Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands

A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

Large-scale discovery of novel genetic causes of developmental disorders

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing3,4,5,6,7,8,9,10,11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders

Using ancestry-informative markers to identify fine structure across 15 populations of European origin

J. Kaprio, A. Keski-Rahkonen, A. Raevuori, A. Palotie ja S. Ripatti työryhmien jäseniä, joita yhteensä 219.Peer reviewe

Families as Partners in Hospital Error and Adverse Event Surveillance

ImportanceMedical errors and adverse events (AEs) are common among hospitalized children. While clinician reports are the foundation of operational hospital safety surveillance and a key component of multifaceted research surveillance, patient and family reports are not routinely gathered. We hypothesized that a novel family-reporting mechanism would improve incident detection.ObjectiveTo compare error and AE rates (1) gathered systematically with vs without family reporting, (2) reported by families vs clinicians, and (3) reported by families vs hospital incident reports.Design, setting, and participantsWe conducted a prospective cohort study including the parents/caregivers of 989 hospitalized patients 17 years and younger (total 3902 patient-days) and their clinicians from December 2014 to July 2015 in 4 US pediatric centers. Clinician abstractors identified potential errors and AEs by reviewing medical records, hospital incident reports, and clinician reports as well as weekly and discharge Family Safety Interviews (FSIs). Two physicians reviewed and independently categorized all incidents, rating severity and preventability (agreement, 68%-90%; κ, 0.50-0.68). Discordant categorizations were reconciled. Rates were generated using Poisson regression estimated via generalized estimating equations to account for repeated measures on the same patient.Main outcomes and measuresError and AE rates.ResultsOverall, 746 parents/caregivers consented for the study. Of these, 717 completed FSIs. Their median (interquartile range) age was 32.5 (26-40) years; 380 (53.0%) were nonwhite, 566 (78.9%) were female, 603 (84.1%) were English speaking, and 380 (53.0%) had attended college. Of 717 parents/caregivers completing FSIs, 185 (25.8%) reported a total of 255 incidents, which were classified as 132 safety concerns (51.8%), 102 nonsafety-related quality concerns (40.0%), and 21 other concerns (8.2%). These included 22 preventable AEs (8.6%), 17 nonharmful medical errors (6.7%), and 11 nonpreventable AEs (4.3%) on the study unit. In total, 179 errors and 113 AEs were identified from all sources. Family reports included 8 otherwise unidentified AEs, including 7 preventable AEs. Error rates with family reporting (45.9 per 1000 patient-days) were 1.2-fold (95% CI, 1.1-1.2) higher than rates without family reporting (39.7 per 1000 patient-days). Adverse event rates with family reporting (28.7 per 1000 patient-days) were 1.1-fold (95% CI, 1.0-1.2; P = .006) higher than rates without (26.1 per 1000 patient-days). Families and clinicians reported similar rates of errors (10.0 vs 12.8 per 1000 patient-days; relative rate, 0.8; 95% CI, .5-1.2) and AEs (8.5 vs 6.2 per 1000 patient-days; relative rate, 1.4; 95% CI, 0.8-2.2). Family-reported error rates were 5.0-fold (95% CI, 1.9-13.0) higher and AE rates 2.9-fold (95% CI, 1.2-6.7) higher than hospital incident report rates.Conclusions and relevanceFamilies provide unique information about hospital safety and should be included in hospital safety surveillance in order to facilitate better design and assessment of interventions to improve safety

Families as Partners in Hospital Error and Adverse Event Surveillance

ImportanceMedical errors and adverse events (AEs) are common among hospitalized children. While clinician reports are the foundation of operational hospital safety surveillance and a key component of multifaceted research surveillance, patient and family reports are not routinely gathered. We hypothesized that a novel family-reporting mechanism would improve incident detection.ObjectiveTo compare error and AE rates (1) gathered systematically with vs without family reporting, (2) reported by families vs clinicians, and (3) reported by families vs hospital incident reports.Design, setting, and participantsWe conducted a prospective cohort study including the parents/caregivers of 989 hospitalized patients 17 years and younger (total 3902 patient-days) and their clinicians from December 2014 to July 2015 in 4 US pediatric centers. Clinician abstractors identified potential errors and AEs by reviewing medical records, hospital incident reports, and clinician reports as well as weekly and discharge Family Safety Interviews (FSIs). Two physicians reviewed and independently categorized all incidents, rating severity and preventability (agreement, 68%-90%; κ, 0.50-0.68). Discordant categorizations were reconciled. Rates were generated using Poisson regression estimated via generalized estimating equations to account for repeated measures on the same patient.Main outcomes and measuresError and AE rates.ResultsOverall, 746 parents/caregivers consented for the study. Of these, 717 completed FSIs. Their median (interquartile range) age was 32.5 (26-40) years; 380 (53.0%) were nonwhite, 566 (78.9%) were female, 603 (84.1%) were English speaking, and 380 (53.0%) had attended college. Of 717 parents/caregivers completing FSIs, 185 (25.8%) reported a total of 255 incidents, which were classified as 132 safety concerns (51.8%), 102 nonsafety-related quality concerns (40.0%), and 21 other concerns (8.2%). These included 22 preventable AEs (8.6%), 17 nonharmful medical errors (6.7%), and 11 nonpreventable AEs (4.3%) on the study unit. In total, 179 errors and 113 AEs were identified from all sources. Family reports included 8 otherwise unidentified AEs, including 7 preventable AEs. Error rates with family reporting (45.9 per 1000 patient-days) were 1.2-fold (95% CI, 1.1-1.2) higher than rates without family reporting (39.7 per 1000 patient-days). Adverse event rates with family reporting (28.7 per 1000 patient-days) were 1.1-fold (95% CI, 1.0-1.2; P = .006) higher than rates without (26.1 per 1000 patient-days). Families and clinicians reported similar rates of errors (10.0 vs 12.8 per 1000 patient-days; relative rate, 0.8; 95% CI, .5-1.2) and AEs (8.5 vs 6.2 per 1000 patient-days; relative rate, 1.4; 95% CI, 0.8-2.2). Family-reported error rates were 5.0-fold (95% CI, 1.9-13.0) higher and AE rates 2.9-fold (95% CI, 1.2-6.7) higher than hospital incident report rates.Conclusions and relevanceFamilies provide unique information about hospital safety and should be included in hospital safety surveillance in order to facilitate better design and assessment of interventions to improve safety

A genome-wide association study of anorexia nervosa

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14\u2009860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21\u2009080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 7 10-7) in SOX2OT and rs17030795 (P=5.84 7 10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 7 10-6) between CUL3 and FAM124B and rs1886797 (P=8.05 7 10-6) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 7 10-6), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field