Use of quantitative bias analysis to evaluate single-arm trials with real-world data external controls.

PURPOSE: Use of real-world data (RWD) for external controls added to single-arm trials (SAT) is increasingly prevalent in regulatory submissions. Due to inherent differences in the data-generating mechanisms, biases can arise. This paper aims to illustrate how to use quantitative bias analysis (QBA). METHODS: Advanced non-small cell lung cancer (NSCLC) serves as an example, where many small subsets of patients with molecular tumor subtypes exist. First, some sources of bias that may occur in oncology when comparing RWD to SAT are described. Second, using a hypothetical immunotherapy agent, a dataset is simulated based on expert input for survival analysis of advanced NSCLC. Finally, we illustrate the impact of three biases: missing confounder, misclassification of exposure, and outcome evaluation. RESULTS: For each simulated scenario, bias was induced by removing or adding data; hazard ratios (HRs) were estimated applying conventional analyses. Estimating the bias-adjusted treatment effect and uncertainty required carefully selecting the bias model and bias factors. Although the magnitude of each biased and bias-adjusted HR appeared moderate in all three hypothetical scenarios, the direction of bias was variable. CONCLUSION: These findings suggest that QBA can provide an intuitive framework for bias analysis, providing a key means of challenging assumptions about the evidence. However, the accuracy of bias analysis is itself dependent on correct specification of the bias model and bias factors. Ultimately, study design should reduce bias, but QBA allows us to evaluate the impact of unavoidable bias to assess the quality of the evidence.

Genomic analysis of diet composition finds novel loci and associations with health and lifestyle.

We conducted genome-wide association studies (GWAS) of relative intake from the macronutrients fat, protein, carbohydrates, and sugar in over 235,000 individuals of European ancestries. We identified 21 unique, approximately independent lead SNPs. Fourteen lead SNPs are uniquely associated with one macronutrient at genome-wide significance (P < 5 × 10-8), while five of the 21 lead SNPs reach suggestive significance (P < 1 × 10-5) for at least one other macronutrient. While the phenotypes are genetically correlated, each phenotype carries a partially unique genetic architecture. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (rg ≈ 0.15-0.5). In contrast, relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood deprivation (|rg| ≈ 0.1-0.3) and positive genetic correlations with physical activity (rg ≈ 0.1 and 0.2). Relative fat intake has no consistent pattern of genetic correlations with poor health but has a negative genetic correlation with educational attainment (rg ≈-0.1). Although our analyses do not allow us to draw causal conclusions, we find no evidence of negative health consequences associated with relative carbohydrate, sugar, or fat intake. However, our results are consistent with the hypothesis that relative protein intake plays a role in the etiology of metabolic dysfunction.

Multicomponent Strategies to Prevent SARS-CoV-2 Transmission - Nine Overnight Youth Summer Camps, United States, June-August 2021.

Most U.S. overnight youth camps did not operate during the summer of 2020 because of the COVID-19 pandemic* (1). Several that did operate demonstrated that multiple prevention strategies, including pre- and postarrival testing for SARS-CoV-2, the virus that causes COVID-19, masking, and physical distancing helped prevent the introduction and spread of COVID-19; in contrast, camps that relaxed prevention strategies, such as requiring a single prearrival test without subsequent testing, experienced outbreaks (2-4). The availability of COVID-19 vaccines for persons aged ≥12 years enabled implementation of an additional prevention strategy that was not available in summer 2020. This study assessed the number of COVID-19 cases and potential secondary spread among 7,173 staff members and campers from 50 states, 13 countries, and U.S. military overseas bases at nine independently operated U.S. summer youth camps affiliated with the same organization. The camps implemented multiple prevention strategies including vaccination, testing, podding (cohorting), masking, physical distancing, and hand hygiene during June-August 2021. Vaccination coverage was 93% among eligible persons aged ≥12 years.† All staff members (1,955) and campers (5,218) received site-specific, protocol-defined screening testing, which included prearrival testing and screening tests during the camp session (38,059 tests). Screening testing identified six confirmed COVID-19 cases (one in a staff member and five in campers) by reverse transcription-polymerase chain reaction (RT-PCR) testing (screening test positivity rate = 0.02%). Three additional cases (in two staff members and one camper) were identified based on symptoms and were confirmed by RT-PCR testing. Testing for SARS-CoV-2, isolation, and quarantine in a population with high vaccination coverage resulted in no known secondary transmission of SARS-CoV-2 identified during camp. Implementation of multicomponent strategies is critical for prevention of COVID-19 outbreaks in congregate settings, including overnight youth camps.

