nlme_ode running error - Githubissues

UNCcrawler commented 6 years ago

Hi, thank you for developing such a great package! I am learning your package for my modeling project. I've installed the Github version of nlmixr and RxODE. Could you please look at the error message below and tell me what was wrong? It's nlme_ode() using the theo_md example. The dynmodel() works fine, so I guess it is not an installation problem. Although I did get an error message about the xpose.nlme extension, I read from another post that this is not a problem. Another question is: how can we do naive pool fitting of multiple-dose data (each individual has different dose)? Thank you!

> library(nlmixr)
> ode <- "
+ d/dt(depot) =-KA*depot;
+ d/dt(centr) = KA*depot - KE*centr;
+ "
> dat <- read.table(system.file("examples/theo_md.txt", package = "nlmixr"), head=TRUE)
> mypar <- function(lKA, lKE, lCL)
+ {
+     KA=exp(lKA)
+     KE=exp(lKE)
+     CL=exp(lCL)
+     V = CL/KE
+ }
> 
> specs <- list(fixed=lKA+lKE+lCL~1, random = pdDiag(lKA+lCL~1),
+               start=c(lKA=0.5, lKE=-2.5, lCL=-3.2))
> fit <- nlme_ode(dat, model=ode, par_model=specs, par_trans=mypar,
+                 response="centr", response.scaler="V")
C:/Rtools/mingw_64/bin/gcc  -I"C:/PROGRA~1/R/R-35~1.0/include" -DNDEBUG          -O2 -Wall  -std=gnu99 -mtune=generic -c rx_97ee19c2b05e8b4a202d9dbdfed6d81d_x64.c -o rx_97ee19c2b05e8b4a202d9dbdfed6d81d_x64.o
C:/Rtools/mingw_64/bin/gcc -shared -s -static-libgcc -o rx_97ee19c2b05e8b4a202d9dbdfed6d81d_x64.dll tmp.def rx_97ee19c2b05e8b4a202d9dbdfed6d81d_x64.o -LC:/PROGRA~1/R/R-35~1.0/bin/x64 -lRblas -LC:/PROGRA~1/R/R-35~1.0/bin/x64 -lRlapack -lgfortran -lm -lquadmath -LC:/PROGRA~1/R/R-35~1.0/bin/x64 -lR
Error in nlme.formula(model = DV ~ (nlmixr::nlmeModList("user_fn"))(lKA,  : 
  step halving factor reduced below minimum in PNLS step
>

mattfidler commented 6 years ago

The PNLS step is a common error in nlme. You can adjust this factor up, with the following code:

## Note the theo_md is the same dataset as you specified but is included in the nlmixr package
fit <- nlme_ode(theo_md, model=ode, par_model=specs, par_trans=mypar,
                 response="centr", response.scaler="V",control=nlmeControl(pnlsTol=0.1))

Also note that I don't see the lCL parameter in your ODE specification. So it really shouldn't fit very well.

If you use the unifed model structure you can specify a similar model with:

theo.mod <- function() {
    ini({
        tka <- .5   # Log Ka
        tcl <- -3.2 # Log Cl
        tv <- -1    # Log V
        eta.ka ~ 1
        eta.cl ~ 2
        eta.v ~ 1
        add.err <- 0.1
    })
    model({
        ka <- exp(tka + eta.ka)
        cl <- exp(tcl + eta.cl)
        v <- exp(tv + eta.v)
        d/dt(depot) = -ka * depot
        d/dt(center) = ka * depot - cl / v * center
        cp = center / v 
        cp ~ add(add.err)
    })
}

Then the nlme can be run by:

