Robert W. Grundmeier

Common variants at five new loci associated with early-onset inflammatory bowel disease

The inflammatory bowel diseases (IBD) Crohns disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 × 10−9), 22q12 (rs2412973, P = 1.55 × 10−9), 10q22 (rs1250550, P = 5.63 × 10−9), 2q37 (rs4676410, P = 3.64 × 10−8) and 19q13.11 (rs10500264, P = 4.26 × 10−10). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohns disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

High-resolution mapping and analysis of copy number variations in the human genome: A data resource for clinical and research applications

We present a database of copy number variations (CNVs) detected in 2026 disease-free individuals, using high-density, SNP-based oligonucleotide microarrays. This large cohort, comprised mainly of Caucasians (65.2%) and African-Americans (34.2%), was analyzed for CNVs in a single study using a uniform array platform and computational process. We have catalogued and characterized 54,462 individual CNVs, 77.8% of which were identified in multiple unrelated individuals. These nonunique CNVs mapped to 3272 distinct regions of genomic variation spanning 5.9% of the genome; 51.5% of these were previously unreported, and >85% are rare. Our annotation and analysis confirmed and extended previously reported correlations between CNVs and several genomic features such as repetitive DNA elements, segmental duplications, and genes. We demonstrate the utility of this data set in distinguishing CNVs with pathologic significance from normal variants. Together, this analysis and annotation provides a useful resource to assist with the assessment of CNVs in the contexts of human variation, disease susceptibility, and clinical molecular diagnostics.

Variants of DENND1B Associated with Asthma in Children

BACKGROUND Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10(-13) for the comparison across all samples). The 1q31 locus contains the 1q31 locus contains DENND1B, a gene expressed by natural killer cells and dendritic cells. DENND1B protein is predicted to interact with the tumor necrosis factor α receptor [corrected]. CONCLUSIONS We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.

Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohns disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 × 10−8 and 6.95 × 10−8, respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 × 10−8; OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.

Effect of an outpatient antimicrobial stewardship intervention on broad-spectrum antibiotic prescribing by primary care pediatricians: a randomized trial.

IMPORTANCE Antimicrobial stewardship programs have been effective for inpatients, often through prescribing audit and feedback. However, most antimicrobial use occurs in outpatients with acute respiratory tract infections (ARTIs). OBJECTIVE To evaluate the effect of an antimicrobial stewardship intervention on antibiotic prescribing for pediatric outpatients. DESIGN Cluster randomized trial of outpatient antimicrobial stewardship comparing prescribing between intervention and control practices using a common electronic health record. After excluding children with chronic medical conditions, antibiotic allergies, and prior antibiotic use, we estimated prescribing rates for targeted ARTIs standardized for age, sex, race, and insurance from 20 months before the intervention to 12 months afterward (October 2008-June 2011). SETTING AND PARTICIPANTS A network of 25 pediatric primary care practices in Pennsylvania and New Jersey; 18 practices (162 clinicians) participated. INTERVENTIONS One 1-hour on-site clinician education session (June 2010) followed by 1 year of personalized, quarterly audit and feedback of prescribing for bacterial and viral ARTIs or usual practice. MAIN OUTCOMES AND MEASURES Rates of broad-spectrum (off-guideline) antibiotic prescribing for bacterial ARTIs and antibiotics for viral ARTIs for 1 year after the intervention. RESULTS Broad-spectrum antibiotic prescribing decreased from 26.8% to 14.3% (absolute difference, 12.5%) among intervention practices vs from 28.4% to 22.6% (absolute difference, 5.8%) in controls (difference of differences [DOD], 6.7%; P = .01 for differences in trajectories). Off-guideline prescribing for children with pneumonia decreased from 15.7% to 4.2% among intervention practices compared with 17.1% to 16.3% in controls (DOD, 10.7%; P < .001) and for acute sinusitis from 38.9% to 18.8% in intervention practices and from 40.0% to 33.9% in controls (DOD, 14.0%; P = .12). Off-guideline prescribing was uncommon at baseline and changed little for streptococcal pharyngitis (intervention, from 4.4% to 3.4%; control, from 5.6% to 3.5%; DOD, -1.1%; P = .82) and for viral infections (intervention, from 7.9% to 7.7%; control, from 6.4% to 4.5%; DOD, -1.7%; P = .93). CONCLUSIONS AND RELEVANCE In this large pediatric primary care network, clinician education coupled with audit and feedback, compared with usual practice, improved adherence to prescribing guidelines for common bacterial ARTIs, and the intervention did not affect antibiotic prescribing for viral infections. Future studies should examine the drivers of these effects, as well as the generalizability, sustainability, and clinical outcomes of outpatient antimicrobial stewardship. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01806103.

