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Article sections

- Summary
- 1. Introduction
- 2. Review of the Partially Linear Tree-based Regression (PLTR) Model
- 3. Extension of the PLTR Model to Multivariate Outcomes
- 4. Simulation
- 5. Application
- 6. Discussion
- Supplementary Material
- References

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Biometrics. Author manuscript; available in PMC 2010 May 25.

Published in final edited form as:

Published online 2009 May 7. doi: 10.1111/j.1541-0420.2009.01235.x

PMCID: PMC2875329

NIHMSID: NIHMS117662

Kai Yu,^{1} William Wheeler,^{2} Qizhai Li,^{1,}^{3} Andrew W. Bergen,^{4} Neil Caporaso,^{1} Nilanjan Chatterjee,^{1} and Jinbo Chen^{5}

Address for Correspondence: Kai Yu, Ph.D., 6120 Executive Boulevard, EPS 8050, Rockville, MD 20852, E-mail: yuka/at/mail.nih.gov

The publisher's final edited version of this article is available at Biometrics

See other articles in PMC that cite the published article.

In the genetic study of complex traits, especially behavior related ones, such as smoking and alcoholism, usually several phenotypic measurements are obtained for the description of the complex trait, but no single measurement can quantify fully the complicated characteristics of the symptom because of our lack of understanding of the underlying etiology. If those phenotypes share a common genetic mechanism, rather than studying each individual phenotype separately, it is more advantageous to analyze them jointly as a multivariate trait in order to enhance the power to identify associated genes. We propose a multilocus association test for the study of multivariate traits. The test is derived from a partially linear tree-based regression model for multiple outcomes. This novel tree-based model provides a formal statistical testing framework for the evaluation of the association between a multivariate outcome and a set of candidate predictors, such as markers within a gene or pathway, while accommodating adjustment for other covariates. Through simulation studies we show that the proposed method has an acceptable type I error rate and improved power over the univariate outcome analysis, which studies each component of the complex trait separately with multiple-comparison adjustment. A candidate gene association study of multiple smoking-related phenotypes is used to demonstrate the application and advantages of this new method. The proposed method is general enough to be used for the assessment of the joint effect of a set of multiple risk factors on a multivariate outcome in other biomedical research settings.

In genetic association studies of many complex traits, particularly those related to behavior, such as alcoholism and smoking, we usually do not have a single phenotypic measurement that can quantify fully the complicated characteristics of the trait because of our lack of understanding of the underlying etiology. More often, we obtain multiple phenotypic measurements, with each phenotype variable reflecting one aspect of the complex trait. For example, in a genetic study of asthma, we usually have several pulmonary function related measurements since asthma is associated with a variety of abnormalities in pulmonary function (Lange et al., 2003). If several related phenotypes share a common genetic mechanism, rather than studying each individual phenotype separately, it may be advantageous to analyze them jointly in order to utilize efficiently all of the relevant information.

Xu et al. (2003) provided a brief summary of approaches for testing the association between a multivariate phenotype and genetic variants. A commonly used one is to combine univariate analyses based on individual phenotypes for a global assessment of the association in the framework of the generalized linear model (GLM) by applying he generalized estimating equations (GEE) method (Liang and Zeger, 1986). The GLM is parsimonious for examining main effects of a single or several genetic risk factors, but it is not suitable for modeling complex joint effects (such as high-order gene-gene interactions) of a relatively large number of risk factors. For example, to detect the association between an outcome variable and a candidate gene, it is often desirable to model the joint effect of multiple markers within that candidate gene. The tree-based modeling approach (Breiman et al., 1984; Zhang and Singer, 1999), has an advantage over GLM in that it is more flexible in modeling complicated joint effects, and it has increasingly been applied in genetic studies of complex traits (see, e.g, Cook et al., 2003; Zhang et al., 2000; Yu et al., 2005; Yu et al., 2007).