> fit <- nlmixr(theo.mod,theo_md, calc.resid=FALSE,control=nlmeControl(pnlsTol=0.01))

``` **Iteration 1 LME step: Loglik: -417.1519, nlminb iterations: 1 reStruct parameters: ID1 ID2 ID3 1.086602 1.481263 2.198073 Beginning PNLS step: .. completed fit_nlme() step. PNLS step: RSS = 273.659 fixed effects: 0.2855648 -3.192379 -0.8096679 iterations: 6 Convergence crit. (must all become <= tolerance = 1e-05): fixed reStruct 0.7509161 0.3156169 **Iteration 2 LME step: Loglik: -417.3443, nlminb iterations: 1 reStruct parameters: ID1 ID2 ID3 0.8259257 1.5439870 2.1087332 Beginning PNLS step: .. completed fit_nlme() step. PNLS step: RSS = 273.659 fixed effects: 0.2855648 -3.192379 -0.8096679 iterations: 1 Convergence crit. (must all become <= tolerance = 1e-05): fixed reStruct 0.000000e+00 6.685185e-09 Warning message: In nlmixrUI.nlme.var(obj) : Initial condition for additive error ignored with nlme ```

> fit
Nonlinear mixed-effects model fit by maximum likelihood
  Model: DV ~ (nlmixr::nlmeModList("user_fn"))(tka, tcl, tv, TIME, ID) 
  Log-likelihood: -417.3443
  Fixed: list(tka + tcl + tv ~ 1) 
       tka        tcl         tv 
 0.2855648 -3.1923786 -0.8096679 

Random effects:
 Formula: list(tka ~ 1, tcl ~ 1, tv ~ 1)
 Level: ID
 Structure: Diagonal
              tka       tcl       tv Residual
StdDev: 0.4457658 0.2173986 0.123592 1.018126

Number of Observations: 264
Number of Groups: 12

If you want the nlmixr FOCEi-based residulas and objective function calculated you can use:

> fit <- nlmixr(theo.mod,theo_md, calc.resid=TRUE,control=nlmeControl(pnlsTol=0.01))

```R **Iteration 1 LME step: Loglik: -417.1519, nlminb iterations: 1 reStruct parameters: ID1 ID2 ID3 1.086602 1.481263 2.198073 Beginning PNLS step: .. completed fit_nlme() step. PNLS step: RSS = 273.659 fixed effects: 0.2855648 -3.192379 -0.8096679 iterations: 6 Convergence crit. (must all become <= tolerance = 1e-05): fixed reStruct 0.7509161 0.3156169 **Iteration 2 LME step: Loglik: -417.3443, nlminb iterations: 1 reStruct parameters: ID1 ID2 ID3 0.8259257 1.5439870 2.1087332 Beginning PNLS step: .. completed fit_nlme() step. PNLS step: RSS = 273.659 fixed effects: 0.2855648 -3.192379 -0.8096679 iterations: 1 Convergence crit. (must all become <= tolerance = 1e-05): fixed reStruct 0.000000e+00 6.685185e-09 ## Calculate ETA-based prediction and error derivatives: Calculate Jacobian...................done. Calculate sensitivities....... done. ## Calculate d(f)/d(eta) ## ... ## done ## ... ## done The model-based sensitivities have been calculated. Calculating Table Variables... done Warning message: In nlmixrUI.nlme.var(obj) : Initial condition for additive error ignored with nlme ```

> fit
-- nlmixr nlme fit by maximum likelihood (ODE; µ-ref & covs) -------------------
FOCEi-based goodness of fit metrics:
     OBJF      AIC      BIC Log-likelihood Condition Number
 349.5017 363.5017 388.5333      -174.7508         40.78343

nlme-based goodness of fit metrics:
      AIC      BIC Log-likelihood
 848.6887 873.7203      -417.3443

-- Time (sec; fit$time): -------------------------------------------------------
        nlme setup FOCEi Evaulate covariance table
elapsed 3.02 33.93           0.11          0  0.23

-- Parameters (fit$par.fixed): -------------------------------------------------
        Parameter Estimate     SE %RSE Back-transformed(95%CI) BSV(CV%)
tka        Log Ka    0.286  0.139 48.6       1.33 (1.01, 1.75)    46.9%
tcl        Log Cl    -3.19 0.0664 2.08 0.0411 (0.0361, 0.0468)    22.0%
tv          Log V   -0.810 0.0438 5.41    0.445 (0.408, 0.485)    12.4%
add.err   add.err     1.02                             1.02            
        Shrink(SD)%
tka          1.86% 
tcl         0.543% 
tv           13.1% 
add.err      5.66% 

  No correlations in between subject variability (BSV) matrix
  Full BSV covariance (fit$omega) or correlation (fit$omega.R; diagonals=SDs)
  Distribution stats (mean/skewness/kurtosis/p-value) available in fit$shrink