B-vitamins and body composition: integrating observational and experimental evidence from the B-PROOF study.

PURPOSE: Higher folate and vitamin-B12 have been linked to lower risk of overweight. However, whether this is a causal effect of these B-vitamins on obesity risk remains unclear and evidence in older individuals is scarce. This study aimed to assess the role of B-vitamin supplementation and levels on body composition in older individuals. METHODS: A double-blind, randomized controlled trial in 2919 participants aged ≥ 65 years with elevated homocysteine levels. The intervention comprised a 2-year supplementation with a combination of folic acid (400 µg) and vitamin B12 (500 µg), or with placebo. Serum folate, vitamin-B12, active vitamin-B12 (HoloTC), methylmalonic acid (MMA), and anthropometrics were measured at baseline and after 2 years of follow-up. Dietary intake of folate and vitamin-B12 was measured at baseline in a subsample (n = 603) using a validated food-frequency questionnaire. Fat mass index (FMI) and fat-free mass index (FFMI) were assessed with Dual Energy X-ray absorptiometry (DXA). RESULTS: Cross-sectional analyses showed that a 1 nmol/L higher serum folate was associated with a 0.021 kg/m2 lower BMI (95% CI - 0.039; - 0.004). Higher HoloTC (per pmol/L log-transformed) was associated with a 0.955 kg/m2 higher FMI (95% CI 0.262; 1.647), and higher MMA (per µgmol/L) was associated with a 1.108 kg/m2 lower FMI (95% CI - 1.899; - 0.316). However, random allocation of B-vitamins did not have a significant effect on changes in BMI, FMI or FFMI during 2 years of intervention. CONCLUSIONS: Although observational data suggested that folate and vitamin B12 status are associated with body composition, random allocation of a supplement with both B-vitamins combined versus placebo did not confirm an effect on BMI or body composition.

An Epigenome-Wide Association Study of Obesity-Related Traits.

We conducted an epigenome-wide association study on obesity-related traits. We used data from 2 prospective, population-based cohort studies: the Rotterdam Study (RS) (2006-2013) and the Atherosclerosis Risk in Communities (ARIC) Study (1990-1992). We used the RS (n = 1,450) as the discovery panel and the ARIC Study (n = 2,097) as the replication panel. Linear mixed-effect models were used to assess the cross-sectional associations between genome-wide DNA methylation in leukocytes and body mass index (BMI) and waist circumference (WC), adjusting for sex, age, smoking, leukocyte proportions, array number, and position on array. The latter 2 variables were modeled as random effects. Fourteen 5'-C-phosphate-G-3' (CpG) sites were associated with BMI and 26 CpG sites with WC in the RS after Bonferroni correction (P < 1.07 × 10-7), of which 12 and 13 CpGs were replicated in the ARIC Study, respectively. The most significant novel CpGs were located on the Musashi RNA binding protein 2 gene (MSI2; cg21139312) and the leucyl-tRNA synthetase 2, mitochondrial gene (LARS2; cg18030453) and were associated with both BMI and WC. CpGs at BRDT, PSMD1, IFI44L, MAP1A, and MAP3K5 were associated with BMI. CpGs at LGALS3BP, MAP2K3, DHCR24, CPSF4L, and TMEM49 were associated with WC. We report novel associations between methylation at MSI2 and LARS2 and obesity-related traits. These results provide further insight into mechanisms underlying obesity-related traits, which can enable identification of new biomarkers in obesity-related chronic diseases.

Intake of Different Types of Fatty Acids in Infancy Is Not Associated with Growth, Adiposity, or Cardiometabolic Health up to 6 Years of Age.

