Jacqueline R. Starr

Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer

Testicular germ cell tumors (TGCT) have been expected to have a strong underlying genetic component. We conducted a genome-wide scan among 277 TGCT cases and 919 controls and found that seven markers at 12p22 within KITLG (c-KIT ligand) reached genome-wide significance (P < 5.0 × 10−8 in discovery). In independent replication, TGCT risk was increased threefold per copy of the major allele at rs3782179 and rs4474514 (OR = 3.08, 95% CI = 2.29–4.13; OR = 3.07, 95% CI = 2.29–4.13, respectively). We found associations with rs4324715 and rs6897876 at 5q31.3 near SPRY4 (sprouty 4; P < 5.0 × 10−6 in discovery). In independent replication, risk of TGCT was increased nearly 40% per copy of the major allele (OR = 1.37, 95% CI = 1.14–1.64; OR = 1.39, 95% CI = 1.16–1.66, respectively). All of the genotypes were associated with both seminoma and nonseminoma TGCT subtypes. These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as genes involved in TGCT susceptibility.

Community-wide transcriptome of the oral microbiome in subjects with and without periodontitis

Despite increasing knowledge on phylogenetic composition of the human microbiome, our understanding of the in situ activities of the organisms in the community and their interactions with each other and with the environment remains limited. Characterizing gene expression profiles of the human microbiome is essential for linking the role of different members of the bacterial communities in health and disease. The oral microbiome is one of the most complex microbial communities in the human body and under certain circumstances, not completely understood, the healthy microbial community undergoes a transformation toward a pathogenic state that gives rise to periodontitis, a polymicrobial inflammatory disease. We report here the in situ genome-wide transcriptome of the subgingival microbiome in six periodontally healthy individuals and seven individuals with periodontitis. The overall picture of metabolic activities showed that iron acquisition, lipopolysaccharide synthesis and flagellar synthesis were major activities defining disease. Unexpectedly, the vast majority of virulence factors upregulated in subjects with periodontitis came from organisms that are not considered major periodontal pathogens. One of the organisms whose gene expression profile was characterized was the uncultured candidate division TM7, showing an upregulation of putative virulence factors in the diseased community. These data enhance understanding of the core activities that are characteristic of periodontal disease as well as the role that individual organisms in the subgingival community play in periodontitis.

A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility

Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus. In combined analysis that mutually conditions on both DMRT1 single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) = 1.48, 95% confidence interval (CI) 1.23, 1.78; P = 2.52 × 10(-5)] compared with controls, while the association with rs755383 persisted (per allele OR = 1.26, 95% CI 1.08, 1.47, P = 0.0036). In similar analyses, the association of rs7040024 among men with seminomatous tumors did not differ from that among men with non-seminomatous tumors. In combination with KITLG, the strongest TGCT susceptibility locus found to date, men with TGCT had greatly elevated odds (OR = 14.1, 95% CI 5.12, 38.6; P = 2.98 × 10(-7)) of being double homozygotes for the risk (major) alleles at DMRT (rs7040024) and KITLG (rs4474514) when compared with men without TGCT. Our findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility.

Using Census Data and Birth Certificates to Reconstruct the Early-life Socioeconomic Environment and the Relation to the Development of Alzheimer’s Disease

The early-life environment and its effect on growth and maturation of children and adolescents are associated with several adult chronic diseases, including Alzheimer’s disease. Because it is not feasible to collect information prospectively over the average life span, methods to reconstruct the early-life environment of the aged are necessary to evaluate these associations. In a community-based case-control study conducted in the United States, we collected U.S. census records and birth certificates to reconstruct the early-life socioeconomic environment of each elderly subject. Information was found on 82% of the available Alzheimer’s disease cases (239 of 292) and 87% of the available controls (245 of 282). We investigated risk of Alzheimer’s disease associated with father’s occupation, parental age, household size, sibship size, and birth order. Subjects whose fathers were unskilled manual workers or laborers were at higher risk for Alzheimer’s disease (odds ratio = 1.80, 95% confidence interval = 1.19–2.73). The risk of Alzheimer’s disease was increased with increasing number of people in the household. We also evaluated whether subjects with the apolipoprotein ϵ4 allele (APOE ϵ4), a strong genetic risk factor that is not a necessary cause or a sufficient cause by itself for the development of Alzheimer’s disease, were at higher risk than subjects who did not carry this allele. Among subjects with the APOE ϵ4 allele whose fathers held lower-socioeconomic level occupations, the odds of developing Alzheimer’s disease were higher (odds ratio = 2.35, 95% confidence interval = 1.07–5.16) compared with subjects without the allele (odds ratio = 1.40, 95% confidence interval = 0.78–2.52). Subjects carrying the APOE ϵ4 allele alone have a threefold increased risk of Alzheimer’s disease (odds ratio = 3.17, 95% confidence interval = 1.99–5.04). Compared with subjects with neither risk factor, subjects with both the genetic and the environmental risk factors (household size of seven or more and father’s occupation being manual) had a relatively high risk of Alzheimer’s disease (odds ratio = 14.8, 95% confidence interval = 4.9–46). The data suggest that APOE ϵ4 may modify the associations between father’s occupation, other early-life environmental factors, and development of Alzheimer’s disease in late life.