We recently proposed a new class of semi-parametric regression models for the analysis of univariate phenotypes, termed partially linear tree-based regression (PLTR) model, that integrates the advantages of the generalized linear regression and tree-structure models (Chen et al., 2007). This model includes both linear terms and a tree term, which are assumed to be additive on an appropriate scale, e.g., the logit scale for a binary outcome. The linear part is used to model main effects of some genetic/environmental exposures and to control for confounders. The nonparametric tree part is used for approximating the complex joint effect of multiple genes and environmental exposures.

In this paper, we extend the univariate PLTR model to the study of multivariate outcomes. As in the univariate PLTR model, its multivariate extension consists of linear terms and a tree term. We adopt the GEE method to accommodate the multivariate outcome in the construction of the tree model while allowing the linear term in the model to be appropriately accounted for. We provide a formal testing procedure for assessing the joint effect of multiple risk factors, such as genotypes on a panel of genetic markers within a gene or pathway, modeled as the tree term, on a multivariate outcome while adjusting for a set of covariates. The presence of the linear term in the new model distinguishes our method from existing multivariate tree models (Segal, 1992; Zhang, 1998; Larsen and Speckman, 2004). Also, existing multivariate tree models focus mainly on prediction, while ours emphasizes hypothesis testing. Compared with the standard GEE approach for multivariate outcome, our model is more flexible in modeling complicated joint effects. The new test derived from our proposed model can be used as a multilocus genetic association test for the study of multivariate phenotypes, and it is general enough to be used for the assessment of the joint effect of a set of multiple risk factors on a multivariate outcome in other biomedical research settings.

We provide a brief review of the PLTR model and refer readers to Chen et al. (2007) for more details. Let *Y* be the outcome, *X* be covariates to be modeled linearly, and *G* be the set of risk factors whose joint effect is to be approximated by a tree-structural model. The data {(*Y _{i}*,

(1)

where *h* (•) is the link function, for example, we can use the logit link function
for a binary outcome, and the identity link function for a continuous outcome. In (1), **x** is the standard coding vector for the set of covariates *X*, and **z**(**T**) is the coding vector for the risk factor derived from the tree model **T**. For example, the tree model shown in Figure 1 has five terminal nodes (nodes without offspring nodes) and defines a risk factor (still denoted as **T**) with 5 categories. To test the joint effect of *G*, we can use either the standard likelihood ratio test statistic, which compares the model with the tree term **z**(**T**) to the one without the tree term, or the Wald test statistic, which tests the coefficient vector *γ*. Its significance level is evaluated through a resampling procedure that accounts for any model selection bias introduced by the choice of **T**.

In this section, we extend the PLTR model to study a multivariate outcome with *M* components, (*y*_{1},…, *y _{M}*)′, which we again denote by

(2)

where *h* (•) is the link function. In (2), *β _{m}* and

The tree model **T** is formed by splitting rules based on *G* and defines a risk factor with each level represented by a terminal node. In model (2), we assume the tree structure is the same across different outcomes so that the same risk factor (derived from the tree model **T**) is defined for all outcomes, but we allow the effect to be outcome-specific. This strategy is reasonable when there is a common latent risk factor (either continuous or categorical) underlying all the considered phenotypes. For example, in the association study of smoking-related phenotypes and the gene CYP2B6 (described later), if all three considered phenotypes are related to the same unmeasured functional marker within the gene (so we have a latent risk factor with three categories), we could use the tree model in (2) as a surrogate for the unobserved functional marker.

Our method consists of the following three steps with details provided in the next two sections:

- Step II: Based on
**T**, find a sequence of nested subtrees**T**,_{f}*f*= 2, …,*F*, with**T**having_{f}*f*terminal nodes, and*F*being a pre-specified value, say, 10. - Step III: Find an optimal tree model
**T**from_{}**T**,_{f}*f*= 2, …,*F*, and evaluate the significance level of this optimal tree with respect to the joint effect of*G*.