Background: Studies in adults indicate that a lower saturated and higher unsaturated fat intake is associated with a lower risk of metabolic syndrome and cardiovascular diseases. However, studies on fat intake in relation to cardiometabolic health during childhood are scarce.Objective: We examined associations between dietary intake of fatty acids (FAs) at age 1 y and measures of growth, adiposity, and cardiometabolic health up to age 6 y.Methods: This study was conducted in 2927 children participating in the Generation R Study, a multiethnic, prospective, population-based cohort in the Netherlands. We measured children's total fat intake and intakes of saturated FAs (SFAs), monounsaturated FAs (MUFAs), and polyunsaturated FAs (PUFAs) at a median age of 12.9 mo (95% range: 12.2, 18.9 mo) with a food-frequency questionnaire. We repeatedly measured their height and weight up to age 6 y. At 6 y of age, we measured body fat percentage, diastolic and systolic blood pressure, and serum insulin, triacylglycerol, and HDL cholesterol. These outcomes were combined into a cardiometabolic risk factor score. We examined associations of FA intake with repeated measures of height, weight, and body mass index by using linear mixed models and with cardiometabolic outcomes by using linear regression models, adjusting for sociodemographic and lifestyle factors and taking into account macronutrient substitution effects.Results: In multivariable models, we observed no associations of a higher intake of total fat or SFAs, MUFAs, or PUFAs with growth, adiposity, or cardiometabolic health when fat was consumed at the expense of carbohydrates. In subsequent models, there were also no associations observed for higher MUFA or PUFA intakes at the expense of SFAs with any of the outcomes. Results did not differ by sex, ethnicity, age, or birth weight.Conclusion: The results of this study did not support our hypothesis that intake of different types of FAs was associated with adiposity or cardiometabolic health among children.

Autism Spectrum Disorder Among US Children (2002-2010): Socioeconomic, Racial, and Ethnic Disparities.

OBJECTIVES: To describe the association between indicators of socioeconomic status (SES) and the prevalence of autism spectrum disorder (ASD) in the United States during the period 2002 to 2010, when overall ASD prevalence among children more than doubled, and to determine whether SES disparities account for ongoing racial and ethnic disparities in ASD prevalence. METHODS: We computed ASD prevalence and 95% confidence intervals (CIs) from population-based surveillance, census, and survey data. We defined SES categories by using area-level education, income, and poverty indicators. We ascertained ASD in 13 396 of 1 308 641 8-year-old children under surveillance. RESULTS: The prevalence of ASD increased with increasing SES during each surveillance year among White, Black, and Hispanic children. The prevalence difference between high- and low-SES groups was relatively constant over time (3.9/1000 [95% CI = 3.3, 4.5] in 2002 and 4.1/1000 [95% CI = 3.6, 4.6] in the period 2006-2010). Significant racial/ethnic differences in ASD prevalence remained after stratification by SES. CONCLUSIONS: A positive SES gradient in ASD prevalence according to US surveillance data prevailed between 2002 and 2010, and racial and ethnic disparities in prevalence persisted during this time among low-SES children.

CDC Grand Rounds: Newborn Screening for Hearing Loss and Critical Congenital Heart Disease.

Newborn screening is a public health program that benefits 4 million U.S. infants every year by enabling early detection of serious conditions, thus affording the opportunity for timely intervention to optimize outcomes (1). States and other U.S. jurisdictions decide whether and how to regulate newborn screening practices. Most newborn screening is done through laboratory analyses of dried bloodspot specimens collected from newborns. Point-of-care newborn screening is typically performed before discharge from the birthing facility. The Recommended Uniform Screening Panel includes two point-of-care conditions for newborn screening: hearing loss and critical congenital heart disease (CCHD). The objectives of point-of-care screening for these two conditions are early identification and intervention to improve neurodevelopment, most notably language and related skills among infants with permanent hearing loss, and to prevent death or severe disability resulting from delayed diagnosis of CCHD. Universal screening for hearing loss using otoacoustic emissions or automated auditory brainstem response was endorsed by the Joint Committee on Infant Hearing in 2000 and 2007* and was incorporated in the first Recommended Uniform Screening Panel in 2005. Screening for CCHD using pulse oximetry was recommended by the Advisory Committee on Heritable Disorders in Newborns and Children in 2010 based on an evidence review† and was added to the Recommended Uniform Screening Panel in 2011.§.

