Abstract
The inverse Ising problem and its generalizations to Potts and continuous spin models have recently attracted much attention thanks to their successful applications in the statistical modeling of biological data. In the standard setting, the parameters of an Ising model (couplings and fields) are inferred using a sample of equilibrium configurations drawn from the Boltzmann distribution. However, in the context of biological applications, quantitative information for a limited number of microscopic spins configurations has recently become available. In this paper, we extend the usual setting of the inverse Ising model by developing an integrative approach combining the equilibrium sample with (possibly noisy) measurements of the energy performed for a number of arbitrary configurations. Using simulated data, we show that our integrative approach outperforms standard inference based only on the equilibrium sample or the energy measurements, including error correction of noisy energy measurements. As a biological proofofconcept application, we show that mutational fitness landscapes in proteins can be better described when combining evolutionary sequence data with complementary structural information about mutant sequences.
Introduction
Highdimensional data characterizing the collective behavior of complex systems are increasingly available across disciplines. A global statistical description is needed to unveil the organizing principles ruling such systems and to extract information from raw data. Statistical physics provides a powerful framework to do so. A paradigmatic example is represented by the Ising model and its generalizations to Potts and continuous spin variables, which have recently become popular for extracting information from largescale biological datasets. Successful examples are as different as multiplesequence alignments of evolutionary related proteins^{1,2,3}, geneexpression profiles^{4}, spiking patterns of neural networks^{5,6}, or the collective behavior of bird flocks^{7}. This widespread use is motivated by the observation that the least constrained (i.e. maximumentropy^{8}) statistical model reproducing empirical singlevariable and pairwise frequencies observed in a list of equilibrium configurations is given by a Boltzmann distribution:
with s = (s_{1},..., s_{N}) being a configuration of N binary variables or ‘spins’. Inferring the couplings J = {J_{ij}}_{1≤i<j≤N} and fields h = {h_{i}}_{1≤i≤N} in the Hamiltonian from data, known as the inverse Ising problem, is computationally hard for large systems (N ≫ 1). It involves the calculation of the partition function as a sum over an exponential number of configurations. The need to develop efficient approximate approaches has recently triggered important work within the statisticalphysics community, cf. e.g. refs 9, 10, 11, 12, 13, 14, 15, 16, 17.
Despite the broad interest in inverse problems, the methodological setting has remained rather limited: all of this literature, including the biological cases mentioned in the beginning, seeks to estimate model parameters starting from a set of configurations s, which are considered to be at equilibrium and independently drawn from P(s). Real data, however, may be quite different. In biological systems, “microscopic spins configurations” (e.g. aminoacid sequences) are increasingly accessible to experimental techniques, and quantitative information for a limited number of particular configurations (e.g. threedimensional structures, measured activities or thermodynamic stabilities for selected proteins) is frequently available. It seems reasonable to actually integrate such information into the inverse Ising problem instead of ignoring it. In this work, we use two different types of data (cf. Fig. 1):

As in the standard inverse Ising problem, part of the data comes as a sample of equilibrium configurations assumed to be drawn from the Boltzmann distribution to be inferred.

The second data source is a collection of arbitrary configurations together with noisy measurements of their energy.
These data sets are limited in size and accuracy. Therefore an optimized integration of both data types is expected to improve the overall performance as compared to the individual use of one single data set.
The inspiration to develop this new integrative framework for the inverse Ising problem is taken from protein fitness landscapes in biology, which provide a quantitative mapping from any aminoacid sequence s = (s_{1},..., s_{N}) to a fitness ϕ(s) measuring the ability of the corresponding protein to perform its biological function. Fitness landscapes are of outstanding importance in evolutionary and medical biology, but it appears impossible to deduce a protein’s fitness from its sequence only. Experimental or computational approaches exploiting other data are urgently needed.
Information about fitness landscapes can be found in the aminoacid statistics observed in natural protein sequences, which are related to the protein of interest. In fact they represent diverse but functional configurations sampled by evolution. It has been recently proposed that their statistical variability can be captured by Potts models (generalization of the Ising model to 21state aminoacid variables). Indeed, statistical models inferred from large collections of natural sequences have recently led to good predictions of experimentally measured effects^{18,19,20,21}: in a number of systems, the fitness cost Δϕ(s) ≡ ϕ(s) − ϕ(s^{ref}) of mutating any amino acid in a reference protein s^{ref} strongly correlates with the corresponding energy changes in the inferred statistical model,
suggesting that the Hamiltonian of the inferred models is strictly related to the underlying mutational landscapes.