-- Fit Data (object fit is a modified data.frame): -----------------------------
# A tibble: 264 x 21
  ID     TIME    DV  PRED   RES  WRES IPRED   IRES  IWRES CPRED  CRES CWRES
* <fct> <dbl> <dbl> <dbl> <dbl> <dbl> <dbl>  <dbl>  <dbl> <dbl> <dbl> <dbl>
1 1     0      0.74  0    0.74  0.727  0     0.74   0.727  0    0.74  0.727
2 1     0.25   2.84  2.53 0.315 0.221  3.49 -0.649 -0.637  2.37 0.471 0.279
3 1     0.570  6.57  4.66 1.91  1.06   6.29  0.279  0.274  4.44 2.13  0.991
# ... with 261 more rows, and 9 more variables: eta.ka <dbl>, eta.cl <dbl>,
#   eta.v <dbl>, depot <dbl>, center <dbl>, ka <dbl>, cl <dbl>, v <dbl>,
#   cp <dbl>

The good thing about this type of model specification is you can switch estimation methods easily. For example, if you wanted to use the more precise saem algoritm you can simply change "nlme" to "saem".

fit <- nlmixr(theo.mod,theo_md, est="saem")

```R Compiling RxODE differential equations...done. PKG_CXXFLAGS=-Ic:/R/nlmixr/R/library/nlmixr/include -Ic:/R/nlmixr/R/library/STANHE~1/include -Ic:/R/nlmixr/R/library/Rcpp/include -Ic:/R/nlmixr/R/library/RCPPAR~1/include -Ic:/R/nlmixr/R/library/RCPPEI~1/include -Ic:/R/nlmixr/R/library/BH/include PKG_LIBS= $(BLAS_LIBS) $(LAPACK_LIBS) c:/R/nlmixr/rtools/mingw_64/bin/g++ -I"c:/R/nlmixr/R/include" -DNDEBUG -Ic:/R/nlmixr/R/library/nlmixr/include -Ic:/R/nlmixr/R/library/STANHE~1/include -Ic:/R/nlmixr/R/library/Rcpp/include -Ic:/R/nlmixr/R/library/RCPPAR~1/include -Ic:/R/nlmixr/R/library/RCPPEI~1/include -Ic:/R/nlmixr/R/library/BH/include -O2 -Wall -mtune=generic -c saem1664c61dc195x64.cpp -o saem1664c61dc195x64.o c:/R/nlmixr/rtools/mingw_64/bin/g++ -shared -s -static-libgcc -o saem1664c61dc195x64.dll tmp.def saem1664c61dc195x64.o -Lc:/R/nlmixr/R/bin/x64 -lRblas -Lc:/R/nlmixr/R/bin/x64 -lRlapack -Lc:/R/nlmixr/R/bin/x64 -lR done. 1: 0.0022 -2.9098 -0.6295 0.9500 1.9000 0.9500 9.0092 2: 0.0491 -3.0457 -0.8193 0.9025 1.8050 0.9025 4.6165 3: 0.0733 -3.1430 -0.9340 0.8574 1.7147 0.8574 2.1688 4: 0.0604 -3.1649 -0.9034 0.8145 1.6290 0.8145 1.7806 5: 0.0713 -3.1696 -0.9745 0.7738 1.5476 0.7738 1.4825 6: 0.0531 -3.1564 -0.9802 0.7351 1.4702 0.7351 1.3278 7: 0.0594 -3.1676 -0.9962 0.6983 1.3967 0.6983 1.2401 8: 0.0599 -3.1722 -0.9722 0.6634 1.3268 0.6634 1.1569 9: 0.1141 -3.1712 -0.9320 0.6302 1.2605 0.6302 1.1644 10: 0.0886 -3.1592 -0.9361 0.5987 1.1975 0.5987 1.2026 11: 0.1509 -3.1552 -0.9285 0.5688 1.1376 0.5688 1.1670 12: 0.1522 -3.1600 -0.9225 0.5404 1.0807 0.5404 1.1706 13: 0.1107 -3.1638 -0.9258 0.5133 1.0267 0.5133 1.1489 14: 0.1537 -3.1695 -0.9175 0.4877 0.9753 0.4877 1.1388 15: 0.1766 -3.1647 -0.9011 0.4633 0.9266 0.4633 1.1439 16: 0.1808 -3.1652 -0.8825 0.4401 0.8803 0.4401 1.1093 17: 0.2153 -3.1677 -0.8619 0.4547 0.8362 0.4181 1.0927 18: 0.2136 -3.1764 -0.8806 0.4363 0.7944 0.3972 1.1231 19: 0.2236 -3.1639 -0.8903 0.4314 0.7547 0.3774 1.1035 20: 0.2470 -3.1872 -0.8759 0.4272 0.7170 0.3585 1.0556 21: 0.2181 -3.1724 -0.8619 0.4058 0.6811 0.3406 1.0492 22: 0.2056 -3.1660 -0.8709 0.3856 0.6471 0.3235 1.0601 23: 0.2531 -3.1590 -0.8723 0.3663 0.6147 0.3074 1.0701 24: 0.2225 -3.1645 -0.8676 0.3480 0.5840 0.2920 1.0588 25: 0.2303 -3.1642 -0.8598 0.3499 0.5548 0.2774 1.0595 26: 0.2422 -3.1645 -0.8877 0.3934 0.5270 0.2635 1.0657 27: 0.2223 -3.1538 -0.8752 0.3737 0.5007 0.2503 1.0617 28: 0.2272 -3.1628 -0.8769 0.3760 0.4757 0.2378 1.0510 29: 0.2244 -3.1639 -0.8694 0.3572 0.4519 0.2259 1.0523 30: 0.2317 -3.1746 -0.8710 0.3450 0.4293 0.2146 1.0369 31: 0.2001 -3.1867 -0.8516 0.3278 0.4078 0.2039 1.0978 32: 0.1941 -3.2189 -0.8517 0.3533 0.3874 0.1937 1.0734 33: 0.1700 -3.2056 -0.8552 0.3550 0.3681 0.1840 1.0594 34: 0.2746 -3.1755 -0.8580 0.3961 0.3496 0.1748 1.0284 35: 0.2480 -3.1766 -0.8652 0.3919 0.3322 0.1661 1.0414 36: 0.2384 -3.1870 -0.8533 0.3723 0.3156 0.1578 1.0556 37: 0.2063 -3.1728 -0.8580 0.3814 0.2998 0.1499 1.0660 38: 0.3406 -3.1650 -0.8113 0.3623 0.2848 0.1424 1.0672 39: 0.3268 -3.1796 -0.8159 0.3442 0.2706 0.1353 1.0200 40: 0.2709 -3.1861 -0.7982 0.3270 0.2570 0.1285 1.0755 41: 0.2489 -3.2002 -0.8059 0.3106 0.2442 0.1221 1.0718 42: 0.2822 -3.1942 -0.8080 0.2951 0.2320 0.1160 1.0424 43: 0.2564 -3.1973 -0.8134 0.2804 0.2204 0.1102 1.0517 44: 0.2273 -3.1934 -0.8328 0.2663 0.2093 0.1047 1.0530 45: 0.2223 -3.1801 -0.8383 0.2530 0.1989 0.0994 1.0289 46: 0.2287 -3.1849 -0.8154 0.2404 0.1889 0.0945 1.0584 47: 0.2935 -3.2079 -0.7886 0.2284 0.1795 0.0897 1.0691 48: 0.3212 -3.1887 -0.7912 0.2169 0.1705 0.0853 1.0654 49: 0.2807 -3.1776 -0.8029 0.2061 0.1620 0.0810 1.0819 50: 0.3044 -3.1945 -0.7945 0.2106 0.1539 0.0769 1.0536 51: 0.2853 -3.1916 -0.8175 0.2096 0.1462 0.0731 1.0477 52: 0.3093 -3.1844 -0.8073 0.1991 0.1389 0.0694 1.0154 53: 0.2943 -3.2027 -0.8098 0.2028 0.1319 0.0660 1.0218 54: 0.2188 -3.1804 -0.8379 0.2146 0.1253 0.0627 1.0562 55: 0.2393 -3.1871 -0.8157 0.2039 0.1191 0.0595 1.0712 56: 0.2790 -3.1966 -0.8087 0.2017 0.1131 0.0566 1.0808 57: 0.2803 -3.2060 -0.7980 0.2143 0.1075 0.0537 1.0672 58: 0.2935 -3.1939 -0.8137 0.2239 0.1021 