Critical Congenital Heart Disease Newborn Screening Implementation: Lessons Learned.

Introduction The purpose of this article is to present the collective experiences of six federally-funded critical congenital heart disease (CCHD) newborn screening implementation projects to assist federal and state policy makers and public health to implement CCHD screening. Methods A qualitative assessment and summary from six demonstration project grantees and other state representatives involved in the implementation of CCHD screening programs are presented in the following areas: legislation, provider and family education, screening algorithms and interpretation, data collection and quality improvement, telemedicine, home and rural births, and neonatal intensive care unit populations. Results The most common challenges to implementation include: lack of uniform legislative and statutory mandates for screening programs, lack of funding/resources, difficulty in screening algorithm interpretation, limited availability of pediatric echocardiography, and integrating data collection and reporting with existing newborn screening systems. Identified solutions include: programs should consider integrating third party insurers and other partners early in the legislative/statutory process; development of visual tools and language modification to assist in the interpretation of algorithms, training programs for adult sonographers to perform neonatal echocardiography, building upon existing newborn screening systems, and using automated data transfer mechanisms. Discussion Continued and expanded surveillance, research, prevention and education efforts are needed to inform screening programs, with an aim to reduce morbidity, mortality and other adverse consequences for individuals and families affected by CCHD.

Dietary Intake of Protein in Early Childhood Is Associated with Growth Trajectories between 1 and 9 Years of Age.

BACKGROUND: High protein intake in infancy might lead to a higher body mass index (BMI) in childhood. However, whether these associations differ between different sources of protein is unclear. OBJECTIVE: We investigated associations between the intake of total protein, protein from different sources, and individual amino acids in early childhood and repeatedly measured height, weight, and BMI up to the age of 9 y. METHODS: This study was performed in 3564 children participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, Netherlands. Intakes of total protein, animal protein, vegetable protein, and individual amino acids (including methionine, arginine, lysine, threonine, valine, leucine, isoleucine, phenylalanine, tryptophan, histidine, cysteine, tyrosine, alanine, asparagine, glutamine, glycine, proline, and serine) at 1 y were assessed by using a food-frequency questionnaire. Height and weight were measured at the approximate ages of 14, 18, 24, 30, 36, and 45 mo and at 6 and 9 y, and BMI was calculated. RESULTS: After adjustment for confounders, linear mixed models showed that a 10-g higher total protein intake/d at 1 y was significantly associated with a 0.03-SD greater height (95% CI: 0.00, 0.06), a 0.06-SD higher weight (95% CI: 0.03, 0.09), and a 0.05-SD higher BMI (95% CI: 0.03, 0.08) up to the age of 9 y. Associations were stronger for animal than for vegetable protein intake but did not differ between dairy and nondairy animal protein or between specific amino acids. CONCLUSIONS: A higher intake of protein, especially animal protein, at 1 y of age was associated with a greater height, weight, and BMI in childhood up to 9 y of age. Future studies should explore the role of growth hormones and investigate whether protein intake in early childhood affects health later in life.

Prevalence of Cerebral Palsy among 8-Year-Old Children in 2010 and Preliminary Evidence of Trends in Its Relationship to Low Birthweight.

