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Thesis / Master of Science (MS)

Meta-analysis has been widely used in clinical research because it provides a useful tool for combining results from a series of trials addressing the same question. Two major approaches for study-to-study variation can be used in a meta-analysis: the fixed effects model which assumes that each study has the same true effect size, and the random effects model which assumes that the true effect size is a random variable that varies between studies. When there are covariates arising from the study, regression models can be used to explain the effects of these covariates on the between study variation in effect size. The purpose of this project is to draw some general conclusions about the statistical methods used in meta-analyses by re-examining several clinical examples which presented some problems. Four illustrative examples of recent meta-analyses were selected and re-examined. Both fixed effects and random effects models were used. In addition, regression models were used in two examples. Some general conclusions were made about the statistical aspects of meta-analysis from this project. The overall estimate of the fixed effects model tends to be overly influenced by large trials and may results in contradictory conclusions when extreme trials (small vs. large samples) are combined. Therefore, it is advocated that the weights allocated to each trial in any meta-analysis should be explicitly calculated and displayed. The random effects model takes a more balanced account of all studies and considers other unknown factors which may affect the effect size. Therefore, the random effects model and random effects regression model are more appropriate for these clinical data meta-analyses. / Thesis / Master of Science (MS)

The main purpose of this study was to conduct a meta-analysis with data collected from seven schools in Southwest Virginia school district. Data was collected for students who were referred to the Student Assistance Programs at each school. Tracking forms were used to record data for each student. Each tracking form was completed by the Student Assistance Program coordinators for their respective schools. This research was conducted in order to evaluate measurable performance outcomes of Student Assistance Programs. The results highlight the positive effects that Student Assistance Programs, SAP members, and other individuals associated with Student Assistance Programs have on students in need. The positive effect from participation in Student Assistance Programs is encouraging. However, recommendations are made for future research and implications of the current research are discussed. The need for additional research on this topic is prominent throughout this document. / Ph. D.

