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Joint analysis of three seemingly independent microarray experiments via multivariate mixed-model equations with null residual covariance structure Antonio Reverter1, Yong-Hong Wang1, Keren A Byrne, Siok Hwee Tan1, Gregory S Harper1, Heather L. Bruce2, and Sigrid A Lehnert1 The Cooperative Research Centre for Cattle and Beef Quality 1CSIRO Livestock Industries, Queensland Bioscience Precinct 306 Carmody Rd, St Lucia, QLD 4067, Australia 2Food Science Australia, Tingalpa DC, QLD 4173, Australia applied across experiments yielding 1,424,322 intensity records analysed by fitting a tetra-variate model with 263,938 equations and 18 (co)variance components. The latter were estimated by restricted maximum likelihood. Correlation estimates for gene expressions ranged from 0.477 0.004 (for EXP1 and EXP3) to 0.896 0.002 (for EXP1 and EXP2). These moderate to strong estimates indicate the power to be gained with the joint analysis. The expected percentage of differentially expressed genes, as measured from the gene by treatment interaction, was 1.2% for diet in EXP1, 1.3% for breed in EXP2, and 17.1% and 5.1% for age effect and adipogenic treatment, respectively in EXP3. ABSTRACT: A bovine microarray of muscle and fat cDNAs was used in three gene expression experiments (EXP1, EXP2, and EXP3). EXP1 (14 slides) contrasts the gene expression profiles of muscle in Brahman steers fed varying quality diets. EXP2 (12 slides) compares the expression profile in muscle tissue between two breeds. EXP3 (22 slides) studies the mechanisms underlying adipogenesis in vitro. This study undertook to jointly analyse these three experiments using multivariate mixed-models with the relaxed assumption of a non-zero correlation amongst gene expressions across experiments while imposing a null residual covariance structure. Equivalent editing criteria were EXP1: Rockhampton Diets (LD Muscle) MEDIUM (4 Animals) Same Microarray Slide Across the 3 Experiments (48 slides) LOW (3 Anim, 1 Rep) (pooled 3 Anim) HIGH (pooled 2 Anim) MEDIUM (Pool & Ampl) CORRELATION: EXP2: Marbling Breeds (LD Muscle) TIME 2 There is gain to be made from a joint analysis MODEL: y X Zg Mt e LOW (Pool & Ampl) TIME 1 EXP1 & EXP2 = 0.84 (7,515) EXP1 & EXP3 = 0.56 (8,717) EXP2 & EXP3 = 0.51 (7,316) X T R 1 X T 1 Z R X M T R 1 X X T R 1 Z Z T R 1 Z G 1 I T M T R 1 M T 1 I X T R 1 M Z T R 1 M EXP1 EXP2 Tot+AmpRNA AmpRNA 1,344 9,245 27,678 405,820 1,152 9,245 45,096 329,247 672 9,245 45,474 219,956 1,440 9,245 104,102 469,299 9.3 0.1 1.4 9.7 0.1 1.5 3.8 1.5 3.3 8.8 0.6 2.0 Differentially Expressed % Total Variation 1.2 Actual N (95% CI) 403 1.3 354 17.1 n/a 5.1 546 1 M R Z E 0 i j TIME 3 EXP3 TotRNA AmpRNA i, j BREED 1 BREED 1 BREED 1 BREED 2 BREED 2 BREED 2 Log(Intensity) = Systematic + Gene + Gene*Trt + Error 4 Variables 1,424,322 Records 263,938 Equations 18 (co)variances EXP3: Adipogenesis (in vitro) REML V(G) V(G*T) V(E) T1 T2 T3 T4 T5 RESULTS: Jointly Differentially Expressed T6 TREAT 1 TREAT 2 IMPLICATIONS Go beyond standard applications: Pleiotropic Patterns of Co-Regulation Evolution Plasticity Diet Restriction Up Down Breed 1 Breed 2 Treat 1 Treat 2 Up Down 84 0 319 Breed 1 Breed 2 Treat 1 Treat 2 2 20 1 5 2 9 1 12 121 0 233 2 15 2 2 403 0 143