BACKGROUND: The public health objective for cerebral palsy (CP) in the United States is to reduce the percentage of children with CP who were born low birthweight (LBW, <2500 g) by 10% between 2006 and 2020. This study reports the prevalence of CP in a constant surveillance area for the years 2006, 2008, and 2010 and describes initial progress towards the CP public health objective. METHODS: Data on children with CP at age 8 years were ascertained by the Autism and Developmental Disabilities Monitoring (ADDM) Network, a population-based surveillance system that monitored CP in four areas of the United States. RESULTS: CP prevalence in 2010 was 2.9 per 1000 [95% confidence interval (CI) 2.6, 3.2], down from 3.5 (95% CI 3.2, 3.9) in the same surveillance area in 2006. Among CP cases with no documented postneonatal aetiology, 49.1% (95% CI 42.9, 55.2) were born LBW in 2010 compared with 54.3% (95% CI 48.4, 60.1) in 2006. In 2010, 28.1% (95% CI 22.9, 30.4) were born very low birthweight (VLBW, <1500 g) compared with 35.4% (95% CI 30.0, 41.2) in 2006. The relative risks for associations between CP and both LBW and VLBW also declined, though not significantly, during the study period. CONCLUSIONS: Declines in the associations between CP and LBW categories may have contributed to declines during the study period in both the prevalence of CP and the percentage of children with CP who were born LBW or VLBW. Ongoing monitoring of these trends is warranted.

Dietary Intakes of Folic Acid and Methionine in Early Childhood Are Associated with Body Composition at School Age.

BACKGROUND: Deficiency of vitamin B-6, vitamin B-12, folate, folic acid, or methionine may lead to dysregulation of DNA methylation, which might lead to disturbed energy and lipid metabolism. OBJECTIVE: We aimed to explore whether intakes of vitamin B-6, vitamin B-12, folate, folic acid, and methionine at 1 y are associated with measures of growth and body composition at the age of 6 y. METHODS: This study was performed in 2922 children participating in The Generation R Study, a population-based prospective cohort study. Dietary intakes of vitamins B-6 and B-12, folate, folic acid, and methionine were assessed at a median age of 12.9 mo by using a validated food-frequency questionnaire. At the age of 6 y, height and weight were measured, and body mass index (BMI; in kg/m(2)) was calculated. Body fat was measured with dual-energy X-ray absorptiometry, and body fat percentage and the ratio of android fat mass to gynoid fat mass (android:gynoid) were calculated. RESULTS: In models adjusted for maternal and child characteristics, children with folic acid intakes in the highest tertile had a 0.16 SD score (SDS) lower weight (95% CI: -0.31, -0.02 SDS) and a 0.14 SDS lower BMI (95% CI: -0.26, -0.01 SDS) than children in the lowest tertile. Children with vitamin B-12 intakes in the highest tertile had a 0.13 SDS higher android:gynoid (95% CI: 0.00, 0.25 SDS) than children in the lowest tertile. In addition, children with intakes in the highest tertile of methionine had a 0.09 SDS higher BMI (95% CI: 0.01, 0.17) and a 0.12 SDS higher android:gynoid (95% CI: 0.02, 0.22) than children in the lowest tertile. Vitamin B-6 and folate intakes were not associated with any of the body composition outcomes measured. CONCLUSIONS: In this population of children, early high folic acid intakes were associated with a lower body weight and BMI at the age of 6 y. In contrast, early higher methionine intakes were associated with unfavorable body composition at the age of 6 y. Future studies should investigate long-term consequences of these outcomes on health.

The role of socio-economic status and perinatal factors in racial disparities in the risk of cerebral palsy.

AIM: To determine whether racial disparities in cerebral palsy (CP) risk among US children persist after controlling for socio-economic status (SES) (here indicated by maternal education) and perinatal risk factors. METHOD: A population-based birth cohort study was conducted using the Autism and Developmental Disabilities Monitoring Network surveillance and birth data for 8-year-old children residing in multi-county areas in Alabama, Georgia, Missouri, and Wisconsin between 2002 and 2008. The birth cohort comparison group included 458 027 children and the case group included 1570 children with CP, 1202 with available birth records. χ(2) tests were performed to evaluate associations and logistic regression was used to calculate relative risks (RR) and adjusted odds ratios (OR) with 95% confidence intervals (CI). RESULTS: The risk of spastic CP was more than 50% higher for black versus white children (RR 1.52, 95% CI 1.33-1.73), and this greater risk persisted after adjustment for SES (OR 1.35, 95% CI 1.18-1.55), but not after further adjustment for preterm birth and size for gestational age. The protective effect of maternal education remained after adjustment for race/ethnicity and perinatal factors. INTERPRETATION: Maternal education appears to independently affect CP risk but does not fully explain existing racial disparities in CP prevalence in the US.

Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - Autism and Developmental Disabilities Monitoring Network, USA, 2008.

AIM: The aim of this study was to report the prevalence and characteristics of children with cerebral palsy (CP). METHOD: Children with CP (n=451) were ascertained by the Autism and Developmental Disabilities Monitoring (ADDM) Network, a population-based, record-review surveillance system monitoring CP in four areas of the USA. Prevalence was calculated as the number of children with CP among all 8-year-old children residing in these areas in 2008. Motor function was categorized by Gross Motor Function Classification System level and walking ability. Co-occurring autism spectrum disorders (ASD) and epilepsy were ascertained using ADDM Network surveillance methodology. RESULTS: The period prevalence of CP for 2008 was 3.1 per 1000 8-year-old children (95% confidence interval 2.8-3.4). Approximately 58% of children walked independently. Co-occurring ASD frequency was 6.9% and was higher (18.4%) among children with non-spastic CP, particularly hypotonic CP. Co-occurring epilepsy frequency was 41% overall, did not differ by ASD status or CP subtype, and was highest (67%) among children with limited or no walking ability. INTERPRETATION: The prevalence of CP in childhood from US surveillance data has remained relatively constant, in the range of 3.1 to 3.6 per 1000, since 1996. The higher frequency of ASD in non-spastic than in spastic subtypes of CP calls for closer examination.

Congenital cerebral palsy and prenatal exposure to self-reported maternal infections, fever, or smoking.

OBJECTIVE: The objective of the study was to investigate the association between maternal self-reported infections, fever, and smoking in the prenatal period and the subsequent risk for congenital cerebral palsy (CP). STUDY DESIGN: We included the 81,066 mothers of singletons born between 1996 and 2003 who participated in the Danish National Birth Cohort. Children were followed up through December 2008. Information on maternal infections, fever, smoking, and other demographic and lifestyle factors during pregnancy were reported by mothers in computer-assisted telephone interviews in early and midgestation. We identified 139 CP cases including 121 cases of spastic CP (sCP) as confirmed by the Danish National Cerebral Palsy Register. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). RESULTS: Self-reported vaginal infections were associated with an increased risk of CP and sCP (aHR, 1.52; 95% CI, 1.04-2.24; and aHR, 1.73; 95% CI, 1.16-2.60, respectively) and particularly untreated vaginal infections were associated with an increased risk of sCP (aHR, 1.95; 95% CI, 1.16-3.26). Fever was associated with the risk of CP (aHR, 1.53; 95% CI, 1.06-2.21). Smoking 10 or more cigarettes per day during pregnancy was also associated with sCP (aHR, 1.80; 95% CI, 1.10-2.94). There was a modest excess in risk for children exposed to both heavy smoking and vaginal infections. No other self-reported infections were significantly associated with CP. CONCLUSION: Self-reported vaginal infections, fever, and smoking 10 or more cigarettes per day during pregnancy were associated with a higher risk of overall CP and/or sCP.

Maternal infections during pregnancy and cerebral palsy: a population-based cohort study.

BACKGROUND: Cerebral palsy (CP) is a common motor disability in childhood. We examined the association between maternal infections during pregnancy and the risk of congenital CP in the child. METHODS: Liveborn singletons in Denmark between 1997 and 2003 were identified from the Danish National Birth Registry and followed from 1 year of life until 2008. Redemption of antibiotics from the National Register of Medicinal Product Statistics and maternal infections reported by the National Hospital Register were used as markers of maternal infection during pregnancy. CP diagnoses were obtained from the Danish Cerebral Palsy Registry. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated by Cox proportional hazard models. RESULTS: Of the 440 564 singletons with follow-up data, 840 were diagnosed with congenital CP. Maternal genito-urinary tract infections (HR 2.1, 95% CI 1.4, 3.2) were associated with CP in all births, in term births (HR 1.9, 95% CI 1.1, 3.2), in children with spastic CP (HR 2.1, 95% CI 1.4, 3.3), and among first-born children (HR 1.9, 95% CI 1.4, 3.3). Overall, we found associations between redeemed nitrofurantoin (HR 1.7, 95% CI 1.1, 2.8) and CP. Among trimester-specific exposures, CP risk was associated with prescriptions redeemed in the first trimester for any antibacterials, beta-lactam antibacterials, and nitrofurantoin, an antibiotic commonly used to treat lower urinary tract infection, and genito-urinary tract infections in the third trimester. CONCLUSION: Genito-urinary tract infections and antibiotic use during pregnancy were associated with increased risks of CP, indicating that some maternal infections or causes of maternal infections present in prenatal life may be part of a causal pathway leading to CP.

