Statistical methods for handling missing data to align with treatment policy strategy.

The International Council for Harmonization (ICH) E9(R1) addendum recommends choosing an appropriate estimand based on the study objectives in advance of trial design. One defining attribute of an estimand is the intercurrent event, specifically what is considered an intercurrent event and how it should be handled. The primary objective of a clinical study is usually to assess a product's effectiveness and safety based on the planned treatment regimen instead of the actual treatment received. The estimand using the treatment policy strategy, which collects and analyzes data regardless of the occurrence of intercurrent events, is usually utilized. In this article, we explain how missing data can be handled using the treatment policy strategy from the authors' viewpoint in connection with antihyperglycemic product development programs. The article discusses five statistical methods to impute missing data occurring after intercurrent events. All five methods are applied within the framework of the treatment policy strategy. The article compares the five methods via Markov Chain Monte Carlo simulations and showcases how three of these five methods have been applied to estimate the treatment effects published in the labels for three antihyperglycemic agents currently on the market.

Effectiveness of antimicrobial guidelines for community-acquired pneumonia in children.

OBJECTIVE: To assess the effectiveness of guidelines and education on empirical therapy for community-acquired pneumonia. METHODS: Administrative records for children with a primary diagnosis of pneumonia from January 2007 to September 2009 were reviewed. Antimicrobial use was measured monthly over 3 periods: (1) before creation of an antimicrobial stewardship task force (ASTF), (2) after ASTF formation but before release of guidelines for antimicrobial use, and (3) after guideline release. Antimicrobial use over time was assessed by using quasi-binomial logistic regression models that incorporated interrupted events, seasonality, and autocorrelation. Allowing calculation of immediate changes due to specific interventions and trends in use over each time period. The primary outcome was use of ampicillin as recommended in the guidelines versus ceftriaxone, the historical standard. Secondary outcomes included other antimicrobial use, length of stay, mortality, and readmission. RESULTS: One thousand two hundred forty-six children met study criteria. Ampicillin use increased from 2% at baseline to 6% after ASTF formation and 44% after guideline release. Ceftriaxone use increased slightly (from 56% to 59%) after ASTF formation but decreased to 28% after guideline release. An immediate change in prescription occurred in the month after guideline publication and remained stable over the following year. CONCLUSIONS: Guidelines and education can have an impact on antimicrobial use in the pediatric setting. Although the optimal strategies for pediatric antimicrobial stewardship programs still are being determined, we believe that our approach offers an inexpensive and low-risk step in the right direction.

Polymorphic genes of detoxification and mitochondrial enzymes and risk for progressive supranuclear palsy: a case control study.

BACKGROUND: There are no known causes for progressive supranuclear palsy (PSP). The microtubule associated protein tau (MAPT) H1 haplotype is the major genetic factor associated with risk of PSP, with both oxidative stress and mitochondrial dysfunction also implicated. We investigated whether specific single nucleotide polymorphisms (SNPs) in genes encoding enzymes of xenobiotic detoxification, mitochondrial functioning, or oxidative stress response, including debrisoquine 4-hydroxylase, paraoxonase 1 and 2, N-acetyltransferase 1 and 2 (NAT2), superoxide dismutase 1 and 2, and PTEN-induced putative kinase are associated with PSP. METHODS: DNA from 553 autopsy-confirmed Caucasian PSP cases (266 females, 279 males; age at onset 68 ± 8 years; age at death 75 ± 8) from the Society for PSP Brain Bank and 425 clinical control samples (197 females, 226 males; age at draw 72 ± 11 years) from healthy volunteers were genotyped using Taqman PCR and the SequenomiPLEX Gold assay. RESULTS: The proportion of NAT2 rapid acetylators compared to intermediate and slow acetylators was larger in cases than in controls (OR = 1.82, p < 0.05). There were no allelic or genotypic associations with PSP for any other SNPs tested with the exception of MAPT (p < 0.001). CONCLUSIONS: Our results show that NAT2 rapid acetylator phenotype is associated with PSP, suggesting that NAT2 may be responsible for activation of a xenobiotic whose metabolite is neurotoxic. Although our results need to be further confirmed in an independent sample, NAT2 acetylation status should be considered in future genetic and epidemiological studies of PSP.

H1/H1 genotype influences symptom severity in corticobasal syndrome.

We evaluated 38 consecutive patients with corticobasal syndrome to determine if inheritance of the H1/H1 genotype influences age at onset and disease severity and if Apolipoprotein E e4 increases the risk of cognitive disturbances. Inheritance of the H1/H1 genotype was associated with severity of motor function, but did not affect age at onset or cognition. There was a trend toward shorter survival in the H1/H1 group, but this study was underpowered to test influence on survival, even though it served to estimate the sample size for future studies. ApoE inheritance did not influence cognition.

A bioinformatics approach to identifying tail-anchored proteins in the human genome.

Intracellular proteins with a carboxy-terminal transmembrane domain and the amino-terminus oriented toward the cytosol are known as 'tail-anchored' proteins. Tail-anchored proteins have been of considerable interest because several important classes of proteins, including the vesicle-targeting/fusion proteins known as SNAREs and the apoptosis-related proteins of the Bcl-2 family, among others, utilize this unique membrane-anchoring motif. Here, we use a bioinformatic technique to develop a comprehensive list of potentially tail-anchored proteins in the human genome. Our final list contains 411 entries derived from 325 unique genes. We also analyzed both known and predicted tail-anchored proteins with respect to the amino acid composition of the transmembrane segments. This analysis revealed a distinctive composition of the membrane anchor in SNARE proteins.