While evolutionary diverged sequences can be regarded as a global sample of the fitness landscape, further information can be obtained from direct measurements on particular ‘microstates’ of the system, i.e. individual protein sequences. Recent advances in experimental technology allow for conducting largescale mutagenesis studies: in a typical experiment, a reference protein of interest is chosen, and a large number (10^{3}–10^{5}) of mutant proteins (having sequences differing by one or few amino acids from the reference) are synthesized and then characterized in terms of fitness. This provides a systematic local measurement of the fitness landscape^{22,23,24}. Regression analysis may be used to globally model mutational landscapes^{25}. A secondorder parameterization of ϕ arises naturally in this context, when considering an expansion of effects in terms of independent additive effects and pairwise ‘epistatic’ interactions between sites^{26},
However, the number of accessible mutant sequences remains small compared to the number of terms in this sum, and mutagenesis data alone are not sufficient to faithfully model fitness landscapes^{27}.
In situations where no single dataset is sufficient for accurate inference, integrative methods accounting for complementary data sources will improve the accuracy of computational predictions. In this paper, (i) we define a generalized inference framework based on the availability of an equilibrium sample and of complementary quantitative information; (ii) we propose a Bayesian integrative approach to improve over the limited accuracy obtainable using standard inverse problems; (iii) we demonstrate the practical applicability of our method in the context of predicting mutational effects in proteins, a problem of outstanding biomedical importance for questions related to genetic disease and antibiotic drug resistance.
Results
An integrated modeling
The inference setting
Inspired by this discussion, we consider two different datasets originating from a true model . The first one, D_{eq} = {s^{1},..., s^{M}}, is a collection of M equilibrium configurations independently drawn from the Boltzmann distribution P^{0}(s). For simplicity, we consider binary variables s_{i} ∈ {0, 1}, corresponding to a “latticegas” representation of the Ising model in Eq. (1). This implies that energies are measured with respect to the reference configuration s^{ref} = (0,..., 0). The standard approach to the inverse Ising problem uses only this type of data to infer parameters of : couplings and fields in Eq. (1) are fitted so that the inferred model reproduces the empirical single and pairwise frequencies,
The second dataset provides a complementary source of information, which shall be modeled as noisy measurements of the energies of a set of P arbitrary (i.e. not necessarily equilibrium) configurations σ^{a}. These data are collected in the dataset D_{E} = {(E^{a}, σ^{a})_{a=1,...,P}}, with
The noise ξ^{a} models measurement errors or uncertainties in mapping measured quantities to energies of the Ising model. For simplicity, we consider ξ^{a} to be white Gaussian noise with zero mean and variance Δ^{2}: 〈ξ^{a}ξ^{b}〉 = δ_{a,b}Δ^{2}.
As schematically represented in Fig. 1, datasets D_{eq} and D_{E} constitute different sources of information about the energy landscape defined by Hamiltonian . Observables in Eq. (4) are empirical averages computed from equilibrium configurations in D_{eq}, providing global information about the energy landscape. On the contrary, configurations in D_{E} are arbitrarily given, and a (noisy) measurement of their energies provides local information on particular points in the landscape.
A maximumlikelihood approach
To infer the integrated model, we consider a joint description of the probabilities of the two data types for given parameters J and h of tentative Hamiltonian . The probability of observing the sampled configurations in D_{eq} equals the product of the Boltzmann probability of each configuration,
To derive an analogous expression for the second dataset, we integrate over the Gaussian distribution of the noise obtaining a Gaussian probability of the energies (remember configurations in D_{E} are arbitrarily given):
The combination of these expressions provides the joint loglikelihood for the model parameters given the data:
Maximizing the above likelihood with respect to parameters {h_{i}}_{1≤i≤N} and {J_{ij}}_{1≤i<j≤N} leads to the following selfconsistency equations:
with , being single and pairwise averages in the model Eq. (1). We have introduced the parameter : in practical applications, the error Δ may not be known, and the parameter 0 ≤ λ < 1 allows to weigh data sources differently. For λ = 0 (i.e. large noise), the standard inverse Ising problem is recovered: optimal parameters are such that the model exactly reproduces magnetizations and correlations of the sample. For λ > 0, the second dataset containing quantitative data is taken into account: whenever energies computed from the Hamiltonian do not match the measured ones, the model statistics deviates from the sample statistics. Both loglikelihood terms in (8) are concave, and thus their sum: Eq. (9) has a unique solution.
