Alphas, betas and skewy distributions: two ways of getting the wrong answer

Although many parametric statistical tests are considered to be robust, as recently shown in Methodologist’s Corner, it still pays to be circumspect about the assumptions underlying statistical tests. In this paper I show that robustness mainly refers to α, the type-I error. If the underlying distribution of data is ignored there can be a major penalty in terms of the β, the type-II error, representing a large increase in false negative rate or, equivalently, a severe loss of power of the test

Surveillance of iclaprim activity: In vitro susceptibility of gram-positive pathogens collected from 2012 to 2014 from the United States, Asia Pacific, Latin American and Europe

Iclaprim is a diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and it is highly active against Gram-positive pathogens including emerging drug-resistant pathogens. In vitro activity of iclaprim and comparators against 2814 Gram-positive clinical isolates from the United States, Asia Pacific, Latin American and Europe collected between 2012 and 2014 were tested. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. MIC50/MIC90 for all S. aureus, methicillin susceptible S. aureus, methicillin resistant S. aureus, beta-hemolytic streptococci, and Streptococcus pneumoniae were 0.06/0.12, 0.06/0.12, 0.06/0.5, 0.06/0.25, and 0.06/2 μg/mL, respectively. Iclaprim was 8 to 32-fold more potent than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all Gram-positive isolates including resistant phenotypes. The MIC90 of iclaprim was also lower than most of the comparators including linezolid and vancomycin against Gram-positive pathogens. Iclaprim demonstrated potent activity against a contemporary collection (2012–2014) of Gram-positive clinical isolates from the United States, Asia Pacific, Latin America and Europe

A nearly continuous measure of birth weight for gestational age using a United States national reference

BACKGROUND: Fully understanding the determinants and sequelae of fetal growth requires a continuous measure of birth weight adjusted for gestational age. Published United States reference data, however, provide estimates only of the median and lowest and highest 5(th )and 10(th )percentiles for birth weight at each gestational age. The purpose of our analysis was to create more continuous reference measures of birth weight for gestational age for use in epidemiologic analyses. METHODS: We used data from the most recent nationwide United States Natality datasets to generate multiple reference percentiles of birth weight at each completed week of gestation from 22 through 44 weeks. Gestational age was determined from last menstrual period. We analyzed data from 6,690,717 singleton infants with recorded birth weight and sex born to United States resident mothers in 1999 and 2000. RESULTS: Birth weight rose with greater gestational age, with increasing slopes during the third trimester and a leveling off beyond 40 weeks. Boys had higher birth weights than girls, later born children higher weights than firstborns, and infants born to non-Hispanic white mothers higher birth weights than those born to non-Hispanic black mothers. These results correspond well with previously published estimates reporting limited percentiles. CONCLUSIONS: Our method provides comprehensive reference values of birth weight at 22 through 44 completed weeks of gestation, derived from broadly based nationwide data. Other approaches require assumptions of normality or of a functional relationship between gestational age and birth weight, which may not be appropriate. These data should prove useful for researchers investigating the predictors and outcomes of altered fetal growth

The Effect of Pulmonary Surfactant on the In Vitro Activity of Iclaprim Against Common Respiratory Bacterial Pathogens

The in vitro antimicrobial activity of iclaprim, a novel diaminopyrimidine, against common respiratory bacteria remained unchanged in the presence of pulmonary surfactant (Survanta®) at concentrations that greatly antagonized the antimicrobial activity of daptomycin. These results indicate that iclaprim could be a potential treatment for pneumonia caused by susceptible and multidrug resistant bacteria

Ceftaroline Fosamil Therapy in Patients With Acute Bacterial Skin and Skin Structure Infections With Systemic Inflammatory Signs: A Retrospective Dose Comparison Across Three Pivotal Trials.