The role of migration and choice of denominator on the prevalence of cerebral palsy.

AIM: Differential migration and choice of denominator have been hypothesized to contribute to differences between period prevalence and birth prevalence of cerebral palsy (CP). The purpose of this study was to evaluate the effects of migration and choice of denominator on the prevalence of CP. METHOD: Data from the Metropolitan Atlanta Developmental Disabilities Surveillance Program and census and birth certificate files were used to calculate various CP prevalence estimates for 2000. RESULTS: The overall CP period prevalence was 3.2 (95% confidence interval [CI] 2.7-3.8) per 1000 8-year-olds and was similar for those born in Atlanta who resided there at age 8 years (3.3; 95% CI 2.7-4.1) and those born outside Atlanta who moved into Atlanta by age 8 years (3.0; 95% CI 2.3-3.9). CP prevalence in these two migration strata was similar by sex and race/ethnicity. CP birth prevalence of 8-year-olds in Atlanta in 2000 was 2.0 (95% CI 1.6-2.5) per 1000 live births in 1992. INTERPRETATION: The authors found no evidence to support the hypothesis that differential in-migration explained higher period than birth prevalence of CP in Atlanta. Comparability of CP prevalence across geographic areas will be enhanced if future studies report both period and birth prevalence.

Use of a real-world synthetic control arm for direct comparison of lisocabtagene maraleucel and conventional therapy in relapsed/refractory large B-cell lymphoma.

This study used a real-world population as a synthetic comparator for the single-arm TRANSCEND NHL 001 study (TRANSCEND; NCT02631044) to evaluate the efficacy of lisocabtagene maraleucel (liso-cel) compared with conventional (noncellular) therapies in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Inclusion and exclusion criteria for the real-world study closely matched the enrollment criteria in TRANSCEND. The analytic comparator cohort was created by matching and balancing observed baseline characteristics of real-world patients with those in TRANSCEND using propensity score methodology. Efficacy outcomes comparing liso-cel- (n = 257) and conventional therapy-treated (n = 257) patients, respectively, significantly favored liso-cel: overall response rate (74% vs 39%; p < 0.0001), complete response rate (50% vs 24%; p < 0.0001), median overall survival (23.5 vs 6.8 months; p < 0.0001), and median progression-free survival (3.5 vs 2.2 months; p < 0.0001). These results demonstrated a statistically significant and clinically meaningful benefit of liso-cel in patients with third- or later-line R/R LBCL relative to conventional therapies.Clinical trial registration: ClinicalTrials.gov identifier: NCT02631044.

Methyl Donor Nutrient Intake and Incidence of Type 2 Diabetes: Results From Three Large U.S. Cohorts.

