TY  - JOUR
AB  - IMPORTANCE: Single gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated. OBJECTIVE: To evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies. DATA SOURCES: Published pathogenic or likely pathogenic variants in OMIM genes identified with exome sequencing in clinical (n = 1345) or research (n = 496) cohorts of CP were analyzed. A systematic literature review for evidence of effective therapies for specific genetic etiologies was performed. STUDY SELECTION: Nonstandard interventions that led to a detectable improvement in a defined outcome in individuals with variants in the gene of interest were included. DATA EXTRACTION AND SYNTHESIS: Literature was evaluated using PRISMA guidelines. A diverse, expert working group was established, scoring rubrics adapted, and scoring consensus built with a modified Delphi approach. MAIN OUTCOMES AND MEASURES: Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety and practicality of the intervention, and anticipated intervention efficacy on a scale from 0 to 3. RESULTS: Of 1841 patients with CP who underwent exome sequencing, 502 (27%) had pathogenic or likely pathogenic variants related to their phenotype. A total of 243 different genes were identified. In 1841 patients with identified genetic etiologies of CP, 140 (8%) had a genetic etiology classified as actionable, defined as prompting a change in clinical management. Also identified were 58 of 243 genes with pathogenic or likely pathogenic variants with actionable treatment options: 16 targeting the primary disease mechanism, 16 with specific prevention strategies, and 26 with specific symptom management. The level of evidence was also graded according to ClinGen criteria; 45 of 101 interventions (44.6%) had evidence class D or below. The potential interventions have clinical utility with 98 of 101 outcomes (97%) being moderate-high severity if left untreated and 63 of 101 interventions (62%) predicted to be of moderate-high efficacy. Most interventions (72 of 101 [71%]) were considered moderate-high safety and practicality. CONCLUSIONS AND RELEVANCE: The findings indicate that actionable genetic findings occurred in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy, outcome severity, and intervention safety and practicality indicates moderate-high clinical utility of these genetic findings. Genetic sequencing can identify precision medicine interventions that provide clinical benefit to individuals with CP. The relatively limited evidence base underscores the need for additional research.
AU  - Lewis, S.A.*
AU  - Chopra, M.*
AU  - Cohen, J.S.*
AU  - Bain, J.M.*
AU  - Aravamuthan, B.*
AU  - Carmel, J.B.*
AU  - Fahey, M.C.*
AU  - Segel, R.*
AU  - Wintle, R.F.*
AU  - Zech, M.
AU  - May, H.T.*
AU  - Haque, N.*
AU  - Fehlings, D.*
AU  - Srivastava, S.*
AU  - Kruer, M.C.*
C1  - 72592
C2  - 56661
CY  - 330 N Wabash Ave, Ste 39300, Chicago, Il 60611-5885 Usa
TI  - Clinical actionability of genetic findings in cerebral palsy: A systematic review and meta-analysis.
JO  - JAMA Pediatr.
PB  - Amer Medical Assoc
PY  - 2024
SN  - 2168-6203
ER  - 

TY  - JOUR
AB  - Importance: Genome-wide association studies have identified genetic loci influencing obesity risk in children. However, the importance of these loci in the associations with weight reduction through lifestyle interventions has not been investigated in large intervention trials. Objective: To evaluate the associations between various obesity susceptibility loci and changes in body weight in children during an in-hospital, lifestyle intervention program. Design, Setting, and Participants: Long-term Effects of Lifestyle Intervention in Obesity and Genetic Influence in Children (LOGIC), an interventional prospective cohort study, enrolled 1429 children with overweight or obesity to participate in an in-hospital lifestyle intervention program. Genotyping of 56 validated obesity single-nucleotide variants (SNVs) was performed, and the associations between the SNVs and body weight reduction during the intervention were evaluated using linear mixed-effects models for each SNV. The LOGIC study was conducted from January 6, 2006, to October 19, 2013; data analysis was performed from July 15, 2015, to November 6, 2016. Exposures: A 4- to 6-week standardized in-hospital lifestyle intervention program (daily physical