide (VAPWNSDAL). KIR2DL3‐positive NK cells were more sensitive to changes in the peptide content of MHC class I than KIR2DL2‐positive NK cells. These differences were observed for the weakly inhibitory peptide VAPWNSRAL in single peptide and double peptide experiments (p < 0.01 and p < 0.03, respectively). More significant differences were observed in experiments using all three peptides (p < 0.0001). Mathematical modeling of the experimental data demonstrated that VAPWNSRAL was dominant over VAPWNSFAL in distinguishing KIR2DL3‐ from KIR2DL2‐positive donors. Donors with different KIR genotypes have different responses to changes in the peptide bound by MHC class I. Differences in the response to the peptide content of MHC class I may be one mechanism underlying the protective effects of different KIR genes against infectious disease.