Noiseless measurements
The case of noiseless energy measurements in Eq. (5) (i.e. λ → 1) has to be treated separately. First, energies have to be perfectly fitted by the model, by solving the following linear problem:
where we have introduced a N(N + 1)/2 dimensional vectorial representation of the model parameters, and contains the exactly measured energies. The matrix
specifies which parameters contribute to the energies of configurations in the second dataset. If K = N(N + 1)/2 − rank(X) > 0, the parameters cannot be uniquely determined from the measurements: The sample D_{eq} can be used to remove the resulting degeneracy. To do so, we parametrize the set of solutions of Eq. (10) as follows:
where is any particular solution of the non homogeneous Eq. (10), and a basis of observables spanning the null space of the associated homogeneous problem . The free parameters can be fixed by maximizing their likelihood given sample D_{eq},
with . The maximization provides conditions for the observables (k = 1,..., K),
Equation (14) shows that the α_{k} have to be fixed such that empirical averages equal model averages . Any possible sparsity of the matrix of measured configurations X (entries are 0 or 1 by definition) can be exploited to find a sparse representation of the . In the protein example discussed above, mutagenesis experiments typically quantify all possible singleresidue mutations of a reference sequence (denoted (0,..., 0) without loss of generality). In this case, the pairwise quantities s_{i}s_{j} with 1 < i < j < N can be chosen as the basis of the null space. A particular solution of the nonhomogeneous system (10) is given by the paramagnetic Hamiltonian , with E^{i} being the energy shift due to spin flip .
Artificial data
We first evaluate our method on artificial data (Materials and Methods). Random couplings J^{0} and fields h^{0} are chosen for a system of N = 32 spins. Dataset D_{eq} is created by Markov chain Monte Carlo (MCMC) sampling, resulting in M = 100 equilibrium configurations. To mimic a protein ‘mutagenesis’ experiment, one of these configurations is chosen at random as the reference sequence, and the energies of all N configurations differing by a single spin flip from the reference (thereafter referred to as single mutants) are calculated, resulting in dataset D_{E} (after adding noise of standard deviation Δ_{0}). Datasets D_{E} and D_{eq} will subsequently called “local” and “global” data respectively.
Equations (9) are solved using steepest ascent, updating parameters J and h in direction of the gradient of the joint loglikelihood (8). Since the noise Δ_{0} may not be known in practical applications, we solve the equations for several values of λ ∈ [0, 1], weighing data sources differently. We expect the optimal inference to take place at a value λ that maximizes the likelihood in Eq. (8), i.e. . For λ = 0, this procedure is equivalent to the classical Boltzmann machine^{28}, but for λ > 0, the term corresponding to the quantitative essay constrains energies of sequences in D_{E} to stay close to the measurements. As explained above, the case λ = 1 has to be treated separately; a similar gradient ascent method is used. Since exact calculations of gradients are computationally hard, the meanfield approximation is used (Materials and Methods).
To evaluate the accuracy of the inference, most of the existing literature on the inverse Ising modeling simply compares the inferred parameters with the true ones. However, a low error in the estimation of each inferred parameter does not guarantee that the inferred distribution matches the true one. On the contrary, in the case of a high susceptibility of the statistics with respect to parameter variations, or if the estimation of parameters is biased, the distributions of the inferred and true models could be very different even for small errors on individual parameters. For this reason, we introduce two novel evaluation procedures. First, to estimate the accuracy of the model on a local region of the configuration space, we test its ability to reproduce energies of configurations in D_{E}. Then, we estimate the global similarity of true and inferred distributions using a measure from information theory.
Error correction of local data
We first test the ability of our approach to predict the true singlemutant energies, when noisy measurements are presented in D_{E}, i.e. to correct the measurement noise using the equilibrium sample D_{eq}. For every λ, J and h are inferred and used to compute predicted energies of the N configurations in D_{E}. The linear correlation between such predicted energies (measured with the inferred Hamiltonian) and the true energies (measured with the true Hamiltonian) is plotted as a function of λ in Fig. 2.
In the very low noise regime, , the top curve in Fig. 2 reaches its peak at , which is expected as local data is then sufficient to accurately “predict” energies from single mutants. On the contrary, in the high noise regime, the maximum is located close to λ = 0, pointing to the fact that local data is of little use in this case. Between those two extremes, an optimal integration strength can be found, yielding a better prediction of energies in D_{E} as for any of the datasets taken individually. It is interesting to notice that even for highly noisy data, integrating the two sources of information with the right weight λ results in an improved modeling.
The insert of Fig. 2 shows the integration strength λ at which the best correlation is reached, against the corresponding theoretical value for different realizations. On average, optimal integration is reached close to the theoretical case of equation (8). This result highlights the possibility of using this integrative approach to correct measurement errors in the energies of single mutants. If a dataset such as D_{eq} provides global information about the energy landscape, and the measurement noise Δ_{0} can be estimated, an appropriate integration can then be used to infer more accurately the energies of the single mutants.