A comparison of nasendoscopy and multiview videofluoroscopy in assessing velopharyngeal insufficiency.

OBJECTIVES: 1) To compare nasendoscopy (NE) and multiview fluoroscopy (MVF) in assessing velopharyngeal gap size; and 2) to determine the relationship between these assessments and velopharyngeal insufficiency (VPI) severity. STUDY DESIGN AND SETTING: Retrospective review of consecutive patients with VPI at a tertiary care childrens hospital, assessed with NE and MVF between 1996 and 2003. RESULTS: 177 subjects. NE and MVF gap areas were correlated (R = 0.34, 95% CI 0.26-0.41). In adjusted analysis, VPI severity was associated with: 1) NE gap area (OR = 2.78, 95% CI 1.96-3.95), 2) MVF gap area (OR 1.64, 95% CI 1.37-1.95), 3) age <5 years (OR 3.30, 95% CI 1.47-7.38), and 4) previously repaired cleft palate (OR 0.48, 95% CI 0.25-0.94). CONCLUSIONS AND SIGNIFICANCE: NE and MVF assessments provide complementary information and are correlated. Both are associated with VPI severity. However, the “birds-eye view” provided by NE has a stronger correlation with VPI severity than MVF.

Association of marijuana use and the incidence of testicular germ cell tumors

The incidence of testicular germ cell tumors (TGCTs) has been increasing the past 4 to 6 decades; however, exposures that account for this rise have not been identified. Marijuana use also grew during the same period, and it has been established that chronic marijuana use produces adverse effects on the human endocrine and reproductive systems. In this study, the authors tested the hypothesis that marijuana use is a risk factor for TGCT.

Characteristics of 2733 Cases Diagnosed With Deformational Plagiocephaly and Changes in Risk Factors Over Time

Objectives: To describe infant and maternal characteristics among infants with plagiocephaly and to quantify time trends in potential risk factors for plagiocephaly. Design: Case-only study. We described the characteristics of individuals born between 1987 and 2002. We also compared characteristics of individuals born from 1987 through 1990, before the American Academy of Pediatrics 1992 sleep-position recommendations, with those of individuals born from 1991 to 2002. Setting: Childrens Craniofacial Center at Childrens Hospital and Regional Medical Center in Seattle, Washington. Participants: Subjects included 2733 infants diagnosed with deformational plagiocephaly or brachycephaly before 18 months of age who were born from 1987 to 2002. Main Outcome Measure: Descriptive statistics, odds ratios, and 95% confidence intervals. Results: Among individuals born from 1991 to 2002, 91.6% had occipital-only flattening, 17.2% were brachycephalic, 67.7% were boys, and 9.9% were multiple birth infants. As compared with individuals born from 1987 through 1990, those born from 1991 to 2002 were more apt to be a multiple birth (odds ratio [OR] 3.4, 95% confidence interval [CI]: 0.8, 14.1) and to have a mother ≥35 years of age (OR, 3.2; 95% CI, 1.4 to 7.3); they were hospitalized less commonly at birth for 4 or more days (OR, 0.02; 95% CI, 0.01 to 0.06). Conclusions: Several risk factors for plagiocephaly were more common among individuals born after the 1992 American Academy of Pediatrics sleep-position recommendations. These results are consistent with the explanation that supine sleeping modifies the association between such risk factors and plagiocephaly. Further studies with a control group are needed to validate this conclusion.