Impact of clinical alerts within an electronic health record on routine childhood immunization in an urban pediatric population.

OBJECTIVES. The objective of this study was to test the hypothesis that clinical alerts for routine pediatric vaccinations within an electronic health record would reduce missed opportunities for vaccination and improve immunization rates for young children in an inner-city population. METHODS. A 1-year intervention study (September 1, 2004, to August 31, 2005) with historical controls was conducted in 4 urban primary care centers affiliated with an academic medical center. All children who were younger than 24 months were enrolled. Electronic health record–based clinical reminders for routine childhood vaccinations were programmed to appear prominently at every patient encounter with vaccines due. The main outcome measures were rates of captured immunization opportunities and overall immunization rates at 24 months of age. RESULTS. Immunization alerts appeared at 15928 visits during the intervention. Alert implementation was associated with increases in captured immunization opportunities from 78.2% to 90.3% at well visits and from 11.3% to 32.0% at sick visits. Adjusted up-to-date immunization rates at 24 months of age increased from 81.7% to 90.1% from the control to intervention period. Children in the intervention group also became up-to-date earlier than control patients. Patient characteristics were stable throughout the study. CONCLUSIONS. An electronic health record–based clinical alert intervention was associated with increases in captured opportunities for vaccination at both sick and well visits and significant improvements in immunization rates at 2 years of age. As electronic health records become more common in medical practice, such systems may transform immunization delivery to children.

Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes.

OBJECTIVE—Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject–parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals. RESEARCH DESIGN AND METHODS—From our existing datasets, we selected 982 markers with P < 0.05 in both GWA cohorts. Genotyping these in an independent set of 636 nuclear families with 974 affected offspring revealed 75 markers that also had P < 0.05 in this third cohort. Among these, six single nucleotide polymorphisms in five novel loci also had P < 0.05 in the Wellcome Trust Case-Control Consortium dataset and were further tested in 1,303 type 1 diabetes probands from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) plus 1,673 control subjects. RESULTS—Two markers (rs9976767 and rs3757247) remained significant after adjusting for the number of tests in this last cohort; they reside in UBASH3A (OR 1.16; combined P = 2.33 × 10−8) and BACH2 (1.13; combined P = 1.25 × 10−6). CONCLUSIONS—Evaluation of a large number of statistical GWA candidates in several independent cohorts has revealed additional loci that are associated with type 1 diabetes. The two genes at these respective loci, UBASH3A and BACH2, are both biologically relevant to autoimmunity.

Effectiveness of Decision Support for Families, Clinicians, or Both on HPV Vaccine Receipt

OBJECTIVE: To improve human papillomavirus (HPV) vaccination rates, we studied the effectiveness of targeting automated decision support to families, clinicians, or both. METHODS: Twenty-two primary care practices were cluster-randomized to receive a 3-part clinician-focused intervention (education, electronic health record-based alerts, and audit and feedback) or none. Overall, 22 486 girls aged 11 to 17 years due for HPV vaccine dose 1, 2, or 3 were randomly assigned within each practice to receive family-focused decision support with educational telephone calls. Randomization established 4 groups: family-focused, clinician-focused, combined, and no intervention. We measured decision support effectiveness by final vaccination rates and time to vaccine receipt, standardized for covariates and limited to those having received the previous dose for HPV #2 and 3. The 1-year study began in May 2010. RESULTS: Final vaccination rates for HPV #1, 2, and 3 were 16%, 65%, and 63% among controls. The combined intervention increased vaccination rates by 9, 8, and 13 percentage points, respectively. The control group achieved 15% vaccination for HPV #1 and 50% vaccination for HPV #2 and 3 after 318, 178, and 215 days. The combined intervention significantly accelerated vaccination by 151, 68, and 93 days. The clinician-focused intervention was more effective than the family-focused intervention for HPV #1, but less effective for HPV #2 and 3. CONCLUSIONS: A clinician-focused intervention was most effective for initiating the HPV vaccination series, whereas a family-focused intervention promoted completion. Decision support directed at both clinicians and families most effectively promotes HPV vaccine series receipt.