0.0510 1.0330 59: 0.2886 -3.1967 -0.8052 0.2127 0.0970 0.0485 1.0513 60: 0.2974 -3.1946 -0.8052 0.2274 0.0921 0.0461 1.0129 61: 0.3015 -3.1723 -0.7991 0.2458 0.0875 0.0438 1.0648 62: 0.2934 -3.1837 -0.7944 0.2335 0.0832 0.0416 1.0405 63: 0.3428 -3.2005 -0.7861 0.2218 0.0790 0.0395 1.0274 64: 0.3282 -3.1796 -0.7920 0.2107 0.0750 0.0375 1.0155 65: 0.3417 -3.1913 -0.8048 0.2059 0.0713 0.0356 1.0206 66: 0.2953 -3.1955 -0.8029 0.1956 0.0677 0.0339 1.0153 67: 0.2859 -3.2057 -0.8075 0.1859 0.0643 0.0322 1.0147 68: 0.2685 -3.2041 -0.7757 0.1766 0.0611 0.0306 1.0606 69: 0.2802 -3.2080 -0.7987 0.1745 0.0581 0.0290 1.0720 70: 0.2694 -3.2038 -0.7959 0.1854 0.0552 0.0276 1.0522 71: 0.2673 -3.1774 -0.8253 0.1810 0.0524 0.0262 1.0650 72: 0.2300 -3.1908 -0.8217 0.1720 0.0498 0.0252 1.0291 73: 0.2901 -3.1839 -0.7974 0.1634 0.0473 0.0239 1.0345 74: 0.2930 -3.2065 -0.7963 0.1649 0.0449 0.0227 1.0375 75: 0.2932 -3.2037 -0.7703 0.1744 0.0504 0.0216 1.0328 76: 0.3265 -3.1937 -0.7645 0.1664 0.0479 0.0205 1.0666 77: 0.3755 -3.1932 -0.7773 0.1647 0.0455 0.0205 1.0665 78: 0.3553 -3.2002 -0.7729 0.1800 0.0444 0.0195 1.0306 79: 0.3374 -3.1981 -0.7792 0.2168 0.0447 0.0185 1.0800 80: 0.3249 -3.1983 -0.7776 0.2395 0.0425 0.0176 1.0953 81: 0.3282 -3.2026 -0.7801 0.2275 0.0446 0.0201 1.0689 82: 0.3220 -3.2076 -0.7772 0.2162 0.0437 0.0201 1.0559 83: 0.3093 -3.1860 -0.7822 0.2054 0.0534 0.0191 1.0602 84: 0.2996 -3.1881 -0.8025 0.1951 0.0507 0.0182 1.0295 85: 0.3159 -3.1949 -0.7842 0.1960 0.0482 0.0173 1.0566 86: 0.3011 -3.1908 -0.7883 0.1935 0.0488 0.0183 1.0208 87: 0.3153 -3.2080 -0.7977 0.1838 0.0464 0.0174 1.0408 88: 0.2613 -3.2133 -0.7914 0.1935 0.0441 0.0189 1.0337 89: 0.3016 -3.2012 -0.7942 0.1869 0.0457 0.0183 1.0197 90: 0.2864 -3.2079 -0.8027 0.1906 0.0434 0.0174 1.0336 91: 0.2717 -3.2127 -0.8267 0.2040 0.0412 0.0165 1.0339 92: 0.2676 -3.1792 -0.8264 0.2474 0.0429 0.0187 1.0417 93: 0.2363 -3.1861 -0.8306 0.2435 0.0458 0.0177 1.0401 94: 0.2639 -3.1889 -0.8266 0.2313 0.0464 0.0168 1.0196 95: 0.2611 -3.1837 -0.8183 0.2355 0.0479 0.0160 1.0269 96: 0.2310 -3.1973 -0.8201 0.2573 0.0455 0.0152 1.0285 97: 0.2779 -3.1817 -0.8129 0.2444 0.0433 0.0152 1.0543 98: 0.2712 -3.1715 -0.8150 0.2322 0.0468 0.0147 1.0509 99: 0.2777 -3.1937 -0.8204 0.2206 0.0464 0.0159 1.0236 100: 0.2655 -3.1876 -0.8174 0.2096 0.0445 0.0151 1.0111 101: 0.2186 -3.1929 -0.8390 0.1991 0.0466 0.0144 1.0039 102: 0.2120 -3.1964 -0.8456 0.1891 0.0448 0.0148 1.0349 103: 0.2613 -3.1936 -0.8217 0.1842 0.0425 0.0141 1.0311 104: 