Urinary amine and organic acid metabolites evaluated as markers for childhood aggression : the ACTION biomarker study

Biomarkers are of interest as potential diagnostic and predictive instruments in personalized medicine. We present the first urinary metabolomics biomarker study of childhood aggression. We aim to examine the association of urinary metabolites and neurotransmitter ratios involved in key metabolic and neurotransmitter pathways in a large cohort of twins (N = 1,347) and clinic-referred children (N = 183) with an average age of 9.7 years. This study is part of ACTION (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies), in which we developed a standardized protocol for large-scale collection of urine samples in children. Our analytical design consisted of three phases: a discovery phase in twins scoring low or high on aggression (N = 783); a replication phase in twin pairs discordant for aggression (N = 378); and a validation phase in clinical cases and matched twin controls (N = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (beta = 0.36; SE = 0.09; p = 0.004), and gamma-L-glutamyl-L-alanine (beta = 0.32; SE = 0.09; p = 0.01) remained significant after multiple testing. Although non-significant, the directions of effect were congruent between the discovery and replication analyses for six biomarkers and two neurotransmitter ratios and the concentrations of 6 amines differed between low and high aggressive twins. In the validation analyses, the top biomarkers and neurotransmitter ratios, with congruent directions of effect, showed no significant associations with childhood aggression. We find suggestive evidence for associations of childhood aggression with metabolic dysregulation of neurotransmission, oxidative stress, and energy metabolism. Although replication is required, our findings provide starting points to investigate causal and pleiotropic effects of these dysregulations on childhood aggression

Statistical Auditing and the AOQL-method

Om te bepalen welke en hoeveel gegevensgerichte controles de accountant moet uitvoeren zal hij ondermeer willen weten hoe de interne beheersingsmaatregelen functioneren, die van belang zijn voor de controle van de jaarrekening. Wanneer de accountant het idee heeft dat deze niet goed werken dan zal de accountant meer gegevensgerichte controles moeten uitvoeren om het controle risico te beperken. Bij beide soorten controles kan de statistiek, en dan voornamelijk de steekproeftheorie, de accountant helpen. Dit proefschrift geeft onder meer een overzicht van de statistische methoden die de accountant van dienst kunnen zijn. Nieuwe ontwikkelingen omtrent interne beheersing, veroorzaakt door frauduleuze rapportering door enkele grote Amerikaanse en Europese beursgenoteerde ondernemingen, zorgen er onder meer voor dat er behoefte is aan goede en betrouwbare controleprocedures, zowel voor gebruik door de organisatie zelf als voor gebruik door de externe accountant. Een procedure die in de praktijk al jaren gebruikt wordt om te bepalen of een proces voldoet aan de regels die door de interne beheersing worden opgelegd is de AOQL (Average Outgoing Quality Limit) procedure. Naar aanleiding van een onderzoek dat wij hebben uitgevoerd bij de IB-Groep, presenteren wij een verbeterde versie van de AOQL-procedure. Deze verbeterde versie, de EEOQL (Exact Expected Outgoing Quality Limit) procedure maakt voor de bepaling van de optimale steekproefgrootte gebruik van de werkelijk onderliggende verdeling, de hypergeometrische verdeling, in plaats van een benadering door de Poisson verdeling. Bovendien worden in dit proefschrift nieuwe eigenschappen van de hypergeometrische verdeling ontwikkeld die gebruikt worden in door ons ontwikkelde algoritmes voor het bepalen van de optimale steekproefgrootte in de EEOQL-procedure. Deze algoritmes blijken accuraat en zeer efficiënt te zijn.

