SAMPLE SIZE DETERMINATION IN ANIMAL HEALTH STUDIES

Oftentimes in animal health studies, a treatment group is randomly assigned to a pen of animals, and the pen of animals as a whole is treated (fed the same medicated feed or water) together. In this scenario, the pen of animals is the experimental unit and the individual animal may be an observational unit. In addition to having the pen as the experimental unit, if multiple sites are used and site is treated as a random factor, this adds complexity to the study. To properly design the study, it is necessary to determine the number of animals in a pen, the number of pens per treatment group, and the number of sites in order to detect treatment differences with desired power. The method for sample size determination depends on the statistical distribution of the primary endpoint in the study, the design of the study, and the proposed statistical analysis method. Focusing on the case where individual animal is not the experimental unit, this paper demonstrates methods and discusses issues for sample size determination in animal health studies with continuous or binary primary endpoints, and gives a simple approach for determining an appropriate number of sites in a multi-site model analyzed with a linear mixed model

A COMPARISON OF MULTIPLE TESTING METHODS: SPINOSAD AS A TREATMENT FOR LICE ON CATTLE

A common problem in statistics is making multiple tests of hypotheses without controlling for the type I error rate. SAS has identified several different methods to adjust p-values for multiple testing. To compare the effect of these methods, an animal health dataset that deals with the treatment of cattle lice was examined. Clinical trials were conducted in Illinois and Wisconsin to evaluate the efficacy of two formulations of a new product Spinosad, two commercially available positive controls, and an untreated negative control. A baseline lice count was recorded prior to the treatment. After treatment, weekly measurements of lice counts were taken for 8 weeks. Counts of 4 lice species were recorded separately. A linear mixed model analysis was conducted for each species of lice after transforming the counts with a natural logarithm transformation. Simple contrasts between treatment groups at each week were performed. Treatment differences were also compared using 5 multiple testing methods: Bonferroni, Sidak, Holm’s step-down Bonferroni, Hochberg\u27s step-up Bonferroni, and false discovery rate. Seventy-one out of 96 simple tests showed significant differences among the treatment groups. The five multiple testing methods confirmed only 48-67 significances out of the 96 tests. Comparatively, Bonferroni and Sidak methods provided similar and the most conservative multiplicity test results, i.e. fewest significant differences. The Holm’s step-down and Hochberg\u27s step-up Bonferroni methods provided similar but less conservative results. Finally, the false discovery rate method provided the least conservative results

THE EFFECT OF MONENSIN ON LACTATION DAIRY COWS: A DOSE RESPONSE EVALUATION

Monensin (Rumensin®) was fed at doses of 0, 8, 16, or 24 ppm to 966 dairy cows in nine different geographical locations in the USA and Canada. A dose response analysis was conducted on the primary variable, milk production efficiency, to determine the most appropriate dose response function, establish a minimum effective dose, and, when possible, determine a maximum effective dose. Linear mixed models (SAS® Proc Mixed v6.12) were fit to the data. Linear contrasts comparing the non-zero doses of monensin to the control were done to initially determine a minimum effective dose from the 3 non-zero design points. In addition, eight predefined linear contrasts were used to initially determine the general linear-plateau shape of a dose response function for each primary variable. A weighted regression analysis of the least squares means and corresponding standard errors was used when it was necessary to discriminate between the competing linear-plateau functions. A non-overlapping confidence interval process was followed, if it was deemed appropriate, to establish a minimum effective dose for a nondesign point. In cases where the dose response function had a plateau, the dose where the plateau began was classified as the “maximum effective dose” (minimum dose for maximum effect). In cases where the dose response function did not have a plateau, the maximum effective dose was the largest dose used in the study if the response rate was significant

Signal Processing

Contains research objectives, summary of research and reports on two research projects.Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DAAB07-71-C-0300U. S. Coast Guard (Contract DOT-CG-13446-A

Signal Processing

Contains research objectives and reports on work completed and one research project.Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DA 28-043-AMC-02536(E

Signal Processing

Contains research objectives and reports on two research projects.Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DA 28-043-AMC-02536(E

Prospective Safety Surveillance of GH-Deficient Adults: Comparison of GH-Treated vs Untreated Patients.

