Cost-benefit analysis of polysomnography versus Clinical Assessment Score-15 (CAS-15) for treatment of pediatric sleep-disordered breathing.

OBJECTIVE: To determine the cost of medical care using the Clinical Assessment Score-15 (CAS-15) scale versus polysomnography (PSG) for children with sleep-disordered breathing in terms of benefit. STUDY DESIGN: Cost-benefit analysis. SETTING: Hospital-based pediatric otolaryngology practice. SUBJECTS AND METHODS: Ninety-three patients from our original CAS-15 study were included. Four clinical measures were used and payment data were obtained. Cost-benefit analysis was performed for 2 clinical pathways. In pathway 1, all children had PSG; those with positive studies were referred for adenotonsillectomy. In pathway 2, children with CAS-15 ≥ 32 were referred for adenotonsillectomy regardless of PSG. Paired t test compared intrasubject mean total cost (pathway 1 vs pathway 2). Further analyses computed a change score for the clinical measures (follow-up minus baseline); these were divided by estimated treatment cost, producing 4 cost-benefit ratios for each pathway. Paired t tests compared the mean of these ratios between the pathways. RESULTS: Of 65 PSG+ (15 CAS-), 54 underwent surgery; of 28 PSG- (17 CAS-), 7 underwent surgery. Model estimated costs demonstrate a mean cost benefit of $US1172 (SE = $214) for pathway 2 versus pathway 1 (P < .001). CAS-15 is also cost-beneficial versus PSG in 3 of 4 clinical measures (Child Behavior Checklist total problem T score, P = .008, mean OSA-18 survey score, P < .001, apnea hypopnea index, P < .001). CONCLUSIONS: We present evidence that a CAS-15-based treatment decision criterion is superior to PSG in terms of monetary cost and in benefit per unit cost for 3 of 4 clinical measures evaluated.

A recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13.

Primary vesicoureteral reflux (pVUR) is one of the most common causes of pediatric kidney failure. Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance. Absence of pVUR in parents of affected individuals raises the possibility of a recessive contribution to pVUR. We performed a genome-wide linkage scan in 12 large families segregating pVUR, comprising 72 affected individuals. To avoid potential misspecification of the trait locus, we performed a parametric linkage analysis using both dominant and recessive models. Analysis under the dominant model yielded no signals across the entire genome. In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping. This interval achieved a peak heterogeneity LOD score of 3.6 with 60% of families linked. This heterogeneity LOD score improved to 4.5 with exclusion of two high-density pedigrees that failed to link across the entire genome. The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations. In conclusion, this study identifies a major new locus for pVUR and suggests that in addition to genetic heterogeneity, recessive contributions should be considered in all pVUR genome scans.

Localization of a gene for nonsyndromic renal hypodysplasia to chromosome 1p32-33.

Nonsyndromic defects in the urinary tract are the most common cause of end-stage renal failure in children and account for a significant proportion of adult nephropathy. The genetic basis of these disorders is not fully understood. We studied seven multiplex kindreds ascertained via an index case with a nonsyndromic solitary kidney or renal hypodysplasia. Systematic ultrasonographic screening revealed that many family members harbor malformations, such as solitary kidneys, hypodysplasia, or ureteric abnormalities (in a total of 29 affected individuals). A genomewide scan identified significant linkage to a 6.9-Mb segment on chromosome 1p32-33 under an autosomal dominant model with reduced penetrance (peak LOD score 3.5 at D1S2652 in the largest kindred). Altogether, three of the seven families showed positive LOD scores at this interval, demonstrating heterogeneity of the trait (peak HLOD 3.9, with 45% of families linked). The chromosome 1p32-33 interval contains 52 transcription units, and at least 23 of these are expressed at stage E12.5 in the murine ureteric bud and/or metanephric mesenchyme. These data show that autosomal dominant nonsyndromic renal hypodysplasia and associated urinary tract malformations are genetically heterogeneous and identify a locus for this common cause of human kidney failure.

Familial vesicoureteral reflux: testing replication of linkage in seven new multigenerational kindreds.

Vesicoureteral reflux (VUR) (OMIM %193000), a common cause of childhood renal failure, is strongly influenced by hereditary factors. Familial VUR most closely conforms to autosomal-dominant inheritance, but because of variable penetrance and expressivity, large multigenerational pedigrees tractable to linkage analysis have been difficult to ascertain. A single genome-wide study of familial VUR has demonstrated linkage to chromosome 1p13, with 78% locus heterogeneity. Previous studies in humans have also suggested loci on chromosomes 6p21, 10q26, and 19q13, whereas mutations in ROBO2 were recently reported in some patients with VUR. Replication of these studies was attempted in seven previously undescribed families from Italy and the United States. Simulation studies, assuming 50% locus heterogeneity, showed that these kindreds had 85% power to replicate linkage and 53% power to achieve genome-wide significance at candidate intervals. Thirty-five markers on chromosomes 1p13, 3p12, 6p21, 10q26, and 19q13 were genotyped and analysis of linkage under a variety of models was performed. Parametric analysis excluded linkage to all candidate loci under genetic homogeneity; moreover, the data did not support statistically significant linkage under models of locus heterogeneity. Similarly, nonparametric, allele-sharing analysis did not reveal any evidence of linkage at any of the loci tested. Thus, despite sufficient power, linkage of familial VUR to previously reported candidate intervals could not be replicated. These data demonstrate substantial genetic heterogeneity of VUR and suggest that mapping strategies relying on a large number of kindreds or single "loaded" pedigrees will be most effective to achieve replication or detection of linkage.