1. Exploring Network Inference Models Math-in-Industry Camp & Workshop: Michael Grigsby: Cal Poly, Pomona Mustafa Kesir: Northeastern University Nancy Rodriguez: University of California, Los Angeles Man Vu: Cal State University, Long Beach

2. Introduction-Problem Statement Problem proposed by Ruye Wang from Harvey Mudd College. Some biological processes are modeled by networks comprised of a group of interacting components such as genes in a gene regulatory network, neurons in the brain, or proteins. Biologists want to know how the components of the network are related and how they interact to make predictions about the behavior of a biological system.

3. Introduction Network Inference is an approach for modeling and analyzing networks composed of many interacting component units. That is, given a set of genes a biologist performs a series of experiments to test how the genes affect (excite or inhibit) one another and also determine the magnitude of that affect.

4. Introduction There are several different mathematical models for network inference each with it’s own advantages and disadvantages. One is the Boolean Network Model which simulates the components by a group of binary nodes interacting with each other that follow logical operations.

5. Introduction Another is the Linear and Quasi-Linear models that assume the components are linearly or quasi-linearly related in the network. Then there is the Differential Equation (DE) model that simulates the dynamics of the network by a system of differential equations. This is the model we studied.

6. Introduction Given a set of n nodes (genes) in the network and a set of k data points taken over time the differential equation governing the dynamics of the network is: r i v i ’ (t) + λ i v i (t) = g[Σ T im v m (t) + h i ] Where (i=1,…,n and t=1,…m) v i (t) is the observed data and the other parameters are unknown where r i is a time constant, λ i is a scaling factor, T im is a constant that describes how node m affects node i, and h i is a constant.

7. Introduction The goal is to find estimates for the n by n matrix T, along with the other unknown parameters from the observed data V i (t). However an optimal search of a O(n 2 )- dimensional space must be conducted in order to find the parameters that minimize the error. This is very computationally expensive and can realistically be done for a network with only a small number of nodes.

8. Our first Attempt rv’ + λv= g(X) Try to find a relationship between r and λ to reduce parameters. λ r λ r = f(λ)

9. But How? Given g(x), some s function with range (-1,1) g(x)= e x -1 then g’(x) Є (0,1] e x +1 rv’ + λv = g(X) rv’’ + λv = g’(X) α Є (-1,1) and β Є (0,1] a b c d rλrλ = αβαβ

10. Other Methods Most existing methods requires a heuristic approach Requires many assumptions and parallel programming Other than heuristic methods, statistical methods are viable but not feasible for large numbers of genes

11. Bayesian Networks Statistical approach for modeling gene networks Treats each gene as a random variable Joint distribution over all genes represents the cell states Goal: estimate and study the structures of the distributions 1.http://www.cs.huji.ac.il/labs/compbio/ismb01/ismb01.pdfhttp://www.cs.huji.ac.il/labs/compbio/ismb01/ismb01.pdf 2.http://www.cs.unm.edu/~patrik/networks/robust.pdfhttp://www.cs.unm.edu/~patrik/networks/robust.pdf

12. To Name a Few Boolean Networks: uses 0’s and 1’s to represent the excitation or not http://www.cs.ucdavis.edu/~filkov/classes/289a-W03/l10.pdf http://www.cs.ucdavis.edu/~filkov/classes/289a-W03/l10.pdf Differential Equation Models:  Many unknown parameters and assumptions  Nonlinear models needs to be linearized  Computationally costly for large number of genes http://www.biochemsoctrans.org/bst/031/1519/bst0311519.htm

13. Simulated Annealing 1. Let X := initial configuration 2. Let E := Energy(X) 3. Let i = random move from the Moveset 4. Let Ei := Eval(move(X,i)) 5. If E < Ei then X := move(X,i) E := Ei Else with some probability, accept the move even though things get worse: X := move(X,i) E := Ei 6. Goto 3 unless we have reached t_max Allowable moves. Choosing this is key!

14. Algorithm: Choosing (τ,λ) The domain of g -1 is (-1,1)! This is where conditions for λ come in.

15. Algorithm: Solving for T and h i.e

16. Algorithm: Decreasing Cost Tm decreases with each iteration. The more iterations the less likely you make possible “bad moves” same for change in cost.

17. Possible Area of Improvement If we had more time where would we focus?  Simulated Annealing is a good idea provided you move within your moveset intelligently.  Choosing the moveset is also important, for us g(x) helps restrict the domain of λ based on τ. How do you know the domain of τ.  Finding the derivative matrix can possibly be improved.  Recovering the data, solving the ODE.  Choosing the correct energy function.  Solving the system of algebraic equations.

18. Ideas for moving within Moveset Recall the computations: Might be better to check if λ 0 lies within the range dictated by τ 1, and compare C(λ 0, τ 1 ) to C(λ 0, τ 0 ). Neighborhood of search must be small enough.

19. When k is not big enough, i.e. when k<n; One obvious way could be:  Once we interpolate to get v i (t);  We can get as many time observations as we need, i.e. we can make k as big as necessary.

20. Another way could be: Again taking DE as the model;  We can reduce the number of nodes, i.e. get a smaller number of nodes  To get all unknowns, ,Tij, hi we need to have k=n+1 or bigger. If k<n, then eliminate (n-k-1) nodes.  It can result in a loss of important data, the way we do that is really important. Thinking of v i (t) ’s as functions, it’s possible that all n of them are linearly independent.

21. Functional Data Analysis (FDA) (*) could be extremely helpful in this manner. The thing is, in biological applications, we usually have huge n(~10000), and FDA is extremely useful in dealing with big data samples. (*) Ramsay, J. O. and Silverman, B.W. (2002) Applied functional data analysis : methods and case studies, Springer series in statistics, New York ; London : Springer (*) Ramsay, J. O. and Silverman, B.W. (2005) Functional data analysis, 2nd ed., New York : Springer Also available to view online through Claremont campus: http://site.ebrary.com/lib/claremont/docDetail.action?docID=5006429

22. Working with the DE model, one immediately notices that computational cost (O(n 2 )) is a major obstacle. As long as complexity of FDA is not as big as O(n 2 ), at does not make things any worse. (Actually, even if O(n 2 ) is fine).