The dairy industry today is beginning to dedicate more focus on the growth of the calf from birth to first breeding to better improve the milk production as well as the overall performance of the individual cows. While the development of the rumen is one of the most vital contributors to the performance of the calf, it remains unknown what molecular mechanisms are responsible for the development of the rumen, and more specifically the proliferation of rumen epithelial cells. The objectives of this study were to investigate the existing data on rumen development through meta-analysis and to explore the effects of sodium butyrate and lipopolysaccharide (LPS) on rumen development in calves through experiment. In the first study a meta-analysis was performed to summarize the literature on calf performance and derive equations that relate rumen (e.g., rumen pH, reticulorumen weight, papillae area) and non-rumen factors (e.g., feed composition, form of feed, housing) to animal performance (e.g., intake of milk replacer (MR), starter, and forage; average daily gain (ADG); and feed efficiency). We looked at four different relationships to further investigate the connections between rumen, non-rumen, and performance factors. In the first and second relationships of interest, the effect of dietary and environmental variables on rumen variables and performance variables were examined, respectively. The third relationship of interest was how rumen variables influenced performance variables. The final relationship of interest was investigating the additive effects of the rumen, dietary, and environmental variables on the performance variables. Forward selection, multiple regression was used to derive equations to select variables that explained variation in the response variable in each model. Results showed that the variation in calf ADG was explained by daily forage intake, calves that were weaned, total starter intake, and total MR intake (concordance correlation coefficient (CCC) = 0.976). The variation in feed to gain ratio was explained by the weight of the ruminal contents, daily forage, MR, and starter intakes, percent of starter in the diet, and total starter intake (CCC = 0.992). The variation in daily forage intake was explained by the percent of the diet that was starter or MR (CCC = 0.998). The variation in daily starter intake was explained by the percent of acid detergent fiber in the starter, a pelleted starter (versus a texturized), diets including starter and forage (versus a milk replacer only diet), and the percent of the diet that was MR (CCC = 0.998). The variation in daily MR intake was explained by the percent of the diet that was starter, final body weight, ruminal propionate concentration, and daily starter intake (CCC = 0.918). Based on these analyses, although dietary and environmental factors are closely associated with calf performance, ruminal factors such as volatile fatty acid (VFA) concentration and ruminal contents appear to have additional, additive influences on calf performance. In the second study, 24 Holstein bull calves were challenged with oral doses of LPS and sodium butyrate. The hypothesis here was that LPS and sodium butyrate would instigate rumen cell proliferation independently and additively. Calves were assigned to one of four treatments: control (CON; n=5), butyrate (BUTY; n=5), LPS only (LPS-O) (n=6), or LPS plus butyrate (LPSB; n=6). All treatments were administered orally twice daily consisting of either: 0.9% saline (CON); 11 mM sodium butyrate (BUTY); LPS ranging from 2.5 to 40 µg/kg metabolic body weight (BW0.75, LPS), or both butyrate and LPS (LPSB). Calves were fed milk replacer (22% CP, 20% fat, as-fed) and starter (20% CP, 3% fat, as-fed) based on metabolic BW, or about 12% BW of MR and 3% BW of starter. Feed intake, fecal and respiratory scores, and rectal temperature were recorded daily. Calf BW, hip height, jugular blood samples, and rumen content samples (via oroesophageal tube) were collected weekly. Calves were weaned at 6 wk of age and euthanized at 8 wk of age, whereupon ruminal weights and ruminal samples for papillae area and epithelial thickness were collected. Blood and rumen samples were analyzed for concentrations of beta-hydroxybutyrate, glucose, LPS-binding protein, and VFA. Data were analyzed as a 2x2 factorial with the repeated effect of week. Three non-orthogonal contrasts (CON versus the average of all other treatments; LPS-O versus LPSB, and LPSB versus BUTY) were investigated. Feed intake, health measures, and blood metabolites did not differ by treatment. Calf BW increased by week (P < 0.0001). Irrespective of week, LPS calves weighed more and had higher ADG than BUTY calves (P = 0.020). Irrespective of week, withers height was greater in LPS compared to CON (P = 0.006). Rumen pH and rumen VFA concentrations did not differ by treatment but did decrease and increase, respectively, with week in conjunction with increased starter intake. Total empty forestomach (P = 0.014) and reticulorumen weights (P = 0.012) were greater in LPSB compared to BUTY. Overall, LPS and sodium butyrate appeared to have synergistically affected some, but not all rumen measurements without affecting calf growth, intake, or health. Results from the meta-analysis emphasize the importance of continuing to focus on the solid feed intake of the calf from birth through weaning. Implications from the LPS study are imperative to other dairy scientists who will attempt to further study the effects of LPS on the rumen. / Master of Science in Life Sciences / Dairy calves are born with an under-developed stomach. The stomach has four compartments: the rumen, reticulum, omasum, and abomasum. The rumen is the largest component where finger-like projections called papillae grow to absorb nutrients for the calf. It is vital to the calf that the rumen develops not only the papillae to absorb nutrients but also to foster a microbe-rich environment so the microbes can act as a defense mechanism for the calf to aid in fighting disease. While it is known that things like solid feed support the development of the rumen, the mechanism behind how that is happening still remains unclear in the literature. The objective of this study was first to better understand the relationships that exist in the literature between dietary, environmental, and ruminal factors, and second to investigate the claim that certain components of the bacteria in the rumen are stimulating rumen development independently and additively with sodium butyrate. In order to investigate the relationships amongst the dietary, environmental, and ruminal parameters, a computer program called R Studio was used to analyze over 30 different models that extracted data from a database that included a collection of 36 studies from the literature. This is also known as a meta-analysis. The associations of interest that we found were: average daily gain (ADG) of the calf was associated with daily forage intake, calves that were weaned, total starter intake, and total MR intake. Feed efficiency of the calf was associated with the weight of the ruminal contents, daily forage, milk replacer (MR), and starter intakes, percent of the diet composed of starter, and total starter intake. Daily forage intake was associated with the percent of the diet that was starter or MR. Daily starter intake was associated with acid detergent fiber in the starter, a pelleted starter (versus a texturized starter), diets including starter and forage (versus a MR only diet), and the percent of the diet that was MR. Daily MR intake was associated with the percentage of the diet that was starter, final body weight (BW), ruminal propionate concentration, and daily starter intake. These relationships emphasized that although dietary and environmental factors are more closely associated with calf performance, ruminal factors such as rumen contents and volatile fatty acid concentrations appear to have additional, additive influences on calf performance. The second part of the study objective was to explore an idea that, to our knowledge, has not been published in the literature. In the second study, 24 dairy calves were challenged with oral doses of a gram-negative bacteria lipopolysaccharide (LPS), and a short-chain fatty acid sodium butyrate. The hypothesis in this study was that the LPS and sodium butyrate would trigger metabolic pathways on the rumen cell membranes to a greater extent together, versus independently, to increase the amount of cells growing. Calves were assigned to one of four treatments: control (CON), butyrate (BUTY), LPS only (LPS-O), or LPS plus butyrate (LPSB). To study this effect, each treatment group was administered their respective treatment orally as a liquid twice daily. To measure the results, the following data was collected: feed intake, fecal and respiratory scores, rectal temperature BW, hip and withers height, blood samples, rumen content and pH samples, papillae area, epithelial thickness, and organ weights. Blood and rumen samples were analyzed for blood metabolites and volatile fatty acids concentrations respectively. Data were analyzed and results showed no difference amongst feed intake, health measures, rumen pH, rumen VFA concentration, and blood metabolites by treatment. Calves on the LPS treatment weighed more and had higher ADG than BUTY treatment calves. Withers height was higher in the LPS group when compared to CON. Stomach weights were higher in the LPSB group when compared to the BUTY group.

