ClustR: A Space-Time Cluster Analysis R Package for Individual-level Data.

BACKGROUND: Until recently, large individual-level longitudinal data were unavailable to investigate clusters of disease, driving a need for suitable statistical tools. We introduce a robust, efficient, intuitive R package, ClustR, for space-time cluster analysis of individual-level data. METHODS: We developed ClustR and evaluated the tool using a simulated dataset mirroring the population of California with constructed clusters. We assessed Cluster's performance under various conditions and compared it with another space-time clustering algorithm: SaTScan. RESULTS: ClustR mostly exhibited high sensitivity for urban clusters and low sensitivity for rural clusters. Specificity was generally high. Compared with SaTScan, ClustR ran faster and demonstrated similar sensitivity, but had lower specificity. Select cluster types were detected better by ClustR than SaTScan and vice versa. CONCLUSION: ClustR is a user-friendly, publicly available tool designed to perform efficient cluster analysis on individual-level data, filling a gap among current tools. ClustR and SaTScan exhibited different strengths and may be useful in conjunction.

Spatial-Temporal Cluster Analysis of Childhood Cancer in California.

BACKGROUND: The observance of nonrandom space-time groupings of childhood cancer has been a concern of health professionals and the general public for decades. Many childhood cancers are suspected to have initiated in utero; therefore, we examined the spatial-temporal randomness of the birthplace of children who later developed cancer. METHODS: We performed a space-time cluster analysis using birth addresses of 5,896 cases and 23,369 population-based, age-, sex-, and race/ethnicity-matched controls in California from 1997 to 2007, evaluating 20 types of childhood cancer and three a priori designated subgroups of childhood acute lymphoblastic leukemia (ALL). We analyzed data using a newly designed semiparametric analysis program, ClustR, and a common algorithm, SaTScan. RESULTS: We observed evidence for nonrandom space-time clustering for ALL diagnosed at 2-6 years of age in the South San Francisco Bay Area (ClustR P = 0.04, SaTScan P = 0.07), and malignant gonadal germ cell tumors in a region of Los Angeles (ClustR P = 0.03, SaTScan P = 0.06). ClustR did not identify evidence of clustering for other childhood cancers, although SaTScan suggested some clustering for Hodgkin lymphoma (P = 0.09), astrocytoma (P = 0.06), and retinoblastoma (P = 0.06). CONCLUSIONS: Our study provides evidence that childhood ALL diagnosed at 2-6 years and malignant gonadal germ cell tumors sporadically occurs in nonrandom space-time clusters. Further research is warranted to identify epidemiologic features that may inform the underlying etiology.

Genomic Analyses from Non-invasive Prenatal Testing Reveal Genetic Associations, Patterns of Viral Infections, and Chinese Population History.

We analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1. Finally, we identify a unique pattern of circulating viral DNA in plasma with high prevalence of hepatitis B and other clinically relevant maternal infections. A GWAS for viral infections identifies an exceptionally strong association between integrated herpesvirus 6 and MOV10L1, which affects piwi-interacting RNA (piRNA) processing and PIWI protein function. These findings demonstrate the great value and potential of accumulating NIPT data for worldwide medical and genetic analyses.

In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia.

It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P = .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted.

Genotyping Oral Commensal Bacteria to Predict Social Contact and Structure.

Social network structure is a fundamental determinant of human health, from infectious to chronic diseases. However, quantitative and unbiased approaches to measuring social network structure are lacking. We hypothesized that genetic relatedness of oral commensal bacteria could be used to infer social contact between humans, just as genetic relatedness of pathogens can be used to determine transmission chains of pathogens. We used a traditional, questionnaire survey-based method to characterize the contact network of the School of Public Health at a large research university. We then collected saliva from a subset of individuals to analyze their oral microflora using a modified deep sequencing multilocus sequence typing (MLST) procedure. We examined micro-evolutionary changes in the S. viridans group to uncover transmission patterns reflecting social network structure. We amplified seven housekeeping gene loci from the Streptococcus viridans group, a group of ubiquitous commensal bacteria, and sequenced the PCR products using next-generation sequencing. By comparing the generated S. viridans reads between pairs of individuals, we reconstructed the social network of the sampled individuals and compared it to the network derived from the questionnaire survey-based method. The genetic relatedness significantly (p-value < 0.001) correlated with social distance in the questionnaire-based network, and the reconstructed network closely matched the network derived from the questionnaire survey-based method. Oral commensal bacterial are thus likely transmitted through routine physical contact or shared environment. Their genetic relatedness can be used to represent a combination of social contact and shared physical space, therefore reconstructing networks of contact. This study provides the first step in developing a method to measure direct social contact based on commensal organism genotyping, potentially capable of unmasking hidden social networks that contribute to pathogen transmission.

Mode of delivery and risk of childhood leukemia.

BACKGROUND: Childhood infection and immune response have long been suspected in the etiology of childhood leukemia, specifically acute lymphoblastic leukemia (ALL). Normal primary inoculation of the core human microbiome is circumvented by cesarean section (CS) delivery, which is a proposed modulator of both immune response and early-life infection. METHODS: In this study, we examined CS delivery and the risk of childhood leukemia using data from the California Childhood Leukemia Study (CCLS) case-control study and additive logistic regression models. RESULTS: We observed no association between CS and acute myelogenous leukemia [OR, 0.96; 95% confidence interval (CI), 0.52-1.55]. We observed a suggestive association for ALL and CS (OR, 1.22; 95% CI, 0.97-1.54). When examining common ALL (cALL), defined as ALL with expression of CD10 and CD19 surface antigens and diagnosis occurring between 2 and 5.9 years of age, we found a significant association with CS (OR, 1.44; 95% CI, 1.0-2.06). ALL subjects that are not cALL showed a similar risk as ALL overall (OR, 1.15; 95% CI, 0.91-1.44). Because of previous findings suggesting effect modification, we stratified cALL subjects by Hispanic status. Although we observed no relationship for CS in non-Hispanics (OR, 1.14; 95% CI, 0.72-1.79), we did observe a strong association between cALL and CS in Hispanics (OR, 2.34; 95% CI, 1.23-4.46). CONCLUSION: Within the CCLS, CS delivery seems to be associated with cALL and Hispanic subjects may be driving the association. IMPACT: Further research combined with investigations into response to early infection and the microbiome is warranted.