Annual International Conference on Research in Computational Molecular Biology

RECOMB 2007: Research in Computational Molecular Biology pp 503-517

An Efficient and Accurate Graph-Based Approach to Detect Population Substructure

  • Srinath Sridhar
  • Satish Rao
  • Eran Halperin
Conference paper

DOI: 10.1007/978-3-540-71681-5_35

Volume 4453 of the book series Lecture Notes in Computer Science (LNCS)
Cite this paper as:
Sridhar S., Rao S., Halperin E. (2007) An Efficient and Accurate Graph-Based Approach to Detect Population Substructure. In: Speed T., Huang H. (eds) Research in Computational Molecular Biology. RECOMB 2007. Lecture Notes in Computer Science, vol 4453. Springer, Berlin, Heidelberg

Abstract

Currently, large-scale projects are underway to perform whole genome disease association studies. Such studies involve the genotyping of hundreds of thousands of SNP markers. One of the main obstacles in performing such studies is that the underlying population substructure could artificially inflate the p-values, thereby generating a lot of false positives. Although existing tools cope well with very distinct sub-populations, closely related population groups remain a major cause of concern.

In this work, we present a graph based approach to detect population substructure.Our method is based on a distance measure between individuals. We show analytically that when the allele frequency differences between the two populations are large enough (in the l2-norm sense), our algorithm is guaranteed to find the correct classification of individuals to sub-populations.

We demonstrate the empirical performance of our algorithms on simulated and real data and compare it against existing methods, namely the widely used software method STRUCTURE and the recent method EIGENSTRAT. Our new technique is highly efficient (in particular it is hundreds of times faster than STRUCTURE), and overall it is more accurate than the two other methods in classifying individuals into sub-populations. We demonstrate empirically that unlike the other two methods, the accuracy of our algorithm consistently increases with the number of SNPs genotyped. Finally, we demonstrate that the efficiency of our method can be used to assess the significance of the resulting clusters. Surprisingly, we find that the different methods find population sub-structure in each of the homogeneous populations of the HapMap project. We use our significance score to demonstrate that these substructures are probably due to over-fitting.

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Copyright information

© Springer Berlin Heidelberg 2007

Authors and Affiliations

  • Srinath Sridhar
    • 1
  • Satish Rao
    • 2
  • Eran Halperin
    • 3
  1. 1.Computer Science Dept, Carnegie Mellon University 
  2. 2.Computer Science Dept, University of California, Berkeley 
  3. 3.International Computer Science Institute (ICSI), Berkeley