Yes / Objective: Past research has suggested that social influences on drinking can be manipulated with subsequent reductions in alcohol intake. However, the experimental evidence for this and the best strategies to positively change these social influences have not been meta-analyzed. This research addressed these gaps. Method: Randomized controlled trials testing social influence-based interventions on adults’ drinking were systematically reviewed and meta-analyzed. The behavior change techniques used in each study were coded and the effect sizes showing the impact of each intervention on (a) social influence and (b) alcohol intake were calculated. Meta-regressions identified the association between these effect sizes, as well as the effect of specific behavior change techniques on social influences. Results: Forty-one studies comprising 17445 participants were included. Changes in social influences were significantly associated with changes in alcohol intake. However, even moderate-to-large changes in social influences corresponded with only a small change in drinking behavior and changing social influences did not reduce alcohol-related problems. Providing normative information about others’ behavior and experiences was the most effective technique to change social influences. Conclusions: Social influences and normative beliefs can be changed in drinkers, particularly by providing normative information about how much others’ drink. However, even generating large changes in these constructs are likely to engender only small changes in alcohol intake. / NHS Leeds, UK.

Reliability generalization (RG) is a method for meta-analysis of reliability coefficients to estimate average score reliability across studies, determine variation in reliability, and identify study-level moderator variables influencing score reliability. A total of 107 peer-reviewed RG studies published from 1998 to 2013 were systematically reviewed to characterize the meta-analytic methods employed and to evaluate quality of reporting practice against standards for transparency in meta-analysis reporting. Most commonly, RG studies meta-analyzed alpha coefficients, which were synthesized using an unweighted, fixed-effects model applied to untransformed coefficients. Moderator analyses most frequently included multiple regression and bivariate correlations employing a fixed-effects model on untransformed, unweighted coefficients. Based on a unit-weighted scoring system, mean reporting quality for RG studies was statistically less than that for a comparison study of 198 meta-analyses in the organizational sciences across 42 indicators; however, means were not statistically significantly different between the two studies when evaluating reporting quality on 18 indicators deemed essential to ethical reporting practice in meta-analyses. Since its inception a wide variety of statistical methods have been applied to RG, and meta-analysis of reliability coefficients has extended to fields outside of psychological measurement, such as medicine and business. A set of guidelines for conducting and reporting RG studies is provided.

Conclusions. The sensitivity and positive predictive value are generally more concerned than the specificity and negative predictive value in assessing and adjusting publication bias in meta-analyses. In this sense, Egger's regression can be recommended for its high sensitivity, while any positive result from Tang's method would suggest a probability of bias that should be taken seriously. Given the different patterns of the accuracy with the OR and the P1-P2 combination, a combination of Egger's regression and Tang's regression would be advisable. Further studies are needed to study the accuracy of methods used in combination. / Due to sampling error and true heterogeneity, a single study cannot provide a comprehensive picture and a precise estimate of, say the effectiveness of a treatment. Systematic reviews that identify and integrate relevant studies have become the most important scientific, quantitative method to summarize scientific research. Meta-analysis is the statistical method used in systematic reviews to combine results from individual studies. / However, due to selective submission and publication, not all relevant studies conducted, especially those unpublished studies with an insignificant negative result, are easily accessible to those who conduct reviews. As a result, the truth, say, the effect of a treatment, would be overestimated. This phenomenon is known as publication bias. A few methods for detecting the bias have been developed and used in meta-analyses. Although their accuracy has been studied, some important issues remain to be answered, such as when would a method be good enough for practical use and is it similarly good for different definitions of the odds ratio? / Methods. We conducted a simulation study to examine the accuracy of four commonly used bias-detection methods with various ORs and P1-P2 combinations. In a simulation study, the true bias status can be predetermined and thus be compared with the results of the bias-detection methods. The four methods are Egger's regression, funnel plot regression, rank correlation regression, and Tang's regression. Realistic sample size was used for simulating individual studies and the numbers of studies in a meta-analysis was also varied. Both the sensitivity and specificity are examined against the magnitude of the OR and the P1-P 2 combination to identify the ORs and P1-P 2 combinations for which a method is sufficiently accurate. Predictive values are also examined for the same reason and in the same manner. / Results. The sensitivity and positive predictive value are generally low and in particular when the OR is close to one for which publication bias is of a particular concern. Egger's regression has the highest sensitivity among the four, in particular when the OR is neither close to one nor exceptionally large or small. Due to the relatively lower specificity, the positive predictive value of Egger's regression is not as high as that for Tang's regression and funnel plot regression. Tang's regression and funnel plot regression are very similar in sensitivity, specificity and predictive values, with the former being slightly better. Rank correlation seems the least accurate method overall. Tang's regression has in general the highest positive predictive value among the four methods in particular when the OR is below one. / Chung Chi-keung. / "June 2006." / Adviser: Tang Jin Ling. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1588. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 116-124). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

