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January 25, 2007
DIMACS - Complex networks and their applications (Day 3)
The third day of the workshop focused on applications to biochemical networks (no food webs), with a lot of that focus being on the difficulties of taking fuzzy biological data (e.g., gene expression data) and converting it into an accurate and meaningful form for further analysis or for hypothesis testing. Only a few of the talks were theoretical, but this perhaps reflects the current distribution of focus in biology today. After the workshop was done, I wondered just how much information crossed between the various disciplines represented at the workshop - certainly, I came away from it with a few new ideas, and a few new insights from the good talks I attended. And I think that's the sign of a successful workshop.
Complex Networks in Biology
Chris Wiggins (Columbia) delivered a great survey of interesting connections between machine learning and biochemical networks. It's probably fair to say that biologists are interested in constructing an understanding of cellular-level systems that compares favorably to an electrical engineer's understanding of circuits (Pointer: Can a Biologist Fix a Radio?). But, this is hard because living stuff is messy, inconsistent in funny ways, and has a tendency to change while you're studying it. So, it's harder to get a clean view of what's going on under the hood than it was with particle physics. This, of course, is where machine learning is going to save us - ML offers powerful and principled ways to sift through (torture) all this data.
The most interesting part of his talk, I think, was his presentation of NetBoost, a mechanism discriminator that can tell you which (among a specific suite of existing candidates) is the most likely to have generated your observed network data [1]. For instance, was it preferential attachment (PA) or duplication-mutation-complementation (DMC) that produced a given protein-interaction network (conclusion: the latter is better supported). The method basically works by constructing a decision tree that looks at the subgraph decomposition of a network and scores it's belief that each of the various mechanisms produced it [2]. With the ongoing proliferation of network mechanisms (theorists really don't have enough to do these days), this kind of approach serves as an excellent way to test a new mechanism against the data it's supposed to be emulating.
One point Chris made that resonated strongly with me - and which Cris and Mark made yesterday - is the problem with what you might call "soft validation" [3]. Typically, a study will cluster or do some other kind of analysis with the data, and then tell a biological story about why these results make sense. On the other hand, forcing the clustering to make testable predictions would be a stronger kind of validation.
Network Inference and Analysis for Systems Biology
Just before lunch, Joel Bader (Johns Hopkins) gave a brief talk about his work on building a good view of the protein-protein interaction network (PPIN). The main problems with this widely studied data are the high error rate, both for false positives (interactions that we think exist, but don't) and false negatives (interactions that we think don't exist, but do). To drive home just how bad the data is, he pointed out that two independent studies of the human PPIN showed just 1% overlap in the sets of "observed" interactions.
He's done a tremendous amount of work on trying to improve the accuracy of our understanding of PPINs, but here he described a recent approach that fits degree-based generative models [4] to the data using our old friend expectation-maximization (EM) [5]. His results suggest that we're seeing about 30-40% of the real edges, but that our false positive rate is about 10-15%. This is a depressing signal-to-noise ratio (roughly 1%), because the number of real interactions is O(n), while our false positive rate is O(n^2). Clearly, the biological methods used to infer the interactions need to be improved before we have a clear idea of what this network looks like, but it also suggests that a lot of the previous results on this network are almost surely wrong. Another question is whether it's possible to incorporate these kinds of uncertainties into our analyses of the network structure.
Activating Interaction Networks and the Dynamics of Biological Networks
Meredith Betterton (UC-Boulder) presented some interesting work on signaling and regulatory networks. One of the more surprising tidbits she used in her motivation is the following. In yeast, the mRNA transcription undergoes a consistent 40-minute genome-wide oscillation, but when exposed to an antidepressant (in this case, phenelzine), the period doubles [6]. (The fact that gene expression oscillates like this poses another serious problem for the results of gene expression analysis that doesn't account for such oscillations.)
The point Meredith wanted to drive home, though, was we shouldn't just think of biochemical networks as static objects - they also represent the form that the cellular dynamics must follow. Using a simple dynamical model of activation and inhibition, she showed that the structure (who points to who, and whether an edge inhibits or activates its target) of a real-world circadian rhythm network and a real-world membrane-based signal cascade basically behave exactly as you would expect - one oscillates and the other doesn't. But, then she showed that it only takes a relatively small number of flips (activation to inhibition, or vice versa) to dramatically change the steady-state behavior of these cellular circuits. In a sense, this suggests that these circuits are highly adaptable, given a little pressure.
There are several interesting questions that came to mind while she was presenting. For instance, if we believe there are modules within the signaling pathways that accomplish a specific function, how can we identify them? Do sparsely connected dense subgraphs (assortative community structure) map onto these functional modules? What are the good models for understanding these dynamics, systems of differential equations, discrete time and matrix multiplication, or something more akin to a cellular version of Ohm's Law? [7]
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[1] M. Middendorf, E. Ziv and C. Wiggins, "Inferring Network Mechanisms: The Drosophila melanogaster Protein Interaction Network." PNAS USA 102 (9), 3192 (2005).
[2] Technically, it's using these subgraphs as generic features and then crunching the feature vectors from examples of each mechanism through a generalized decision tree in order to learn how to discriminate among them. Boosting is used within this process in order to reduce the error rates. The advantage of this approach to model selection and validation, as Chris pointed out, is that it doesn't assume a priori which features (e.g., degree distribution, clustering coefficient, distance distribution, whatever) are interesting, but rather chooses the ones that can actually discriminate between things we believe are different.
[3] Chris called it "biological validation," but the same thing happens in sociology and Internet modeling, too.
[4] I admit that I'm a little skeptical of degree-based models of these networks, since they seem to assume that we're getting the degree distribution roughly right. That assumption is only reasonable if our sampling of the interactions attached to a particular vertex is unbiased, which I'm not sure about.
[5] After some digging, I couldn't find the reference for this work. I did find this one, however, which illustrates a different technique for a related problem. I. Iossifov et al., "Probabilistic inference of molecular networks from noisy data sources."
[6] C. M. Li and R. R. Klevecz, "A rapid genome-scale response of the transcriptional oscillator to perturbation reveals a period-doubling path to phenotypic change." PNAS USA 103 (44), 16254 (2006).
[7] Maribeth Oscamou pointed out to me during the talk that any attempt to construct such rules have to account for processes like the biochemical degradation of the signals. That is, unlike electric circuits, there's no strict conservation of the "charge" carrier.
posted January 25, 2007 01:20 PM in Scientifically Speaking | permalink