activity, calorie-restricted diet, and behavioral therapy). Main Outcomes and Measures: The association between 56 obesity-relevant SNVs and changes in body weight and body mass index. Results: Of 1429 individuals enrolled in the LOGIC Study, 1198 individuals (mean [SD] age, 14.0 [2.2] years; 670 [56%] girls) were genotyped. A mean (SD) decrease was noted in body weight of -8.7 (3.6) kg (95% CI, -15.7 to -1.8 kg), and body mass index (calculated as weight in kilograms divided by height in meters squared) decreased by -3.3 (1.1) (95% CI, -5.4 to -1.1) (both P < .05). Five of 56 obesity SNVs were statistically significantly associated with a reduction of body weight or body mass index (all P < 8.93 × 10-4 corresponding to Bonferroni correction for 56 tests). Compared with homozygous participants without the risk allele, homozygous carriers of the rs7164727 (LOC100287559: 0.42 kg; 95% CI, 0.31-0.53 kg, P = 4.00 × 10-4) and rs12940622 (RPTOR: 0.35 kg; 95% CI, 0.18-0.52 kg; P = 1.86 × 10-5) risk alleles had a lower reduction of body weight, whereas carriers of the rs13201877 (IFNGR1: 0.65 kg; 95% CI, 0.51-0.79 kg; P = 2.39 × 10-5), rs10733682 (LMX1B: 0.45 kg; 95% CI, 0.27-0.63 kg; P = 6.37 × 10-4), and rs2836754 (ETS2: 0.56 kg; 95% CI, 0.38-0.74 kg; P = 1.51 × 10-4) risk alleles were associated with a greater reduction of body weight after adjustment for age and sex. Conclusions and Relevance: Genes appear to play a minor role in weight reduction by lifestyle in children with overweight or obesity. The findings suggest that environmental, social, and behavioral factors are more important to consider in obesity treatment strategies.
AU  - Heitkamp, M.*
AU  - Siegrist, M.*
AU  - Molnos, S.
AU  - Brandmaier, S.
AU  - Wahl, S.
AU  - Langhof, H.*
AU  - Grallert, H.
AU  - Halle, M.*
C1  - 60755
C2  - 49542
CY  - 330 N Wabash Ave, Ste 39300, Chicago, Il 60611-5885 Usa
TI  - Obesity genes and weight loss during lifestyle intervention in children with obesity.
JO  - JAMA Pediatr.
VL  - 175
IS  - 1
PB  - Amer Medical Assoc
PY  - 2021
SN  - 2168-6203
ER  - 

TY  - JOUR
AU  - Beyerlein, A.
AU  - Wehweck, F.
AU  - Ziegler, A.-G.
AU  - Pflüger, M.
C1  - 50493
C2  - 42316
CY  - Chicago
SP  - 93
TI  - Miscalculation and errors in numbers reported in table.
JO  - JAMA Pediatr.
VL  - 171
IS  - 1
PB  - Amer Medical Assoc
PY  - 2017
SN  - 2168-6203
ER  - 

TY  - JOUR
AB  - IMPORTANCE Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. OBJECTIVE To test the association between early-life antibiotic use and islet or celiac disease (CD) autoimmunity in genetically at-risk children prospectively followed up for type 1 diabetes (T1D) or CD. DESIGN, SETTING, AND PARTICIPANTS HLA-genotyped newborns from Finland, Germany, Sweden, and the United States were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY) study between November 20, 2004, and July 8, 2010. The dates of analysis were November 20, 2004, to August 31, 2014. Individuals from the general population and those having a first-degree relative with T1D were enrolled if they had 1 of 9 HLA genotypes associated with a risk for T1D. EXPOSURES Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. MAIN OUTCOMES AND MEASURES Islet autoimmunity and CD autoimmunitywere defined as being positive for islet or tissue transglutaminase autoantibodies at 2 consecutive clinic visits at least 3 months apart. Hazard ratios and 95% CIs calculated from Cox proportional hazards regression models were used to assess the relationship between antibiotic use in early life before seroconversion and the development of autoimmunity. RESULTS Participants were 8495 children (49.0% female) and 6558 children (48.7% female) enrolled in the TEDDY study who were tested for islet and tissue transglutaminase autoantibodies, respectively. Exposure to and frequency of use of any antibiotic assessed in this study in early life or before seroconversion did not influence the risk of developing islet autoimmunity or CD autoimmunity. Cumulative use of any antibiotic during the first 4 years of life was not associated with the appearance of any autoantibody (hazard ratio [HR], 0.98; 95% CI, 0.95-1.01), multiple islet autoantibodies (HR, 0.99; 95% CI, 0.95-1.03), or the transglutaminase autoantibody (HR, 1.00; 95% CI, 0.98-1.02). CONCLUSIONS AND RELEVANCE The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD.
