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6.7.1 Numerical Examples of the Generalized Inverse As a means of motivating a simple numerical example of how the generalized inverse works, we develop a brief application to the linear model where the X X matrix is noninvertible because X is singular. In this context, the generalized inverse provides a solution to the normal equations (Campbell and Meyer 1979, p. 94), and both the tted values of Y and the residual error variance are invariant to the choice of G (Searle 1971, pp. 169 71). We use the Moore Penrose generalized inverse. Let 9 5 2 5 11 2 1 2 Y= X= 5 3 2 3 2 2.95 1 3 (Our omission of the constant term makes the numerical calculations cleaner but is not material to our points.) Applying the least squares model to these data (X is of full rank) yields the coef cient vector b = (X X) 1 X Y = (222.22, 11.89, 215.22) , tted values, Y = Xb = (11.22, 2.11, 2.78, 2.00) , and variance matrix 57283.95 1580.25 56395.06 187.65 1491.36 . = 1580.25 56395.06 1491.36 55550.62 What we call the standardized correlation matrix, a correlation matrix with standard deviations on the diagonal, is then 239.34 0.48 0.99 0.46 . Cs = 0.48 13.69 0.99 0.46 235.69 Now suppose that we have a matrix of explanatory effects that is identical to X except that we have changed the bottom left number from 2.95 to 2.99: 5 2 5 2 1 2 . X2 = 3 2 3 2.99 1 3

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k=0 The constraints imply that from Sk , either we reach Sk 1 or Sk+1 , or we remain in Sk Also, if m(p) > k0 , place p has no more effect on the behavior of the net So matrix Q of the in nitesimal generator of the net presents beyond k0 regularities that are expressed by the existence of three matrices: A0 is the transition submatrix from Sk to Sk+1 ; A1 is the transition submatrix from Sk to Sk ; A2 is the transition submatrix from Sk to Sk 1 Assume that the chain is irreducible and ergodic with a steady-state distribution and denote by k the distribution of states Sk The equilibrium equation can be rewritten for k > k0 : k A0 + k+1 A1 + k+2 A2 = 0 We want to establish a recurrence between k and k+1 .

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Rare variants (frequency of less than 1%) cannot account for a high proportion of frequently occurring ADRs, but they may play an important role in unusual ADRs, such as prolonged apnea, which occurred in fewer than 1% of patients receiving succinylcholine (Evans, 1963), or myelosuppression in about 0.3% of Caucasians receiving mercaptopurines (Weinshilboum, 2001). Polymorphic variants may account for ADRs to seldom-used drugs but will have little effect on the magnitude of ADRs. On the other hand, polymorphic variants associated with ADRs that follow the use of frequently prescribed drugs could make a substantial contribution to all ADRs. Phillips et al. recently gathered information on ADRs that were reported in two or more studies. Not surprisingly, 24 of the 27 were observed among the 200 most frequently prescribed drugs. Sixteen of the 27 (59%) drugs are metabolized by enzymes encoded by genes with known polymorphisms (Phillips et al., 2001). They could account for a high proportion of the adverse reactions to these drugs in Caucasians (Table 9.1), particularly when, as is often the case, the polymorphisms occur with a higher frequency in some population groups than the rate of ADRs.

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Using the structure of Q, A1 is invertible and A 1 is a positive matrix Consequently 1 k+1 + k A0 A 1 = k+2 A2 A 1 0 1 1 We improve this relation by de ning a sequence of increasing matrices: R0 = A0 A 1 1 and Rn+1 = A0 + Rn.

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