Combining information from multiple data sources to create multivariable risk models: Illustration and preliminary assessment of a new method

A common practice of metanalysis is combining the results of numerous studies onthe effects of a risk factor on a disease outcome. If several of these composite relativerisks are estimated from the medical literature for a specific disease, they cannot becombined in a multivariate risk model, as is often done in individual studies, becausemethods are not available to overcome the issues of risk factor colinearity andheterogeneity of the different cohorts. We propose a solution to these problems forgeneral linear regression of continuous outcomes using a simple example ofcombining two independent variables from two sources in estimating a joint outcome.We demonstrate that when explicitly modifying the underlying data characteristics(correlation coefficients, standard deviations, and univariate betas) over a wide range,the predicted outcomes remain reasonable estimates of empirically derived outcomes(gold standard). This method shows the most promise in situations where the primaryinterest is in generating predicted values as when identifying a high-risk group ofindividuals. The resulting partial regression coefficients are less robust than thepredicted values

Dissimilarity in aflatoxin dose-response relationships between DNA adduct formation and development of preneoplastic foci in rat liver

Earlier work in this laboratory and that carried out by others demonstrated that after a single dose of aftatoxin B1 (AFB) the resulting liver AFB-DNA adduct levels were directly proportional to dose. Earlier workalso showed that after ten daily doses the AFB dose response relationship with y-glutamyl transpeptidase (GGT)positive preneoplastic foci measured at 3 months was sublinear, with a threshold at a dose of about 150 µg/kgbody weight/day. The objective of this study is to determine the factors influencing the shift in AFB doseresponse between AFB-DNA adducts and GGT foci. Male Fisher 344 weanling rats were orally administered oneor ten doses of AFB ranging from 50 to 350 µg/kg body weight/day. The animals were killed 2 or 24 h after the first AFB dose, or after the tenth AFB dose. The first and tenth doses were tritiated in these animals and 3HAFB-guanine adducts isolated from liver DNA were measured by HPLC. Another group was killed 3 months after receiving ten doses in order to measure GGT foci development. AFB-guanine adduct levels were directlyproportional to dose after the first dose, but after the tenth dose were much lower in the 200-350 µg/kg groupsthan after a single dose. The GGT foci response confirmed earlier work concerning a sublinear response. Among the individual animals in the 200-350 µg/kg groups there was a positive relationship, after controlling for dose,between GGT foci development and weight gained both during dosing (P = 0.018) and also to a lesser extent during the early promotional period (P = 0.066). Enzyme activity levels of GGT in liver homogenates were higherin the highest dose groups and reflected biliary proliferation rather than histological GGT stained foci. Urinary levels of AFB metabolites changed proportions in the high dosage multiply dosed animals reflecting alteration in AFB metabolism or excretion. The differences between the linear adduct and the sublinear foci dose response curves may be the result of non adduct effects of higher multiple AFB doses on foci formation including acutecytotoxicity, altered AFB metabolism and disposition, enhanced weight gains, or shortened foci latency but notthrough enhanced guanine adduct levels. Other studies that showed a linear relationship between AFB dose and liver tumor development used continuous feeding of maximal doses an order of magnitude less than the lowestdose in this study and thus avoided acutely toxic effects. We hypothesize that liver tumor development may mirror foci response in a IO-dose AFB regimen with doses above 100 µg/kg due to acute toxicity effect

Adding Multiple Risk Factors improves Framingham coronary Heart Disease risk scores

Purpose: Since the introduction of the Framingham Risk Score (FRS), numerous versions of coronary heart disease(CHD) prediction models have claimed improvement over the FRS. Tzoulaki et al challenged the validity of these claims by illustrating methodology defi - cies among the studies. However, the question remains: Is it possible to create a newCHD model that is better than FRS while overcoming the noted deficiencies? To address this, a new CHD prediction model was developed by integrating additional risk factors, using a novel modeling process. Methods: Using the National Health Nutritional Examination Survey III data set with CHD- specific mortality outcomes and the Atherosclerosis Risk in Communities data set with CHD incidence outcomes, two FRSs (FRSv1 from 1998 andFRSv2 from National Cholesterol Education Program Adult Treatment Panel III), along with an additional risk score in which the high density lipoprotein (HDL) component of FRSv1 was ignored (FRSHDL), were compared with a newCHD model (NEW-CHD). This new model contains seven elements: the original Framingham equation, FRSv1, and sixadditional risk factors. Discrimination, calibration, and reclassification improvements all were assessed among models. Results: Discrimination was improved for NEW-CHD in both cohorts when compared with FRSv1 and FRSv2 (P,0.05)and was similar in magnitude to the improvement of FRSv1 over FRSHDL. NEW-CHD had a similar calibration to FRSv2 and was improved over FRSv1. Net reclassification for NEW-CHD was substantially improved over both FRSv1and FRSv2, for both cohorts, and was similar in magnitude to the improvement of FRSv1 over FRSHDL. Conclusion: While overcoming several methodology deficiencies reported by earlier authors, the NEW-CHD model improved CHDrisk assessment when compared with the FRSs, compa- rable to the improvement of adding HDL to the FR