Context:In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown.Objective:The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement.Design and Setting:This was a prospective observational study in the setting of US clinical practices.Patients and Outcome Measures:AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates.Results:After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P ≤ .05) included insomnia (6.4% vs 2.7%), dyspnea (4.2% vs 2.0%), anxiety (3.4% vs 0.9%), sleep apnea (3.3% vs 0.9%), and decreased libido (2.1% vs 0.2%). Some of these AEs were related to baseline risk factors (including obesity and cardiopulmonary disease), higher GH dose, or concomitant GH side effects.Conclusions:In GH-deficient adults, there was no evidence for a GH treatment effect on death, cancer, intracranial tumor recurrence, diabetes, or cardiovascular events, although the follow-up period was of insufficient duration to be conclusive for these long-term events. The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement

Assessment of primary cancers in GH-treated adult hypopituitary patients: an analysis from the Hypopituitary Control and Complications Study

Objective: GH and IGFs have mitogenic properties, causing speculation that GH treatment could increase risk of malignancy. While studies in GH-treated childhood cancer survivors have suggested a slight increase in second neoplasms, studies in GH-treated adults have been equivocal. Design: Incidence of de novo and second cancers was evaluated in 6840 GH-treated and 940 non GH-treated adult patients in the Hypopituitary Control and Complications Study pharmacoepidemiological database. Methods: Evident cancer cases were evaluated in the main analysis, with sensitivity analyses including probable and possible cancers. Standardized incidence ratios (SIRs) for cancers were calculated using Surveillance, Epidemiology and End Results for the USA and GLOBOCAN for all other countries. Results: During the mean follow-up of 3.7 years/GH-treated patient, 142 evident cancer cases were identified, giving an overall SIR of 0.88 (95% confidence interval (CI) 0.74-1.04); 95% CIs included the value of 1.0 for each country examined. The SIR for GH-treated patients from the USA (71 cases) was 0.94 (95% CI 0.73-1.18), and for non GH-treated patients from the USA (27 cases) was 1.16 (95% CI 0.76-1.69). For GH-treated patients from the USA aged < 35 years, the SIR (six cases) was 3.79 (1.39-8.26), with SIR not elevated for all other age categories; SIR for patients from the USA with childhood onset (CO) GH deficiency (GHD) was 2.74 (95% CI 1.18-5.41). The SIR for colorectal cancer in GH-treated patients (11 cases) was 0.60 (95% CI 0.30-1.08). Conclusions: With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs were found for subgroups in the USA cohort defined by age < 35 years or CO GHD

Safety Outcomes During Pediatric GH Therapy : Final Results From the Prospective GeNeSIS Observational Program

Altres ajuts: Financial Support: GeNeSIS was sponsored by Eli Lilly and Company (Indianapolis, IN). In compliance with the Uniform Requirements for Manuscripts, established by the International Committee of Medical Journal Editors, the sponsor of this study did not impose any impediment, directly or indirectly, on the publication of the study's results. Disclosure Summary: C.J.C. and N.J. are employees and stockholders ofEliLilly and Company (Indianapolis, IN).W.F.B. and A.G.Z. are former employees and are stockholders of Lilly. C.L.D., T.H., M.M., and R.G.R. are former members of the GeNeSIS International Advisory Board; S.L., J.P.S., A.R.-U., and M.P. have served as regional advisors. B.P. has consulted for Eli Lilly Italia SpA, and E.C. has received grant support from Lilly. W.F.B. also reports heis aconsultant forAmmonett Pharma,Lilly Germany, and Merck KGaA Darmstadt. C.L.D. also reports receipt of grants, consultancy honoraria, and speaker fees from Lilly,EMD Serono, and Sandoz; grants fromOpko Prolor, Pfizer, and Versatis; honoraria and speaker fees from Roche; honoraria from Pfizer; and speaker fees from Novo Nordisk. The remaining authors have nothing to disclose.Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy. To assess incidence of key safety outcomes. Prospective, multinational, observational study (1999 to 2015). A total of 22,311 GH-treated children from 827 investigative sites in 30 countries. Children with growth disorders. GH treatment. Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries. Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (∼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors. GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors. Safety of GH therapy was assessed in a pediatric observational study. Death and primary cancer rates were not higher than in the general population; T2DM rate was higher owing to risk factors