AU  - Kemppainen, K.M.*
AU  - Vehik, K.*
AU  - Lynch, K.F.*
AU  - Larsson, H.E.*
AU  - Canepa, R.J.*
AU  - Simell, V.*
AU  - Koletzko, S.*
AU  - Liu, E.*
AU  - Simell, O.G.*
AU  - Toppari, J.*
AU  - Ziegler, A.-G.
AU  - Rewers, M.J.*
AU  - Lernmark, A.*
AU  - Hagopian, W.A.*
AU  - She, J.*
AU  - Akolkar, B.*
AU  - Schatz, D.A.*
AU  - Atkinson, M.A.*
AU  - Blaser, M.J.*
AU  - Krischer, J.P.*
AU  - Hyoety, H.*
AU  - Agardh, D.*
AU  - Triplett, E.W.*
C1  - 52530
C2  - 44056
CY  - Chicago
SP  - 1217-1225
TI  - Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity.
JO  - JAMA Pediatr.
VL  - 171
IS  - 12
PB  - Amer Medical Assoc
PY  - 2017
SN  - 2168-6203
ER  - 

TY  - JOUR
AB  - IMPORTANCE Protein, supplied in currently available commercial fortifiers, may be inadequate to meet the requirements of very preterm infants; in addition, intraindividual and interindividual variability of human milk protein and energy content potentially contribute to unsatisfactory early postnatal growth. OBJECTIVE To determine effects on growth of different levels of enteral protein supplementation in predominantly human milk-fed preterm infants. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical and partially blinded single-center trial was conducted in a neonatal tertiary referral center in Germany. Sixty preterm infants (gestation <32 weeks and weight <1500 g at birth) were recruited from October 2012 to October 2014 and included 35% of 173 eligible infants. Median (interquartile range [IQR]) gestational age at birth was 29.9 (28.7-31.2) weeks. All analyses were conducted in an intention-to-treat population. INTERVENTIONS Infants were randomly assigned to either a lower-protein (adding1g of bovine protein/100mLof breast milk through a commercial human milk fortifier; n = 30) or a higher protein group at a median (IQR) postnatal age of 7 (6-8) days. The higher-protein group (n = 30) received either standardized higher-protein supplementation (study fortifier adding 1.8 g of bovine protein/100mLof breast milk [n = 15]) or individualized high-protein supplementation based on protein and fat content of administered breast milk (n = 15). Study interventions were continued for a median (IQR) of 41 (30-57) days and until definite discharge planning. MAIN OUTCOMES AND MEASURES Primary outcome was weight gain (g/kg/d) from birth to the end of intervention. RESULTS Sixty preterm infants (gestation <32weeks andweight < 1500 g at birth), 33 girls, were recruited from October 2012 to October 2014 and included 35% of 173 eligible infants. Median (IQR) gestational age at birth was 29.9 (28.7-31.2) weeks. Demographic characteristics and hospital courses were similar in both groups, and birth weights ranged from 580 to 1495 g in the lower-protein group and 490 to 1470g in the higher-protein group. Weight gain was similar in the lower-and higher-protein groups: mean (95% CI), 16.3 g/kg/d (15.4-17.1 g/kg/d) in the lower protein group vs 16.0g/kg/d (15.1-16.9 g/kg/d) in the higher-protein group) (P =.70), despite an increase in actual protein intake by0.6 g/kg/d (0.4-0.7 g/kg/d) (P <.001). Head circumference and lower leg longitudinal growth were also similar, as was the proportion of cumulative total enteral feeding volume provided as breast milk: median (IQR) proportion of breast milk, 92% (79%-98%) in the lower-protein group vs 94%(62%-99%) in the higher-protein group (P =.89). CONCLUSIONS AND RELEVANCE An increase in protein intake by 0.6 g/kg/d to a mean intake of 4.3 g/kg/d did not further enhance growth of very preterm infants with a median birth weight of 1200 g, who achieved near-fetal growth rates. This might point to a ceiling effect for enteral protein intake with respect to its influence on growth.
AU  - Maas, C.*
AU  - Mathes, M.*
AU  - Bleeker, C.*
AU  - Vek, J.*
AU  - Bernhard, W.*
AU  - Wiechers, C.*
AU  - Peter, A.