Global evaluation of the inferred Ising model
To assess the ability of our integrative procedure to provide a globally accurate model, we use the KullbackLeibler divergence D_{KL}(P^{0}P) between the true model and the inferred (Materials and Methods). The symmetric expression
simplifies to the average difference between true and inferred energies. It can be consistently estimated using MCMC samples D (resp. D^{0}) drawn from P (resp. P^{0}), without the need to calculate the partition functions. Σ(P^{0}, P) has an intuitive interpretation in terms of distinguishability of models: It represents the logodds ratio between the probability to observe samples D and D^{0} in their respective generating models, and the corresponding probability with models and swapped:
where M_{K} is the number of sampled configurations in and D^{0}.
The inferred model undoubtedly benefits from the integration, as a minimal divergence between the generating and the inferred probability distributions is found for an intermediate value of λ, outperforming both datasets taken individually (Fig. 3). It has to be noted that even in the noiseless case Δ_{0} = 0, the minimum in Σ(P^{0}, P) obtained at λ = 1 depends crucially on the availability of the equilibrium sample D_{eq}. The local data D_{E} are not sufficient to fix uniquely all model parameters, and the degeneracy in parametrization is resolved using D_{eq} as explained at the end of Sec. 0.
As a comparison, the same analysis is done using an independent modeling that uses only fields h, and no couplings. The inset of Fig. 3 clearly shows that the pairwise modeling outperforms the independent one. Even the limit λ → 1, where D_{eq} becomes irrelevant in the independent model, the performance of the integrative pairwise scheme is not attained.
Biological data
To demonstrate the practical utility of our integrative framework, we apply it to the challenging problem of predicting the effect of aminoacid mutations in proteins. To do so, we use three types of data: (i) Multiplesequence alignments (MSA) of homologous proteins containing large collections of sequences with shared evolutionary ancestry and conserved structure and function; they are obtained using HMMer^{29} using profile models from the Pfam database^{30}. Due to their considerable sequence divergence (typical Hamming distance ~0.8N), they provide a global sampling of the underlying fitness landscape. (ii) Computational predictions of the impact of all single aminoacid mutations on a protein’s structural stability^{31} are used to locally characterize the fitness landscape around a given protein. The noise term ξ^{a} represents the limited accuracy of this predictor, and the uncertainty in using structural stability as a proxy of protein fitness. (iii) Mutagenesis experiments have been used before to simultaneously quantify the fitness effects of thousands of mutants^{22,23}. While datasets (i) and (ii) play the role of D_{eq} and D_{E} in inference, dataset (iii) is used to assess the quality of our predictions (ideally one would use the most informative datasets (i) and (iii) to have maximally accurate predictions, but no complementary dataset to test predictions would be available in that case).
To apply the inference scheme to such protein data, three modifications with respect to simulated data are needed. First, the relevant description in this case is a 21state Potts Model (Supporting Information), since each variable s_{i}, i = 1,..., N, can now assume 21 states (20 amino acids, one alignment gap)^{32}. Second, since measured fitnesses and model energies are found in a monotonous nonlinear relation, we have used the robust mapping introduced in ref. 18 (reviewed in the Supporting Information). Third, since correlations observed in MSA are typically too strong for the MF approximation to accurately estimate marginals, we relied on Markov Chain Monte Carlo (Materials and Methods), which has recently been shown to outperform other methods in accuracy of inference for proteinsequence data^{33,34}.
We have tested our approach for predicting the effect of single aminoacid mutations in two different proteins: the βlactamase TEM1, a bacterial enzyme providing antibiotic resistance, and the PSD95 signaling domain belonging to the PDZ family. In both systems computational predictions can be tested against recent highthroughput experiments quantifying the invivo functionality of thousands of protein variants^{22,23}. Figure 4 shows the Pearson correlations between inferred energies and measured fitnesses as a function of the weight λ: Maximal accuracy is achieved at finite values of λ when both sources of information are combined, significantly increasing the predictive power of the models inferred considering the statistics of homologs only (λ = 0). When repeating the integrated modeling with a paramagnetic model where all sites are treated independently, (only singlesite frequencies are fitted in this case) the predictive power drops as compared to the Potts model, cf. the red lines in Fig. 4.
Conclusion
In this paper, we have introduced an integrative Bayesian framework for the inverse Ising problem. In difference to the standard setting, which uses only a global sample of independent equilibrium configurations to reconstruct the Hamiltonian of an Ising model, we also consider a local quantification of the energy function around a reference configuration. Using simulated data, we show that the integrated approach outperforms inference based on each single dataset alone. The gain over the standard setting of the inverse Ising problem is particularly large when the equilibrium sample is too small to allow for accurate inference.