We implemented the method by means of an R program using functions from the R packages Rpart (Therneau and Atkinson, 1997) and geepack (Halekoh et al., 2006).

To account for the correlation among multiple outcomes when choosing the splitting variable in the tree-building procedure and when estimating coefficients (*β _{m}*,

- Fit the linear model , by means of the GEE method.
- Iterate between the following steps starting with
*k*= 1.- 2.1Build a tree model
**T**^{(k)}based on*G*, using , as the offset, with being the current estimate for*β*at the_{m}*k*th iteration. - 2.2Use GEE to fit the multivariate GLM , using (
*β*^{(k)})′**x**as the offset. Let the new estimate be_{m}*γ*^{(k)}. - 2.3Use GEE to fit the multivariate GLM , with being the offset. Update the estimate to .

- The iteration stops when converges.

In step 2.1, the tree **T** is constructed recursively by splitting a node into two. Assume that the current estimation for *β _{m}* is
,

where *η _{m}* =(

(3)

A large Wald statistic would suggest that the two offspring nodes probably have different effects on the outcome. For a given node *A*, among all its possible splitting rules, we choose the one that yields the maximum Wald statistic, as given by (3), and use it to grow the tree to the next level. We define the “goodness-of-split” for node *A* as

(4)

where the maximum is chosen over all permissible splitting rules.

Based on this splitting algorithm, we can grow the tree recursively until the number of samples left in a node is insufficient for further splitting. We recommend a relatively large threshold for the sample size at a node, for example 50, so that a sufficient number of subjects are available to fit using the GEE method. The above fitting algorithm requires that the tree in all iterations have the same size. Thus, after the tree **T** is constructed at step 2.1, we prune it back to a predetermined number of terminal nodes, *F* (say, 10). This can be done in either a stepwise backward or forward fashion. To do it in a forward fashion, we start from the subtree with the root node 1 and its two offspring nodes 2 and 3. Then among nodes 2 and 3, we choose the one with a larger “goodness of split”, as defined by (4), and expand the subtree by including the offspring nodes of the chosen node. Suppose we have obtained a subtree with *f* terminal nodes, *f* < *F*. We then can choose the terminal node with the largest “goodness of split” and expand the current subtree by including two offspring nodes of the chosen node to obtain a subtree with *f* +1 terminal nodes. The process can continue until a subtree with *F* terminal nodes is reached. Similarly, we can reverse the process by moving backward. We can start from a current tree and reduce its size by pruning away the pair of terminal nodes whose parent node has the smallest “goodness of split”. The tree **T**^{(k)} in Step 2.1 always has the same size using either strategy. Based on our experience, there is no obvious advantage of one strategy over the other. So, we choose to use the stepwise forward approach to identify the subtree with the given size *F*.

The tree **T** at the end of Step I has a predetermined size *F*, which is usually oversized. We aim to identify an optimal subtree of **T**, so that it presents the joint effect of *G* parsimoniously, and to evaluate its significance level.

First, we identify a sequence of subtrees of **T** as candidates for the optimal subtree, The stepwise forward algorithm that is used in Step I (described in Section 3.1) for selecting a subtree with a given size can again be applied to identify the sequence of candidate trees with various sizes. Let **T*** _{f}*,

(5)

where is the GEE estimation for *γ*, and where * _{γ,γ}* is the principal submatrix corresponding to

Second, we choose as the “optimal” tree, from the list of candidate trees **T*** _{f}*,

For comparison with the multivariate approach described above, we consider a univariate approach (called the univariate-MinP) that analyzes each individual outcome using the univariate PLTR and then adjusts for multiple comparisons. A more detailed description of the univariate-MinP approach is given in the Web Appendix B.