MICROSOMAL HYDROXYLATION OF ANILINE IN THE SOUTHERN ARMYWORM, SPODOPT ERA ER/ DAN IA

Microsomal hydroxylation of aniline in midguts of the southern armyworm, Spodoptera eridania, was found to differ in its requirements for optimal in vitro activity from those of armyworm and rat liver pchloro N-methylaniline Ndemethylase and rat liver aniline hydroxylase. Apparent K,.values for armyworm aniline hydroxylase were substantially higher than those for rat liver aniline hydroxylase and the Ndemethylaseenzymes. The armyworm aniline hydroxylase wasinhibited by several mixed-function oxidase inhibitors as wellas by aldrin and nicotine and was highly inducible bypentamethylbenzene and phenobarbital

Synthesis analysis of regression models with a continuous outcome

To estimate the multivariate regression model from multiple individual studies,it would be challenging to obtain results if the input from individual studiesonly provide univariate or incomplete multivariate regression information.Samsa et al. (J. Biomed. Biotechnol. 2005; 2:113–123) proposed a simple method to combine coefficients from univariate linear regression models into a multivariate linear regression model, a method known as synthesis analysis.However, the validity of this method relies on the normality assumption of thedata, and it does not provide variance estimates. In this paper we propose anew synthesis method that improves on the existing synthesis method byeliminating the normality assumption, reducing bias, and allowing for thevariance estimation of the estimated parameters

Vitamin A and carotenoid status in rural China

Vitamin A status of 260 groups of twenty five males or twenty five females, aged 3 years,surveyed in twenty four provinces of the People's Republic of China, was assessed by. measuringplasma retinol, retinol binding protein and fl-carotene concentrations. Direct measurements of foodintake over a 3 d period and questionnaire data on the frequency of consumption ofvegetables, fruits,animal products and <lther dietary items were also used. Vitamin A status appeared to be low only inspecific counties but in general was satisfactory or only marginally deficient. Plasma JI-carotene levelswere strikingly low in comparison with Western levels despite generous vegetable consumptionsuggests that intake of vitamin A precursors may have been adequate but not abundant enough tomaintain high circulating plasma levels of fl-carotene. Plasma fl-carotene, for both males and females,was significantly correlated with the frequency of consumption of green vegetables. Plasma retinol, formales, was highly correlated with meat, fish, oil and alcohol consumption expressed both in quantity orfrequency of consumption. Higher levels of plasma retinol, together with lower levels of plasma JIcarotenein males compared with females, suggest that men consume more animal products or mayhave higher retinol requirements and therefore a higher rate of conversion of JI-carotene to retinol

Healthy Eating Index 2005 and selected macronutrients are correlated with improved lung function in humans

A number of dietary components have been associated with lung function. However, a comprehensive measure of a healthy diet has not been compared with lung function. Herein, we test the hypothesis that a healthy overall diet, as assessed by the Healthy Eating Index 2005 (HEI-2005), will be associated with increased lung function. This is an investigation using the Atherosclerosis Risk in Communities Research Materials obtained from the National Heart Lung Blood Institute. The study surveyed dietary habits of 15 567 American subjects from 4 communities in 1987 to1990. Spirometric measures of lung function were also taken at entry to the study and a second time 3 years later.Based on food and nutritional data collected by food frequency questionnaire, an HEI-2005 score was calculated for each subject. This total score, together with its 12 components scores and associated macronutrient, was compared with lung function results by linear regression. Models were controlled for smoking behavior, demographics, and other important covariates. The HEI-2005 total scores were positively associated with forced expiratory volume in 1 second per forced vital capacity (FEV(1)/FVC) at visit 1 (ß = .101 per increase in 1 quintile of HEI-2005) and visit 2 (ß = .140), and FEV(1) as percentage of the predicted FEV(1) at visit 2 (ß = .215) (P < .05). In addition, HEI-2005component scores that represented high intakes of whole grains (ß = .127 and .096); saturated fats (ß = -.091); and solid fats, alcohol, and added sugar (ß = -.109 and -.131) were significantly associated with FEV(1)/FVC at either visit 1 or visit 2. Intakes of total calories (ß =-.082 at visit 1) and saturated fatty acids (ß = -.085 at visit 2) werenegatively associated with FEV(1)/FVC. Dietary polyunsaturated fatty acids (ß = .085 and .116) and long-chain omega-3 fatty acids (ß = .109 and .103), animal protein (ß = .132 and .093), and dietary fiber (ß = .129) were positively associated with lung health. An overall healthy diet is associated with higher lung functio