This undersampled situation is particularly important in the context of biological data. The prediction of mutational effects in proteins is of enormous importance in various biomedical applications, as it could help understanding complex and multifactorial genetic diseases, the onset and the proliferation of cancer, or the evolution of antibiotic drug resistance. However, the sequence samples provided by genomic databases, like the multiplesequence alignments of homologous proteins considered here, are typically of limited size, including even in the most favorable situations rarely more than 10^{3}–10^{5} alignable sequences. Fortunately, such sequence data are increasingly complemented by quantitative mutagenesis experiments, which use experimental highthroughput approaches to quantify the effect of thousands of mutants. While it might be tempting to use these data directly to measure mutational landscapes from experiments, it has to be noted that current experimental techniques miss at least 2–3 orders of magnitude in the number of measurable mutants to actually reconstruct the mutational landscape.
In such situations, where no single dataset is sufficient for accurate inference, integrative methods like the one proposed here will be of major benefit.
Methods
Data
Artificial data
For a system of N = 32 binary spins, couplings J^{0} and fields h^{0} are chosen from a Gaussian distribution with zero mean, and standard deviation for J and 0.2 for h (analogous results are obtained for other parameter choices, as long as these correspond to a paramagnetic phase). Dataset D_{eq} is created by Markov chain Monte Carlo (MCMC) simulation, resulting in M = 100 equilibrium configurations. A large number (~10^{5}) of MCMC steps are done between each of those configurations to ensure that they are independent. One of these configurations is chosen at random as the reference sequence (“wildtype”), and the energies of all N configurations differing by a single spin flip from the reference are computed (“single mutants”). Gaussian noise of variance can be added to these energies, resulting in dataset D_{E}.
Biological data
Detailed information about the analysis of biological data is provided in the Supporting Information.
Details of the inference
For artificial data, Eq. (9) are solved using steepest ascent, updating parameters J and h in direction of the gradient. To ensure convergence, we have added an additional regularization to the joint likelihood: . A gradient ascent method has been analogously used for the case λ = 1. To estimate the gradient, it is necessary to compute single and pairwise probabilities p_{i}(J, h) and p_{ij}(J, h). Their exact calculation requires summation over all possible configurations of N spins, which is intractable even for systems of moderate size N, so we relied on the following approximation schemes.
Meanfield inference
In the analysis of artificial data we relied on the meanfield approximation (MF) leading to closed equations for p_{i} and p_{ij}:
The main advantage of the MF approximation is its computational efficiency: The first term is solved by an iterative procedure, the second requires the inversion of the couplings matrix J. However, the approximation is only valid and accurate at “high temperatures”, i.e. small couplings^{35}. This condition is verified in the case of the artificial data described above.
MCMC inference
Correlations observed in MSA of protein sequences are typically too strong for the MF approximation to accurately estimate marginals of the model. Therefore we use MCMC sampling of M^{MC} = 10^{4} independent equilibrium configurations to estimate marginals at each iteration of the previously described learning protocol.
Global evaluation of the inferred Ising model
The KullbackLeibler divergence is a measure of the difference between probability distributions P and Q. It is zero for P ≡ Q, and otherwise positive. In the case of Boltzmann distributions and , its expression simplifies to
Evaluating this expression requires the exponential computation of the partition function of both models and . To overcome this difficulty, we use the symmetrized expression in Eq. (15), which only involves the average of macroscopic observables.
The symmetrized KullbackLeibler divergence is computed by obtaining M_{K} = 128000 equilibrium configurations from both P and Q, using them to estimate the averages in Eq. (15).
Additional Information
How to cite this article: BarratCharlaix, P. et al. Improving landscape inference by integrating heterogeneous data in the inverse Ising problem. Sci. Rep. 6, 37812; doi: 10.1038/srep37812 (2016).
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Acknowledgements
MW acknowledges funding by the ANR project COEVSTAT (ANR13BS04 001201). This work undertaken partially in the framework of CALSIMLAB, supported by the grant ANR11LABX003701 as part of the “Investissements d’ Avenir” program (ANR11IDEX000402).
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M.F. and M.W. designed research; P.B.C., M.F. and M.W. performed research; P.B.C. and M.F. analyzed data; and P.B.C., M.F. and M.W. wrote the paper.
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BarratCharlaix, P., Figliuzzi, M. & Weigt, M. Improving landscape inference by integrating heterogeneous data in the inverse Ising problem. Sci Rep 6, 37812 (2016). https://doi.org/10.1038/srep37812
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