For our simulation, we studied a candidate gene region with 11 SNPs. Their haplotype frequencies are given in Figure 3 of Yeager et al. (2007). There were a total of 25 haplotypes in the study population. To assign genotypes at the 11 SNPs for a subject in the study population, we independently selected pairs of haplotypes according to the haplotype frequencies. To evaluate the power of the proposed multivariate tree model and of the univariate-MinP approach, we designated the 5^{th} SNP in the candidate region as the single functional locus (one-locus risk model) that influences the quantitative traits under study. We assumed that this functional SNP was not typed and that genotypes at the other 10 SNPs were available for the association study. The power was calculated as the probability that the joint effect on the outcome from the genotypes at the 10 measured SNPs is significant under a given significance level (according to the adjusted p-value from the multivariate tree model or the univariate-MinP method). In addition to the genotypes, we considered a non-genetic binary covariate *X* that had to be adjusted for in the analysis. We let Pr(*X* = 1) = 0.4 and Pr(*X* = 0) = 0.6 , and we further assumed that *X* and the genotypes were independent in the study population. Let *g*_{5} be the coded value for the unobserved genotype at the functional locus, with values of 0, 1, and 2 representing the copy number of the minor allele “1”. Conditioned on *X* and *g*_{5}, we generated a multivariate quantitative trait *Y* = (*y*_{1},…, *y _{M}*)′ from the multivariate normal distribution

To evaluate the type I error rate, we considered a bivariate trait (quantitative or its dichotomized version) unrelated to the genotype, i.e., *γ _{m}* = 0,

To evaluate power, we simulated a bivariate trait (quantitative or its dichotomized version) by assuming *γ _{m}* = 0.18 for both phenotypes, and the covariance matrix
, with

We analyzed each simulated dataset using model (2) allowing coefficients to vary for different outcomes. In the tree-building process, we considered splitting rules based on genotypes (coded as 0, 1, and 2, corresponding to the copy number of a chosen allelic type) on a single SNP, and we treated genotypes as continuous variables, i.e., the legitimate splitting rules are: 0 vs. 1 and 2; and 0 and 1 vs. 2, but not 1 vs. 0 and 2. We used different assumptions about the correlation matrices in the GEE method (e.g., independent and unstructured) and obtained quite similar results based on simulated datasets (see Web Table 1). In the following, we present results based on analyses using “independence” as the working correlation matrix in the GEE method.

Estimated type I errors of the multivariate tree model under the analysis of a bivariate phenotype with the covariance matrix
. For either the continuous outcome or its dichotomized version, the type I error rate was estimated based on 2,000 simulated **...**

Simulation results for type I error evaluation are given in Table 1. It appears that the proposed method has a type I error rate close to the nominal levels (*α* = 0.01, 0.05) under all covariance structures considered for both continuous and binary traits. We also evaluated the type I error rate of the multivariate tree model when the tree size was pre-specified. Results are given in Web Table 2. We can see from the table that the p-value estimated from the permutation procedure for a tree with a given size has the desired property.

Power comparison at the significance level of 0.05 for the analyses of a bivariate phenotype with the covariance matrix
simulated under the one locus risk model. For either the continuous outcome or its dichotomized version, the power was estimated **...**

Power calculations for the simulated bivariate outcomes are given in Table 2. Under the given covariance matrix, we compared the power of the multivariate analysis (applying the proposed method to study two phenotypes jointly) with that of the univariate-MinP procedure (multiple-comparison adjusted univariate analysis). Results in Table 2 demonstrate the advantage of using the multivariate approach for both the quantitative and binary traits. Interestingly, the power improvement over the univariate-MinP analysis increases as the correlation between the two outcomes changes from positive to negative. The explanation is that the negative correlation between the two outcomes helps to reduce the variance in the coefficients’ estimation when the underlying effects (*γ*_{1} and *γ*_{2}) for the two correlated phenotypes point in same direction (both either positive or negative).