BACKGROUND: Post-hoc analysis compared pharmacokinetics and clinical outcomes of ceftaroline fosamil 600 mg every 12 (q12h) versus every 8 hours (q8h), in patients with acute bacterial skin and skin structure infections (ABSSSI) and signs of sepsis. METHODS: Clinical outcomes at test-of-cure in patients with ABSSSI and systemic inflammatory signs/systemic inflammatory response (SIRS), and ceftaroline minimum inhibitory concentrations (MICs) against baseline pathogens were compared between COVERS (ceftaroline fosamil 600 mg q8h, 2-h infusion) and the CANVAS 1 and 2 trials (ceftaroline fosamil 600 mg q12h, 1-h infusion). Ceftaroline exposures among patients in COVERS with or without markers of sepsis were compared using population pharmacokinetic (PK) modeling. RESULTS: In COVERS, 62% (312/506) and 41% (208/506) of ceftaroline fosamil-treated patients had ≥1 systemic sign or SIRS, respectively and 55% (378/693) and 22% (152/693), respectively in the CANVAS trials. Clinical cure rates for the modified intent-to-treat (MITT) population in COVERS and CANVAS were similar for ceftaroline fosamil-treated patients with ≥1 sign of sepsis (82% [255/312] and 85% [335/394]) and for those with SIRS (84% [168/199] and 85% [131/155]). Ceftaroline MIC distributions were similar across trials. Sepsis did not affect predicted individual steady-state ceftaroline exposures. CONCLUSIONS: Clinical cure rates in patients with ≥1 systemic inflammatory sign or SIRS were comparable for both ceftaroline fosamil dosage regimens. Pathogen susceptibilities to ceftaroline were similar across trials. Ceftaroline exposures were not affected by disease severity. Ceftaroline fosamil 600 mg q12h is a robust dosage regimen for most ABSSSI patients with sepsis

State-Specific Trends in Preterm Delivery: Are Rates Really Declining Among Non-Hispanic African Americans Across the United States?

Objectives : This study sought to examine state-specific trends in preterm delivery rates among non-Hispanic African Americans and to assess whether these rates are influenced by misclassification of gestational age. Methods : The sample population consisted of singleton non-Hispanic White and non-Hispanic African–American infants born in 1991 and 2001 to U.S. resident mothers. For both time periods, state-specific and national preterm delivery rates were calculated for all infants, stratified by infant race/ethnicity. Next, birth-weight distributions within strata of gestational age were studied to explore possible misclassifications of gestational age. Lastly, state-specific and national preterm delivery rates among infants who weighed less than 2,500 g were separately computed. Results: National analyses showed that the frequency of preterm delivery increased by 15.8% among non-Hispanic Whites but declined by 10.3% among non-Hispanic African Americans over the same period. For both subgroups, a bimodal distribution of birth weights was apparent among preterm births at 28–31 weeks of gestation. The second peak with its cluster of normal-weight infants was more prominent among non-Hispanic African Americans in 1991 than in 2001. After excluding preterm infants who weighed 2,500 g or more, the national trends persisted. State-specific analyses showed that preterm delivery rates increased for both subgroups in 13 states during this period. Of these 13, 6 states had a number of non-Hispanic African–American births classified as preterm that were apparently term births mistakenly assigned short gestational ages. Such misclassification was more frequent in 1991 than in 2001 and inflated 1991 rates. Conclusion : There is heterogeneity in state-specific preterm delivery rates. Such differences are often overlooked when aggregate results are presented.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45321/1/10995_2005_Article_32.pd

Reexamining the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality

BACKGROUND: Low birth weight (<2,500 g) is a strong predictor of infant mortality. Yet low birth weight, in isolation, is uninformative since it is comprised of two intertwined components: preterm delivery and reduced fetal growth. Through nonparametric logistic regression models, we examine the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality. METHODS: We derived data on over 10 million singleton live births delivered at ≥ 24 weeks from the 1998–2000 U.S. natality data files. Nonparametric multivariable logistic regression based on generalized additive models was used to examine neonatal mortality (deaths within the first 28 days) in relation to fetal growth (gestational age-specific standardized birth weight), gestational age, and number of cigarettes smoked per day. All analyses were further adjusted for the confounding effects due to maternal age and gravidity. RESULTS: The relationship between standardized birth weight and neonatal mortality is nonlinear; mortality is high at low z-score birth weights, drops precipitously with increasing z-score birth weight, and begins to flatten for heavier infants. Gestational age is also strongly associated with mortality, with patterns similar to those of z-score birth weight. Although the direct effect of smoking on neonatal mortality is weak, its effects (on mortality) appear to be largely mediated through reduced fetal growth and, to a lesser extent, through shortened gestation. In fact, the association between smoking and reduced fetal growth gets stronger as pregnancies approach term. CONCLUSIONS: Our study provides important insights regarding the combined effects of fetal growth, gestational age, and smoking on neonatal mortality. The findings suggest that the effect of maternal smoking on neonatal mortality is largely mediated through reduced fetal growth

