Suppose we want to know whether a drug is safe or effective for humans, but do not have data on what it does in humans, only on its effects in mice, rats, rhesus macaques and chimpanzees. In general, we can predict the effect of the drug on humans better with the animal data than without it. Information on “nearby” realisations of a random variable (effect of the drug) helps predict the realisation we are interested in. The method should weight nearby observations more than observations further away when predicting. For example, if the drug has a positive effect in animals, then predicts a positive effect in humans, and the larger the effect in animals, the greater the predicted effect in humans.
A limitation of weighting is that it does not take into account the slope of the effect when moving from further observations to nearer. For example, a very large effect of the drug in mice and rats but a small effect in macaques and chimpanzees predicts the same effect in humans as a small effect in rodents and a large one in monkeys and apes, if the weighted average effect across animals is the same in both cases. However, intuitively, the first case should have a smaller predicted effect in humans than the second, because moving to animals more similar to humans, the effect becomes smaller in the first case but larger in the second. The idea is similar to a proportional integral-derivative (PID) controller in engineering.
The slope of the effect of the drug is extra information that increases the predictive power of the method if the assumption that the similarity of effects decreases in genetic distance holds. Of course, if this assumption fails in the data, then imposing it may result in bias.
Assumptions may be imposed on the method using constrained estimation. One constraint is the monotonicity of the effect in some measure of distance between observations. The method may allow for varying weights by adding interaction terms (e.g., the effect of the drug times genetic similarity). The interaction terms unfortunately require more data to estimate.
Extraneous information about the slope of the effect helps justify the constraints and reduces the need for adding interaction terms, thus decreases the data requirement. An example of such extra information is whether the effects of other drugs that have been tested in these animals as well as humans were monotone in genetic distance. Using information about these other drugs imposes the assumption that the slopes of the effects of different drugs are similar. The similarity of the slopes should intuitively depend on the chemical similarity of the drugs, with more distant drugs having more different profiles of effects across animals.
The similarity of species in terms of the effects drugs have on them need not correspond to genetic similarity or the closeness of any other observable characteristic of these organisms, although often these similarities are similar. The similarity of interest is how similar the effects of the drug are across these species. Estimating this similarity based on the similarity of other drugs across these animals may also be done by a weighted regression, perhaps with constraints or added interaction terms. More power for the estimation may be obtained from simultaneous estimation of the drug-effect-similarity of the species and the effect of the drug in humans. An analogy is demand and supply estimation in industrial organisation where observations about each side of the market give information about the other side. Another analogy is duality in mathematics, in this case between the drug-effect-similarity of the species and the given drug’s similarity of effects across these species.
The similarity of drugs in terms of their effects on each species need not correspond to chemical similarity, although it often does. The similarity of interest for the drugs is how similar their effects are in humans, and also in other species.
The inputs into the joint estimation of drug similarity, species similarity and the effect of the given drug in humans are the genetic similarity of the species, the chemical similarity of the drugs and the effects for all drug-species pairs that have been tested. In the matrix where the rows are the drugs and the columns the species, we are interested in filling in the cell in the row “drug of interest” and the column “human”. The values in all the other cells are informative about this cell. In other words, there is a benefit from filling in these other cells of the matrix.
Given the duality of drugs and species in the drug effect matrix, there is information to be gained from running clinical trials of chemically similar human-use-approved drugs in species in which the drug of interest has been tested but the chemically similar ones have not. The information is directly about the drug-effect-similarity of these species to humans, which indirectly helps predict the effect of the drug of interest in humans from the effects of it in other species. In summary, testing other drugs in other species is informative about what a given drug does in humans. Adapting methods from supply and demand estimation, or otherwise combining all the data in a principled theoretical framework, may increase the information gain from these other clinical trials.
Extending the reasoning, each (species, drug) pair has some unknown similarity to the (human, drug of interest) pair. A weighted method to predict the effect in the (human, drug of interest) pair may gain power from constraints that the similarity of different (species, drug) pairs increases in the genetic closeness of the species and the chemical closeness of the drugs.
Define Y_{sd} as the effect of drug d in species s. Define X_{si} as the observable characteristic (gene) i of species s. Define X_{dj} as the observable characteristic (chemical property) j of drug d. The simplest method is to regress Y_{sd} on all the X_{si} and X_{dj} and use the coefficients to predict the Y_{sd} of the (human, drug of interest) pair. If there are many characteristics i and j and few observations Y_{sd}, then variable selection or regularisation is needed. Constraints may be imposed, like X_{si}=X_i for all s and X_{dj}=X_j for all d.
Fused LASSO (least absolute shrinkage and selection operator), clustered LASSO and prior LASSO seem related to the above method.