OBJECTIVE: We examined whether intake of methyl donor nutrients, including vitamins B2, B6, and B12 and folate, from foods and/or supplements is associated with type 2 diabetes risk. RESEARCH DESIGN AND METHODS: We included 203,644 women and men from the Nurses' Health Study (1984-2016), Nurses' Health Study 2 (1991-2017), and Health Professionals Follow-Up Study (1986-2016). Dietary data were collected every 2-4 years with use of semiquantitative food-frequency questionnaires. Cox proportional hazards models with time-varying covariates were used to evaluate associations between each nutrient and type 2 diabetes risk. We combined cohort-specific hazard ratios (HRs) using inverse variance-weighted fixed-effects meta-analyses. RESULTS: During 4,900,181 person-years of follow-up, we documented 19,475 incident type 2 diabetes cases. In multivariable-adjusted meta-analyses, participants in the highest quintiles of total vitamin B2 and B6 intakes had lower risk of diabetes compared with those in the lowest quintiles (HR 0.93 [95% CI 0.89, 0.98] for B2 and 0.93 [0.89, 0.97] for B6). With stratification by source, significant associations remained for B2 from food but not from supplements. Neither association for B6 from food nor association for B6 from supplements attained significance. No association was observed between total B12 intake and diabetes. However, B12 from food was marginally associated with higher diabetes risk (1.05 [1.00-1.11]) but not after additional adjustment for red meat intake (1.04 [0.99-1.10]). No evidence of association was observed between intakes of folate and diabetes. CONCLUSIONS: The results of our study suggest that higher intake of vitamin B2 and B6, especially B2 from food sources, may be associated with a modestly lower type 2 diabetes risk.

C-reactive protein partially mediates the inverse association between coffee consumption and risk of type 2 diabetes: The UK Biobank and the Rotterdam study cohorts.

BACKGROUND: Coffee is among the most consumed beverages worldwide. Coffee consumption has been associated with lower risk of type 2 diabetes mellitus (T2D), but underlying mechanisms are not well understood. We aimed to study the role of classic and novel-T2D biomarkers with anti- or pro-inflammatory activity in the association between habitual coffee intake and T2D risk. Furthermore, we studied differences by coffee types and smoking status in this association. METHODS: Using two large population-based cohorts, the UK-Biobank (UKB; n = 145,368) and the Rotterdam Study (RS; n = 7111), we investigated associations of habitual coffee consumption with incident T2D and repeated measures of insulin resistance (HOMA-IR), using Cox proportional hazards and mixed effect models, respectively. Additionally, we studied associations between coffee and subclinical inflammation biomarkers including C-reactive protein (CRP) and IL-13, and adipokines, such as adiponectin and leptin, using linear regression models. Next, we performed formal causal mediation analyses to investigate the role of coffee-associated biomarkers in the association of coffee with T2D. Finally, we evaluated effect modification by coffee type and smoking. All models were adjusted for sociodemographic, lifestyle and health-related factors. RESULTS: During a median follow-up of 13.9 (RS) and 7.4 (UKB) years, 843 and 2290 incident T2D cases occurred, respectively. A 1 cup/day increase in coffee consumption was associated with 4% lower T2D risk (RS, HR = 0.96 [95%CI 0.92; 0.99], p = 0.045; UKB, HR = 0.96 [0.94; 0.98], p < 0.001), with lower HOMA-IR (RS, log-transformed ß = -0.017 [-0.024;-0.010], p < 0.001), and with lower CRP (RS, log-transformed ß = -0.014 [-0.022;-0.005], p = 0.002; UKB, ß = -0.011 [-0.012;-0.009], p < 0.001). We also observed associations of higher coffee consumption with higher serum adiponectin and IL-13 concentrations, and with lower leptin concentrations. Coffee-related CRP levels partially mediated the inverse association of coffee intake with T2D incidence (average mediation effect RS ß = 0.105 (0.014; 0.240), p = 0.016; UKB ß = 6.484 (4.265; 9.339), p < 0.001), with a proportion mediated by CRP from 3.7% [-0.012%; 24.4%] (RS) to 9.8% [5,7%; 25.8%] (UKB). No mediation effect was observed for the other biomarkers. Coffee-T2D and coffee-CRP associations were generally stronger among consumers of ground (filtered or espresso) coffee and among never and former smokers. CONCLUSIONS: Lower subclinical inflammation may partially mediate the beneficial association between coffee consumption and lower T2D risk. Consumers of ground coffee and non-smokers may benefit the most. KEYWORDS (MESH TERMS): coffee consumptions; diabetes mellitus, type 2; inflammation; adipokines; biomarkers; mediation analysis; follow-up studies.