Optimal fetal growth for the Caucasian singleton and assessment of appropriateness of fetal growth: an analysis of a total population perinatal database

BACKGROUND: The appropriateness of an individual's intra uterine growth is now considered an important determinant of both short and long term outcomes, yet currently used measures have several shortcomings. This study demonstrates a method of assessing appropriateness of intrauterine growth based on the estimation of each individual's optimal newborn dimensions from routinely available perinatal data. Appropriateness of growth can then be inferred from the ratio of the value of the observed dimension to that of the optimal dimension. METHODS: Fractional polynomial regression models including terms for non-pathological determinants of fetal size (gestational duration, fetal gender and maternal height, age and parity) were used to predict birth weight, birth length and head circumference from a population without any major risk factors for sub-optimal intra-uterine growth. This population was selected from a total population of all singleton, Caucasian births in Western Australia 1998–2002. Births were excluded if the pregnancy was exposed to factors known to influence fetal growth pathologically. The values predicted by these models were treated as the optimal values, given infant gender, gestational age, maternal height, parity, and age. RESULTS: The selected sample (N = 62,746) comprised 60.5% of the total Caucasian singleton birth cohort. Equations are presented that predict optimal birth weight, birth length and head circumference given gestational duration, fetal gender, maternal height, age and parity. The best fitting models explained 40.5% of variance for birth weight, 32.2% for birth length, and 25.2% for head circumference at birth. CONCLUSION: Proportion of optimal birth weight (length or head circumference) provides a method of assessing appropriateness of intrauterine growth that is less dependent on the health of the reference population or the quality of their morphometric data than is percentile position on a birth weight distribution

Early response to antibiotic treatment in European patients hospitalized with complicated skin and soft tissue infections: analysis of the REACH study

Background: The treatment of complicated skin and soft tissue infections (cSSTI) is challenging and many patients do not receive adequate first-line therapy. REACH (REtrospective Study to Assess the Clinical Management of Patients With Moderate-to-Severe cSSTI or Community-Acquired Pneumonia in the Hospital Setting) was a retrospective observational study of cSSTI patients in real-life settings in European hospitals. In this analysis, we review characteristics and outcomes of patients with an early response (<= 72 hours) compared with those without an early response to treatment. We also compare the results according to two differing definitions of early response, one of which (Definition 1) requires resolution of fever within 72 hours, in line with previous US FDA guidelines. Methods: Patients were adults hospitalized with cSSTIs 2010-2011 and requiring treatment with intravenous antibiotics. Clinical management, clinical outcomes and healthcare resource use were assessed using a descriptive analysis approach. Results: The analysis set included 600 patients, of which 363 showed early response with Definition 1 and 417 with Definition 2. Initial treatment modification was frequent, and highest in patients without early response (48.1% with Definition 1). Patients without early response were more likely to have diabetes than those with early response (31.6% vs. 22.9%,respectively) and to suffer from more severe disease (e.g. skin necrosis: 14.8% and 7.7%,respectively), to be infected with difficult-to-treat microorganisms and to have recurrent infections. Furthermore, patients without early response had a higher rate of adverse clinical outcomes (e.g. septic shock) and higher use of healthcare resources. The results obtained with the two definitions for early response were largely similar. Conclusions: This study highlights the significance of early evaluation of patients in hospitals, in potentially preventing prolonged use of inappropriate or ineffective antibacterial therapy