Picture perfect? Reliability of craniofacial anthropometry using three-dimensional digital stereophotogrammetry.

Background: Quantification of facial characteristics is important for research in dysmorphology, otolaryngology, oral and maxillofacial, and plastic surgical disciplines, among others. Three-dimensional surface imaging systems offer a quick and practical method for quantifying craniofacial variation and appear to be highly reliable. However, some sources of measurement error have not yet been thoroughly evaluated. Methods: The authors assessed the reliability of using stereophotogrammetry for measuring craniofacial characteristics in 40 individuals, including 20 without craniofacial conditions and 20 with 22q11.2 deletion syndrome. The authors recruited staff and relatives of staff, and individuals with a laboratory-confirmed 22q11.2 deletion. Thirty anthropometric measurements were obtained on participants and on three-dimensional images. Results: Intrarater and interrater reliability for most interlandmark distances on three-dimensional images had intraclass correlation coefficients greater than 95 percent, mean absolute differences of less than 1 mm, relative error measurement less than 5, and technical error of measurement less than 1 mm. The Pearson correlation coefficients of greater than 0.9 for most distances suggest high intermethod reliability between direct and image-based measurements. Three-dimensional image-based measurements were systematically larger for the head length and width, forehead, and skull base widths, and upper and lower facial widths. Conclusions: This study provides further evidence of the high reliability of three-dimensional imaging systems for several craniofacial measurements, including landmarks and interlandmark distances not included in previous studies. The authors also discuss possible errors introduced with palpable landmarks and when working with less compliant participants, such as children. The authors offer guidelines for establishing protocols that can be tailored to each population and research question to maximize the accuracy of image-based measurements.

New Scaphocephaly Severity Indices of Sagittal Craniosynostosis: A Comparative Study With Cranial Index Quantifications

Objective To describe a novel set of scaphocephaly severity indices (SSIs) for predicting and quantifying head- and skull-shape deformity in children diagnosed with isolated sagittal synostosis (ISS) and compare their sensitivity and specificity with those of the traditional cranial index (CI). Methods Computed tomography head scans were obtained from 60 patients diagnosed with ISS and 41 age-matched control patients. Volumetric reformations of the skull and overlying skin were used to trace two-dimensional planes defined in terms of skull-base plane and internal or surface landmarks. For each patient, novel SSIs were computed as the ratio of head width and length as measured on each of these planes. A traditional CI was also calculated and a receiver operating characteristic curve analysis was applied to compare the sensitivity and specificity of the proposed indices with those of CI. Results Although the CI is a sensitive measure of scaphocephaly, it is not specific and therefore not a suitable predictor of ISS in many practical applications. The SSI-A provides a specificity of 95% at a sensitivity level of 98%, in contrast with the 68% of CI. On average, the sensitivity and specificity of all proposed indices are superior to those of CI. Conclusions Measurements of cranial width and length derived from planes that are defined in terms of internal or surface landmarks and skull-base plane produce SSIs that outperform traditional CI measurements.

Development at Age 36 Months in Children With Deformational Plagiocephaly

OBJECTIVES: Infants and toddlers with deformational plagiocephaly (DP) have been shown to score lower on developmental measures than unaffected children. To determine whether these differences persist, we examined development in 36-month-old children with and without a history of DP. METHODS: Participants included 224 children with DP and 231 children without diagnosed DP, all of who had been followed in a longitudinal study since infancy. To confirm the presence or absence of DP, pediatricians blinded to children’s case status rated 3-dimensional cranial images taken when children were 7 months old on average. The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) was administered as a measure of child development. RESULTS: Children with DP scored lower on all scales of the BSID-III than children without DP. Differences were largest in cognition, language, and parent-reported adaptive behavior (adjusted differences = –2.9 to –4.4 standard score points) and smallest in motor development (adjusted difference = –2.7). Children in the control group who did not have previously diagnosed DP but who were later rated by pediatricians to have at least mild cranial deformation also scored lower on the BSID-III than unaffected controls. CONCLUSIONS: Preschool-aged children with a history of DP continue to receive lower developmental scores than unaffected controls. These findings do not imply that DP causes developmental problems, but DP may nonetheless serve as a marker of developmental risk. We encourage clinicians to screen children with DP for developmental concerns to facilitate early identification and intervention.