Electronic health record-based decision support to improve asthma care: a cluster-randomized trial.

OBJECTIVE: Asthma continues to be 1 of the most common chronic diseases of childhood and affects ∼6 million US children. Although National Asthma Education Prevention Program guidelines exist and are widely accepted, previous studies have demonstrated poor clinician adherence across a variety of populations. We sought to determine if clinical decision support (CDS) embedded in an electronic health record (EHR) would improve clinician adherence to national asthma guidelines in the primary care setting. METHODS: We conducted a prospective cluster-randomized trial in 12 primary care sites over a 1-year period. Practices were stratified for analysis according to whether the site was urban or suburban. Children aged 0 to 18 years with persistent asthma were identified by International Classification of Diseases, Ninth Revision codes for asthma. The 6 intervention-practice sites had CDS alerts imbedded in the EHR. Outcomes of interest were the proportion of children with at least 1 prescription for controller medication, an up-to-date asthma care plan, and the performance of office-based spirometry. RESULTS: Increases in the number of prescriptions for controller medications, over time, was 6% greater (P = .006) and 3% greater for spirometry (P = .04) in the intervention urban practices. Filing an up-to-date asthma care plan improved 14% (P = .03) and spirometry improved 6% (P = .003) in the suburban practices with the intervention. CONCLUSION: In our study, using a cluster-randomized trial design, CDS in the EHR, at the point of care, improved clinician compliance with National Asthma Education Prevention Program guidelines.

Delayed antimicrobial therapy increases mortality and organ dysfunction duration in pediatric sepsis.

Objectives: Delayed antimicrobials are associated with poor outcomes in adult sepsis, but data relating antimicrobial timing to mortality and organ dysfunction in pediatric sepsis are limited. We sought to determine the impact of antimicrobial timing on mortality and organ dysfunction in pediatric patients with severe sepsis or septic shock. Design: Retrospective observational study. Setting: PICU at an academic medical center. Patients: One hundred thirty patients treated for severe sepsis or septic shock. Interventions: None. Measurements and Main Results: We determined if hourly delays from sepsis recognition to initial and first appropriate antimicrobial administration were associated with PICU mortality (primary outcome); ventilator-free, vasoactive-free, and organ failure–free days; and length of stay. Median time from sepsis recognition to initial antimicrobial administration was 140 minutes (interquartile range, 74–277 min) and to first appropriate antimicrobial was 177 minutes (90–550 min). An escalating risk of mortality was observed with each hour delay from sepsis recognition to antimicrobial administration, although this did not achieve significance until 3 hours. For patients with more than 3-hour delay to initial and first appropriate antimicrobials, the odds ratio for PICU mortality was 3.92 (95% CI, 1.27–12.06) and 3.59 (95% CI, 1.09–11.76), respectively. These associations persisted after adjustment for individual confounders and a propensity score analysis. After controlling for severity of illness, the odds ratio for PICU mortality increased to 4.84 (95% CI, 1.45–16.2) and 4.92 (95% CI, 1.30–18.58) for more than 3-hour delay to initial and first appropriate antimicrobials, respectively. Initial antimicrobial administration more than 3 hours was also associated with fewer organ failure–free days (16 [interquartile range, 1–23] vs 20 [interquartile range, 6–26]; p = 0.04). Conclusions: Delayed antimicrobial therapy was an independent risk factor for mortality and prolonged organ dysfunction in pediatric sepsis.