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1 The historical section draws heavily on L F FIESER AND M FIESER , Natural Products Related to Phenanthrene, 3rd ed, Reinhold, NY, 1949 2 ANON , FDA Backgrounder on Conjugate Estrogens, 7/7/1905; available at http://wwwfdagov/ cder/news/cebackgroundhtm 3 J W COOK , E C DODDS AND C I HEWETT , Nature, 131, 56 (1933) 4 M S KHARASH AND M KLEINMAN , J Am Chem Soc, 65, 11 (1939) 5 S R SHELTON AND M G VAN CAMPEN , US patent 2,460,991 (1947) 6 R E ALLEN , F P PALAPOLI , E L SCHUMANN AND M G VAN CAMPEN , US patent 2,914,563 (1959) 7 G R BEDFORD AND D N RICHARDSON , Nature, 212, 733 (1966) 8 R J TOIVOLA , A J KARJALAINEN , K O A KURKELA , M-L SODERWALL , LV M KANGAS , G L.

which can be dif cult to compute accurately, particularly in the tails of the distribution Third, the solution relies on solving a nonlinear constrained maximum likelihood problem, and despite assurances that convergence occurs almost every time and that the results are robust to local minima if any exist (King 1997, pp 310 11), no formal proof is provided that the likelihood function is globally concave So one cannot rule out the possibility that the search algorithm will settle at a local optimum Fourth, King s solution uses simulation to reparameterize some of the variables, which requires a generous quantity of Pseudo-random numbers Fortunately, because King supplies the source code to his solution, it is possible to substitute alternative methods for computing some aspects of it (such as PRNGs) and to automate the replication of analysis under numerous combinations of input, options, and methods.

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Volkmar, F, Cook, E H J, Pomeroy, J, Ralmuto, G, Tanguay, P E, American Academy of Child and Adolescent Psychiatry, et al (1999) Practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders Journal of the American Academy of Child & Adolescent Psychiatry, 38(Suppl), 32S 54S Volkmar, F, Lord, C, Bailey, A, Schultz, R, & Klin, A (2004) Autism and pervasive developmental disorders Journal of Child Psychology and Psychiatry, 45, 135 170 Volpe, J J (2001) Neurobiology of periventricular leukomalacia in the premature infant Pediatric Research, 50, 553 562 von Aster, M G (1994) Developmental dyscalculia in children: Review of the literature and clinical validation Acta Paedopsychiatrica, 56, 169 178 von Aster, M G, & Shalev, R S (2007) Number development and developmental dyscalculia.

BLANCO AND H K SUNDQUIST , US patent 4,696,949 (1987) 9 D LEDNICER , S C LYSTER , B D ASPERGEN AND G W DUNCAN , J Med Chem, 9, 172, (1966) 10 C D JONES , M D JEVNIKAR , A J PIKE , L J BLACK , A R THOMPSON , J F FALCONE AND J A CLEMENS , J Med Chem, 27, 1057 (1984) 11 D GIUDICI , G ORNATI , G BRIATICO , F BUZZETI , P LOMBARDI AND F DI SALLE , J Steroid Biochem, 30, 391 (1988) 12 P N EDWARDS AND M S LARGE , US patent 4,935,437 (1990) 13 ANON , Drugs Fut, 21, 123 (1996) 14 M LANG , P BATZL , P FURET , R BOWMAN , A HAUSLER AND A S BHATNAGAR , J Steroid Biochem Mol Biol, 44, 421 (1991) 15 J.

The latter feature is of particular importance when the analysis required running thousands of replications, which at times took months of continuous computer time to complete The purpose is to test the sensitivity of King s solution to oating point error, to errors in the calculation of the bivariate normal distribution function, to search algorithm choice, and to Pseudo-random number generation (see 2) This discussion also applies the perturbation and sensitivity analyses described in 4, which highlight numerical problems and sensitivity to measurement error To examine platform dependence, we ran different versions of the program on HP-Unix and Windows, as these operating systems may vary the underlying binary arithmetic computations To test the accuracy of the bivariate normal distribution function used by EI , we substitute EI s function with a quadruple-precision function based on an extension of Drezner and Wesolowsky (1989).

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