Use of an Improved Method for Analysis of Urinary Aflatoxin M 1 in a Survey of Mainland China and Taiwan

An improved monoclonal antibody immunoaffinity chromatography/high-pressure liquid chromatography/ftuorescence detection method was developed to measure aftatoxin (AF) exposure by quantifying AFM 1 inhuman and rat urine samples.Analysis of different amounts of various AF metabolites showed that the immunoaffinity resin was highlyselective for aftatoxin 81 (AFB1), AFB2, and AFM 1• Recovery of added AFs increased with the amount of immunoaffinity resin and was virtually complete within the range of 0.01-10 ng of AFM 1 by using 7 ml of resin. The detection limit of this method is 0.5 pglml urine. Rats dosed with tritiated AFB 1 excreted in their urine tritiated AFM., among other AF metabolites, as indicated by chemical derivative confirmation and cochromatography with authentic AFM 1 and agreement of radioactivity and ftuorescence quantitation. Alinear dose-response relationship was found over the range of 0.05-50 p.glkg of body weight/day. Two humans dosed with 1.0 µ.g of pure AFB 1 excreted 6-7% of the dose asurinary AFM 1 over 5-7 days. Pooled urine samples from 30 men from each of 69 rural counties in mainland China and 16 survey areas in Taiwan, with two villages per county or area, were analyzed with this improved method (170 villages total). The correlationcoefficient of urinary excretion of AFM 1 compared between villages within all 85 survey areas was 0.50 (P <0.001). Sixty-five % of the samples contained detectable concentrations of AFM 1 with an average excretion of 3.1 ng/12 h. Assuming an excretion rate of 2-6%, this AFM 1 excretion corresponds to a very low average daily AF consumption of 0.1-0.3 p.g/day (possible range, 0-11 p.g/day). Patterns of urinary excretion of AFM 1 were similar in mainland China and Taiwa

Flavonol Intake and Cognitive Decline in Middle-Aged Adults

Cognitive decline occurs with age and may be slowed by dietary measures, including increased intake of dietary phytochemicals. However, evidence from large and long-term studies of flavonol intake is limited. Dietary intakes of flavonols were assessed from a large biracial study of 10,041 subjects, aged 45–64, by analysis of a food frequency ques tionnaire administered at visit 1 of triennial visits.Cognitive function was assessed at visits 2 and 4 with the following three cognitive performance tests: the delayed word recall test, the revised Wechsler Adult Intelligence Scale digit symbol subtest, and the word fluency test of the Multilingual Aphasia Examination. The change in each score over 6 years was calculated, and a combined standardized change score was calculated. Generalized linear models controlled for age, ethnicity, gender, education level, energy intake, current smoking, physical activity,body mass index, diabetes, and vitamin C intake. Total flavonols across quintiles of intake were positively associated with preserved combined cognitive function (P < .001). This pattern with preserved combined cognitive function was consistent for the three major individual flavonols in the diet, myricetin, kaempferol, and quercetin (each P < .001). The positive association with total flavonols was strongest for the digit symbol subtest (P < .001). In this cohort, flavonol intake was correlated with protected cognitive function over tim

Breast cancer and dietary and plasma concentrations of carotenoids and vitamin A

A case-control study of breast cancer was conducted inBuffalo. Participants completed a food frequency questionnaire and donateda fasting blood sample before definitiveworkup for breast masses. Dietaryand plasma concentrationsof carotenoids and retinol for 83 women foundto have breast cancer were compared with those of 1 13 women found to befree of breast cancer (control subjects). There were no case-controldifferences in dietary estimates of vitamin A intakeor in plasma a-caroteneand lycopene. However, subjects with breast cancer had lower concentrationsof plasma fj-carotene than did control subjects (P = 0.02). There was nooverall association between plasma retinol and breast cancer but a positiverelationship was observed between retinol and breast cancerin thesubgroup with low fj-carotene values. These results suggest that low plasmafj-carotene is associated with increased risk of breast cancer. Other studieswill need to determine whether low carotene concentrations are a subtleeffect of the disease or might be causally related to breast cance