Power calculations for the simulation of a trivariate quantitative outcome are given in Table 3. For each simulated dataset, we analyzed various subsets of the multivariate outcome using the joint analysis as well as the univariate-MinP analysis. From Table 3 we can observe the gain in power when individual phenotypes related to the same gene were studied together over the analysis of individual phenotypes. The power to detect the gene reaches its highest level when all relevant phenotypes are studied jointly. But when the multivariate trait under study includes one or more phenotypes not related to the gene under study, the power is diminished to some extent.

Power comparison for the analyses of three phenotypes *Y*_{1} , *Y*_{2} , and *Y*_{3} at the significance level of 0.05. The power was estimated based on 500 simulated datasets, with each consisting of 800 subjects.

We further evaluated the performance of the proposed method by simulating data under a 2-locus risk model, and we found that our method performed very reasonably (See Web Table 3). The simulation design is described in the Web Appendix C.

We evaluated the convergence properties of the iterative algorithm through extensive simulation studies. We found that the algorithm usually converged within 50 iterations in the simulation setup described above. When the sample size was 500, the algorithm converged in 995~1000 out of 1000 replicated datasets under the various considered scenarios. When the sample size increased to 1000, the algorithm converged in 998-1000 out of 1000 replicated datasets. The working matrix did not appear to have an impact on the convergence properties of the algorithm; neither did the type of outcome (continuous or binary). When the algorithm did not converge, it always iterated between two tree models. In these rare situations, we chose the tree model with the larger Wald test statistic.

As part of the Cancer Genetic Markers of Susceptibility (CGEMS) project (Yeager et al., 2007), a multi-stage genome-wide association study of prostate cancer has been conducted. The initial scan was performed on a nested case-control sample drawn from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. To demonstrate the application of the proposed model, we used genotype data generated in this CGEMS prostate cancer project to study the association between the candidate gene CYP2B6 and the multivariate trait, which consists of the following three dichotomized smoking behavior phenotypes relating to smoking intensity, duration of smoking and age at smoking initiation, *Y*_{cig-day}, *Y*_{smk-yr}, and *Y*_{smk-age}, respectively, where *Y* = 1 if the number of cigarettes smoked per day is 4 or more, and 0 otherwise; *Y*_{smk-yr} = 1 if years of smoking is 29 or more and 0 otherwise; and *Y*_{smk-age} = 1 if the age at smoking initiation is 18 or below and 0 otherwise. Each dichotomous cut-point was chosen to be close to the corresponding median value. The gene CYP2B6 was previously reported to be associated with nicotine metabolism (Ring et al., 2007) and nicotine dependence (Saccone et al., 2007).

17 SNPs were genotyped at and around the CYP2B6 gene (20 kb up and downstream) at chromosome 19q13.2. In the linear part of model (2), we adjusted for prostate cancer status (prostate cancer case or control), and age at diagnosis in five-year intervals (55–59, 60–64, 65–69, 70–74), which were stratification variables in the original data collection. We used the tree structure to summarize the joint effect of the 17 SNPs and tested whether there was a significant joint effect from those 17 SNPs on the study phenotypes. During the tree building process, similar to the simulation study, we considered splitting rules based on genotypes (coded as 0, 1, and 2, corresponding to the copy number of a chosen allelic type) on a single SNP. The legitimate splitting rules included: (a) 0 vs. 1 and 2 and (b) 0 and 1 vs. 2.

We focused on 1,318 ever smokers with complete data for all non-genetic covariates and genotypes for the 17 SNPs. Genotypes frequencies are given in Web Table 4. We used the proposed method to assess the association between the gene and various subgroups of the three phenotypes by finding the optimal tree model to summarize the joint effect of those 17 SNPs. Results are summarized in Table 4. The model-selection adjusted p-value, which was obtained through the permutation procedure described in the Methods section, indicated the significance level of the association. When we analyzed each binary trait separately, significant associations between the gene and *Y*_{cig-day} (adjusted p-value = 0.012), and between the gene and *Y*_{smk-yr} (adjusted p-value = 0.032) were observed. But there was no evidence for a significant association between the gene and *Y*_{smk-age} (adjusted p-value = 0.392). By analyzing traits *Y*_{cig-day} (smoking intensity) and *Y*_{smk-yr} (smoking duration) jointly, we detected a stronger association (adjusted p-value = 0.009) than those from univariate analyses. When the third trait *Y*_{smk-age} was included to form a trivariate outcome, the signal for association became weaker (adjusted p-value = 0.015).