AU  - Poets, C.F.*
AU  - Franz, A.R.*
C1  - 50502
C2  - 42367
CY  - Chicago
SP  - 16-22
TI  - Effect of increased enteral protein intake on growth in human milk-fed preterm infants a randomized clinical trial.
JO  - JAMA Pediatr.
VL  - 171
IS  - 1
PB  - Amer Medical Assoc
PY  - 2017
SN  - 2168-6203
ER  - 

TY  - JOUR
AB  - IMPORTANCE Atopic dermatitis is an inflammatory, pruritic skin disease that often occurs in early infancy with a chronic course. However, a specific description of subtypes of atopic dermatitis depending on the timing of onset and progression of the disease in childhood is lacking. OBJECTIVE To identify different phenotypes of atopic dermatitis using a definition based on symptoms before age 6 years and to determine whether some subtypes are more at risk for developing other allergic diseases. DESIGN, SETTING, AND PARTICIPANTS The Protection Against Allergy Study in Rural Environments (PASTURE) is a European birth cohort where pregnant women were recruited between August 2002 and March 2005 and divided in 2 groups dependent on whether they lived on a farm. Children from this cohort with data on atopic dermatitis from birth to 6 years of age were included. EXPOSURES Atopic dermatitis, defined as an itchy rash on typical locations from birth to 6 years. MAIN OUTCOMES AND MEASURES The latent class analysis was used to identify subtypes of atopic dermatitis in childhood based on the course of symptoms. Multivariable logistic regressions were used to analyze the association between atopic dermatitis phenotypes and other allergic diseases. RESULTS We included 1038 children; of these, 506 were girls. The latent class analysis model with the best fit to PASTURE data separated 4 phenotypes of atopic dermatitis in childhood: 2 early phenotypes with onset before age 2 years (early transient [n = 96; 9.2%] and early persistent [n = 67; 6.5%]), the late phenotype with onset at age 2 years or older (n = 50; 4.8%), and the never/ infrequent phenotype (n = 825; 79.5%), defined as children with no atopic dermatitis. Children with both parents with history of allergies were 5 times more at risk to develop atopic dermatitis with an early-persistent phenotype compared with children with parents with no history of allergies. Both early phenotypes were strongly associated with food allergy. The risk of developing asthma was significantly increased among the early-persistent phenotype (adjusted odds ratio, 2.87; 95% CI, 1.31-6.31). The late phenotype was only positively associated with allergic rhinitis. CONCLUSIONS AND RELEVANCE Using latent class analysis, 4 phenotypes of atopic dermatitis were identified depending on the onset and course of the disease. The prevalence of asthma and food allergy by 6 years of age was strongly increased among children with early phenotypes (within age 2 years), especially with persistent symptoms. These findings are important for the development of strategies in allergy prevention.
AU  - Roduit, C.*
AU  - Frei, R.*
AU  - Depner, M.*
AU  - Karvonen, A.M.*
AU  - Renz, H.*
AU  - Braun-Fahrländer, C.*
AU  - Schmaußer-Hechfellner, E.*
AU  - Pekkanen, J.*
AU  - Riedler, J.*
AU  - Dalphin, J.-C.*
AU  - Lauener, R.P.*
AU  - von Mutius, E.
C1  - 51552
C2  - 43247
CY  - Chicago
SP  - 655-662
TI  - Phenotypes of atopic dermatitis depending on the timing of onset and progression in childhood.
JO  - JAMA Pediatr.