Statistical Process Control Methods for Monitoring In-House Reference Standards

For certain types of medicine the biological strength or bioactivity of a drug is the main characteristic for release of products to the market. A pharmaceutical company may decide to use their own in-house reference standard to test the drug instead of using the expensive international reference standard. The company is then legally obliged to verify that the in-house reference standard remains stable over time with respect to the international one. This is a special problem within statistical process control (SPC) since the monitoring period is relatively short and bioassays are typically heterogenous. The objective of this article is to apply methods from SPC and dose-finding studies to different study designs and assess how well these methods perform in detecting a decline in bioactivity. The included methods are the exponentially weighted moving average (EWMA), Shewhart chart, and analysis of variance (ANOVA)-type contrasts (linear, Helmert, and reverse-Helmert). An optimal alpha-spending function was selected first to avoid inflating the familywise error rate. The normal alpha-spending function seemed to perform generally the best. Then from the results, the linear, reverse-Helmert, and the EWMA (lambda 0.6) performed better in later declines. Linear contrasts and the Shewhart chart performed better irrespective of the decline profile. Having more bioassay runs at the beginning of the stability study increased the probability of detecting a decline. If there is no prior information on the expected deterioration profile, linear contrasts or Shewhart chart should be preferred. Otherwise, reverse-Helmert or Helmert contrasts should be chosen for either early or late deterioration, respectively

Equivalence testing for similarity in bioassays using bioequivalence criteria on the relative bioactivity

\u3cp\u3eSimilarity in bioassays means that the test preparation behaves as a dilution of the standard preparation with respect to their biological effect. Thus, similarity must be investigated to confirm this biological property. Historically, this was typically conducted with traditional hypothesis testing, but this has received substantial criticism. Failing to reject similarity does not imply that the 2 preparations are similar. Also, rejecting similarity when bioassay variability is small might simply demonstrate a nonrelevant deviation in similarity. To remedy these concerns, equivalence testing has been proposed as an alternative to traditional hypothesis testing, and it has found its way in the official guidelines. However, similarity has been discussed mainly in terms of the parameters in the dose-response curves of the standard and test preparations, but the consequences of nonsimilarity on the relative bioactivity have never been investigated. This article provides a general equivalence approach to evaluate similarity that is directly related to bioequivalence on the relative bioactivity of the standard and test preparations. Bioequivalence on the relative bioactivity can only be guaranteed for positive (only nonblanks) and finite dose intervals. The approach is demonstrated on 4 case studies in which we also show how to calculate a sample size and how to investigate the power of equivalence on similarity.\u3c/p\u3

A genome-wide association study identifies a region at chromosome 12 as a potential susceptibility locus for restenosis after percutaneous coronary intervention

Percutaneous coronary intervention (PCI) has become an effective therapy to treat obstructive coronary artery diseases (CAD). However, one of the major drawbacks of PCI is the occurrence of restenosis in 5-25% of all initially treated patients. Restenosis is defined as the re-narrowing of the lumen of the blood vessel, resulting in renewed symptoms and the need for repeated intervention. To identify genetic variants that are associated with restenosis, a genome-wide association study (GWAS) was conducted in 295 patients who developed restenosis (cases) and 571 who did not (controls) from the GENetic Determinants of Restenosis (GENDER) study. Analysis of similar to 550 000 single nucleotide polymorphisms (SNPs) in GENDER was followed by a replication phase in three independent case-control populations (533 cases and 3067 controls). A potential susceptibility locus for restenosis at chromosome 12, including rs10861032 (P(combined) = 1.11 x 10(-7)) and rs9804922 (P(combined) = 1.45 x 10(-6)), was identified in the GWAS and replication phase. In addition, both SNPs were also associated with coronary events (rs10861032, P(additive) = 0.005; rs9804922, P(additive) = 0.023) in a trial based cohort set of elderly patients with (enhanced risk of) CAD (PROSPER) and all-cause mortality in PROSPER (rs10861032, P(additive) = 0.007; rs9804922, P(additive) = 0.013) and GENDER (rs10861032, P(additive) = 0.005; rs9804922, P(additive) = 0.023). Further analysis suggests that this locus could be involved in regulatory functions