More detailed results for the joint analysis of *Y*_{cig-day} and *Y*_{smk-yr} are given in Figure 1 and Table 5. The final optimal tree (Figure 1), which summarized the joint effect of 4 SNPs selected from the 17 candidate ones, defined a risk factor with 5 categories. We also used the GEE method to obtain the naïve estimation of OR for each risk category (using the category with the most subjects as the baseline) after adjusting for other covariates (prostate cancer status and age groups). These are summarized in Table 5. Those OR estimates and their associated confidence intervals were biased since the risk factor was defined to fit the outcome. As a comparison, the final tree model for the analysis of all three phenotypes (*Y*_{cig-day},*Y*_{smk-yr}, and *Y*_{smk-age}) is shown in Web Figure 1.

Because of the lack of understanding of the underlying etiology and the uncertain nosology of complex traits, usually several phenotypic measures are obtained for the complex trait under study, with no single phenotypic measurement fully quantifying the complicated characteristics of the complex trait. An attractive tactic in these situations is to combine the relevant phenotypes into a single multivariate trait. We propose a partial linear tree-based regression model to study the joint effect of a given set of markers on a multivariate outcome while allowing for adjustment for the effect of covariates. Within the model, the joint effect is approximated by a nonparametric tree structure that is more flexible than the standard linear modeling approach. The new method provides a novel multilocus association test for multivariate outcomes. It can be useful in the setting of candidate gene association studies, where the main goal is to establish the association between the outcome and the candidate gene. It can also be useful in pathway analysis, where one evaluates the association between the outcome and a panel of genes in the pathway.

The proposed model leverages on the well-established GEE framework and thus can be used to study such types of multivariate outcomes as continuous and binary. Unlike the existing tree-based model for multivariate outcome, the proposed method can formally test the statistical significance of the joint effect, captured by the tree model, while adjusting for the covariates’ effects linearly. Zhang and Singer (1999) suggested another way of adjusting for the covariates in the tree model framework by using them on top of the tree. It would be interesting to compare different ways of covariate adjustment in the tree-framework.

Compared with the univariate PLTR, the multivariate extension gains its efficiency by combining information from multiple outcomes under the assumption that there is a common latent risk factor underlying all the considered univariate outcomes (but allowing the effect from a given risk category to vary across different phenotypes). This multivariate approach becomes less effective if the assumption is violated. For example, in a candidate gene association study of a bivariate trait (*Y*_{1} , *Y*_{2}), if only *Y*_{1} is related to the gene under study, but not *Y*_{2} , an analysis of the bivariate outcome will be less powerful than a univariate analysis of *Y*_{1}, since the inclusion of *Y*_{2} only introduces noise and increases the degrees of freedom (if coefficients are allowed to vary across outcomes). Thus caution is needed when selecting multiple outcomes to study jointly. Finally, we would like to point out that the application of our new method is not limited to genetic association studies. The proposed model provides an effective inference procedure for testing the relationship between a multivariate outcome and any set of potential risk factors, and it could be useful in many other biomedical research settings.

This research utilized the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, Maryland, USA (http://biowulf.nih.gov). The work of K Yu, Q Li, N Caporaso, and N Chatterjee was supported in part by the Intramural Program of the NIH and the National Cancer Institute. The work of Q Li was also partially supported by the National Science Foundation of China, No. 10371126. AW Bergen was supported by U01 DA020830.

**Supplementary Materials** Web Appendices, Tables, and Figures referenced in Sections 3, 4 and 5 are available under the Paper Information link at the *Biometrics* website http://www.biometrics.tibs.org.

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