CRISPhieRmix: a hierarchical mixture model for CRISPR pooled screens

Timothy P Daley; Zhixiang Lin; Xueqiu Lin; Yanxia Liu; Wing Hung Wong; Lei S Qi

doi:10.1186/s13059-018-1538-6

CRISPhieRmix: a hierarchical mixture model for CRISPR pooled screens

Genome Biol. 2018 Oct 8;19(1):159. doi: 10.1186/s13059-018-1538-6.

Authors

Timothy P Daley^{1

2}, Zhixiang Lin^{3

4}, Xueqiu Lin⁵, Yanxia Liu⁵, Wing Hung Wong^{3

6}, Lei S Qi^{5

7

8}

Affiliations

¹ Department of Statistics, Stanford University, 450 Serra Mall, Stanford, 94305, USA. tdaley@stanford.edu.
² Department of Bioengineering, Stanford University, 443 Via Ortega, Stanford, 94305, USA. tdaley@stanford.edu.
³ Department of Statistics, Stanford University, 450 Serra Mall, Stanford, 94305, USA.
⁴ Present Address: Department of Statistics, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
⁵ Department of Bioengineering, Stanford University, 443 Via Ortega, Stanford, 94305, USA.
⁶ Department of Biomedical Data Science, Stanford University, 1265 Welch Road, Stanford, 94305, USA.
⁷ Department of Chemical and Systems Biology, Stanford University, 443 Via Ortega, Stanford, 94305, USA.
⁸ ChEM-H Institute, Stanford University, 443 Via Ortega, Stanford, 94305, USA.

Abstract

Pooled CRISPR screens allow researchers to interrogate genetic causes of complex phenotypes at the genome-wide scale and promise higher specificity and sensitivity compared to competing technologies. Unfortunately, two problems exist, particularly for CRISPRi/a screens: variability in guide efficiency and large rare off-target effects. We present a method, CRISPhieRmix, that resolves these issues by using a hierarchical mixture model with a broad-tailed null distribution. We show that CRISPhieRmix allows for more accurate and powerful inferences in large-scale pooled CRISPRi/a screens. We discuss key issues in the analysis and design of screens, particularly the number of guides needed for faithful full discovery.

Keywords: CRISPR activation; CRISPR interference; CRISPR screen; Local fdr; Mixture models; sgRNA design.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Algorithms
Area Under Curve
Bayes Theorem
Clustered Regularly Interspaced Short Palindromic Repeats / genetics*
Computer Simulation
Databases, Genetic
Genes, Essential
Genetic Testing*
Models, Genetic*
RNA, Guide, CRISPR-Cas Systems / genetics
ROC Curve

Substances

RNA, Guide, CRISPR-Cas Systems

Abstract

Publication types

MeSH terms

Substances

Grants and funding