A clinical trial may have no subject (0%) or every subject (100%) developing the outcome of concern in either of the two comparison groups. This will cause a zero-cell in the four-cell (2x2) table of a trial using a binary outcome and make it impossible to estimate the odds ratio, a commonly used effect measure. A usual way to deal with this problem is to add 0.5 to each of the four cells in the 2x2 table. This is known as Haldane's approximation. In meta-analysis, Haldane's approximation can also be applied. Two approaches are possible: add 0.5 to only the trials with a zero cell or to all the trials in the meta-analysis. Little is known which approach is better when used in combination with different definitions of the odds ratio: the ordinary odds ratio, Peto's odds ratio and Mantel-Haenszel odds ratio. / A new formula is derived for converting Peto's odds ratio to the risk difference. The derived risk difference through the new method was then compared with the true risk difference and the risk difference derived by taking the Peto's odds ratio as the ordinary odds ratio. All simulations and analyses were conducted on the Statistical Analysis Software (SAS). / Conclusions. The estimated confidence interval of a meta-analysis would mostly exclude the truth if an inappropriate correction method is used to deal with zero cells. Counter-intuitively, the combined result of a meta-analysis will be worse as the number of studies included becomes larger. Mantel-Haenszel odds ratio without applying Haldane's approximation is recommended in general for dealing with sparse data in meta-analysis. The ordinary odds ratio with adding 0.5 to only the trials with a zero cell can be used when the trials are heterogeneous and the odds ratio is close to 1. Applying Haldane's approximation to all trials in a meta-analysis should always be avoided. Peto's odds ratio without Haldane's approximation can always be considered but the new formula should be used for converting Peto's odds ratio to the risk difference. / In addition, the odds ratio needs to be converted to a risk difference to aid decision making. Peto's odds ratio is preferable in some situations and the risk difference is derived by taking Peto's odds ratio as an ordinary odds ratio. It is unclear whether this is appropriate. / Methods. For studying the validity of Haldane's approximation, we defined 361 types of meta-analysis. Each type of meta-analysis is determined by a unique combination of the risk in the two compared groups and thus provides a unique true odds ratio. The number of trials in a meta-analysis is set at 5, 10 and 50 and the sample size of each trial in a meta-analysis varies at random but is made sufficiently small so that at least one trial in a meta-analysis will have a zero-cell. The number of outcome events in a comparison group of a trial is generated at random according to the pre-determined risk for that group. One thousand homogeneous meta-analyses and one thousand heterogeneous meta-analyses are simulated for each type of meta-analysis. Two Haldane's approximation approaches in addition to no approximation are evaluated for three definitions of the odds ratio. Thus, nine combined odds ratios are estimated for each type of meta-analysis and are all compared with the true odds ratio. The percentage of meta-analyses with the 95% confidence interval including the true odds ratio is estimated as the main index for validity of the correction methods. / Objectives. (1) We conducted a simulation study to examine the validity of Haldane's approximation as applied to meta-analysis, and (2) we derived and evaluated a new method to covert Peto's odds ratio to the risk difference, and compared it with the conventional conversion method. / Results. By using the true ordinary odds ratio, the percentage of meta-analyses with the confidence interval containing the truth was lowest (from 23.2% to 53.6%) when Haldane's approximation was applied to all the trials regardless the definition of the odds ratios used. The percentage was highest with Mantel-Haenszel odds ratio (95.0%) with no approximation applied. The validity of the corrections methods increases as the true odds ratio gets close to one, as the number of trials in a meta-analysis decreases, as the heterogeneity decreases and the trial size increases. / The proposed new formula performed better than the conventional method. The mean relative difference between the true risk difference and the risk difference obtained from the new formula is -0.006% while the mean relative difference between the true risk difference and the risk difference obtained from the conventional method is -10.9%. / The validity is relatively close (varying from 86.8% to 95.8%) when the true odds ratio is between 1/3 and 3 for all combinations of the correction methods and definitions of the odds ratio. However, Peto's odds ratio performed consistently best if the true Peto's odds ratio is used as the truth for comparison among the three definitions of the odds ratio regardless the correction method (varying from 88% to 98.7%). / Tam Wai-san Wilson. / "Jan 2006." / Adviser: J. L. Tang. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6488. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 151-157). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.