VL  - 171
IS  - 7
PB  - Amer Medical Assoc
PY  - 2017
SN  - 2168-6203
ER  - 

TY  - JOUR
AB  - Importance: Probiotics have been hypothesized to affect immunologic responses to environmental exposures by supporting healthy gut microbiota and could therefore theoretically be used to prevent the development of type 1 diabetes mellitus (T1DM)-associated islet autoimmunity. Objective: To examine the association between supplemental probiotic use during the first year of life and islet autoimmunity among children at increased genetic risk of T1DM. Design, Setting, and Participants: In this ongoing prospective cohort study that started September 1, 2004, children from 6 clinical centers, 3 in the United States (Colorado, Georgia/Florida, and Washington) and 3 in Europe (Finland, Germany, and Sweden), were followed up for T1DM-related autoantibodies. Blood samples were collected every 3 months between 3 and 48 months of age and every 6 months thereafter to determine persistent islet autoimmunity. Details of infant feeding, including probiotic supplementation and infant formula use, were monitored from birth using questionnaires and diaries. We applied time-to-event analysis to study the association between probiotic use and islet autoimmunity, stratifying by country and adjusting for family history of type 1 diabetes, HLA-DR-DQ genotypes, sex, birth order, mode of delivery, exclusive breastfeeding, birth year, child's antibiotic use, and diarrheal history, as well as maternal age, probiotic use, and smoking. Altogether 8676 infants with an eligible genotype were enrolled in the follow-up study before the age of 4 months. The final sample consisted of 7473 children with the age range of 4 to 10 years (as of October 31, 2014). Exposures: Early intake of probiotics. Main Outcomes and Measures: Islet autoimmunity revealed by specific islet autoantibodies. Results: Early probiotic supplementation (at the age of 0-27 days) was associated with a decreased risk of islet autoimmunity when compared with probiotic supplementation after 27 days or no probiotic supplementation (hazard ratio [HR], 0.66; 95% CI, 0.46-0.94). The association was accounted for by children with the DR3/4 genotype (HR, 0.40; 95% CI, 0.21-0.74) and was absent among other genotypes (HR, 0.97; 95% CI, 0.62-1.54). Conclusions and Relevance: Early probiotic supplementation may reduce the risk of islet autoimmunity in children at the highest genetic risk of T1DM. The result needs to be confirmed in further studies before any recommendation of probiotics use is made.
AU  - Uusitalo, U.*
AU  - Liu, X.*
AU  - Yang, J.*
AU  - Aronsson, C.A.*
AU  - Hummel, S.
AU  - Butterworth, M.*
AU  - Lernmark, A.*
AU  - Rewers, M.*
AU  - Hagopian, W.*
AU  - She, J.X.*
AU  - Simell, O.*
AU  - Toppari, J.*
AU  - Ziegler, A.-G.
AU  - Akolkar, B.*
AU  - Krischer, J.*
AU  - Norris, J.M.*
AU  - Virtanen, S.M.*
AU  - TEDDY Study Group (*)
C1  - 47225
C2  - 39351
CY  - Chicago
SP  - 20-28
TI  - Association of early exposure of probiotics and islet autoimmunity in the TEDDY study.
JO  - JAMA Pediatr.
VL  - 170
IS  - 1
PB  - Amer Medical Assoc
PY  - 2016
SN  - 2168-6203
ER  - 

TY  - JOUR
AB  - IMPORTANCE There is evidence for a role of infections within the pathogenesis of islet autoimmunity and type 1 diabetes mellitus (T1D), but previous studies did not allow assessment of potential critical time windows in this context. OBJECTIVE To examine whether early, short-term, or cumulative exposures to episodes of infection and fever during the first 3 years of life were associated with the initiation of persistent islet autoimmunity in children at increased T1D risk. DESIGN Prospective cohort study with daily infection records and regular assessment of islet autoimmunity. SETTING Diabetes Research Institute, Munich, Germany. PARTICIPANTS A total of 148 children at high T1D risk with documentation of 1245 infectious events in 90 750 person-days during their first 3 years of life. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) for seroconversion to persistent islet autoantibodies were assessed in Cox regression models with numbers of respiratory, gastrointestinal, and other infections, adjusting for sex, delivery mode, intervention group, season of birth, and antibiotic use. RESULTS An increased HR of islet autoantibody seroconversion was associated with respiratory infections during the first 6 months of life (HR = 2.27; 95% CI, 1.32-3.91) and ages 6.0 to 11.9 months (HR = 1.32; 95% CI, 1.08-1.61). During the second year of life, no meaningful effects were detected for any infectious category. A higher number of respiratory infections in the 6 months prior to islet autoantibody seroconversion was also associated with an increased HR (HR = 1.42; 95% CI, 1.12-1.80). CONCLUSIONS AND RELEVANCE Respiratory infections in early childhood are a potential risk factor for the development of T1D.
AU  - Beyerlein, A.
AU  - Wehweck, F.
AU  - Ziegler, A.-G.
AU  - Pflüger, M.
C1  - 25531
C2  - 31868
SP  - 800-807
TI  - Respiratory infections in early life and the development of islet autoimmunity in children at increased type 1 diabetes risk: Evidence from the BABYDIET study.
JO  - JAMA Pediatr.
VL  - 167
IS  - 9
PB  - Amer. Medical Assoc.
PY  - 2013
SN  - 2168-6203
ER  -