0.2609 -3.1718 -0.8149 0.1977 0.0426 0.0134 1.0503 105: 0.2669 -3.1862 -0.8177 0.2091 0.0499 0.0127 1.0509 106: 0.2685 -3.1857 -0.8191 0.2151 0.0554 0.0121 1.0484 107: 0.2778 -3.1660 -0.8248 0.2169 0.0599 0.0115 1.0684 108: 0.2632 -3.1839 -0.8271 0.2061 0.0569 0.0114 1.0320 109: 0.2550 -3.1851 -0.8130 0.2112 0.0619 0.0109 1.0475 110: 0.2679 -3.1968 -0.8267 0.2007 0.0588 0.0126 1.0203 111: 0.2727 -3.1853 -0.8220 0.2046 0.0559 0.0135 1.0105 112: 0.2616 -3.1902 -0.8350 0.2099 0.0583 0.0129 1.0321 113: 0.2483 -3.1657 -0.8326 0.1994 0.0554 0.0122 1.0222 114: 0.2539 -3.1724 -0.8313 0.1894 0.0609 0.0116 1.0113 115: 0.2841 -3.1900 -0.8209 0.1816 0.0578 0.0129 1.0348 116: 0.2798 -3.1897 -0.8080 0.2003 0.0549 0.0141 1.0431 117: 0.2463 -3.1769 -0.8099 0.1903 0.0522 0.0137 1.0368 118: 0.2754 -3.1872 -0.8202 0.1897 0.0510 0.0130 1.0143 119: 0.2676 -3.1889 -0.8155 0.2215 0.0484 0.0182 1.0196 120: 0.2372 -3.1957 -0.8179 0.2345 0.0460 0.0184 1.0173 121: 0.2666 -3.1789 -0.8145 0.2228 0.0480 0.0185 1.0359 122: 0.2810 -3.2002 -0.8033 0.2117 0.0456 0.0176 1.0317 123: 0.3266 -3.1694 -0.8161 0.2210 0.0480 0.0167 1.0091 124: 0.3009 -3.1621 -0.8211 0.2326 0.0497 0.0159 1.0143 125: 0.3114 -3.1619 -0.8276 0.2210 0.0504 0.0151 1.0146 126: 0.2727 -3.1606 -0.8359 0.2280 0.0552 0.0143 1.0277 127: 0.2627 -3.1728 -0.8378 0.2166 0.0524 0.0158 1.0402 128: 0.2402 -3.1735 -0.8317 0.2417 0.0540 0.0181 1.0559 129: 0.2771 -3.1733 -0.8256 0.2763 0.0513 0.0172 1.0168 130: 0.2887 -3.1759 -0.8254 0.2637 0.0528 0.0174 0.9922 131: 0.2760 -3.1877 -0.8345 0.2506 0.0593 0.0194 1.0204 132: 0.2205 -3.1712 -0.8440 0.2380 0.0563 0.0184 1.0344 133: 0.2600 -3.1777 -0.8349 0.2261 0.0535 0.0196 1.0664 134: 0.2856 -3.1969 -0.8045 0.2148 0.0508 0.0270 1.0303 135: 0.2693 -3.1858 -0.8095 0.2113 0.0483 0.0256 1.0317 136: 0.3041 -3.1913 -0.7943 0.2007 0.0459 0.0243 1.0072 137: 0.3179 -3.2044 -0.7899 0.1916 0.0436 0.0231 1.0234 138: 0.3144 -3.1932 -0.7891 0.1855 0.0414 0.0220 1.0134 139: 0.3089 -3.1904 -0.7809 0.1927 0.0425 0.0226 1.0194 140: 0.3252 -3.1830 -0.7751 0.2047 0.0408 0.0214 1.0283 141: 0.3201 -3.1995 -0.7780 0.2165 0.0451 0.0204 1.0178 142: 0.3393 -3.2020 -0.7754 0.2138 0.0497 0.0193 1.0307 143: 0.3001 -3.1903 -0.7878 0.2031 0.0484 0.0184 1.0366 144: 0.3368 -3.1932 -0.7770 0.1930 0.0460 0.0175 1.0313 145: 0.3306 -3.1795 -0.8050 0.2143 0.0489 0.0166 0.9969 146: 0.2796 -3.1853 -0.8019 0.2115 0.0504 0.0175 1.0293 147: 0.2368 -3.1857 -0.8202 0.2010 0.0496 0.0166 1.0486 148: 0.2682 -3.1926 -0.8020 0.1909 0.0471 0.0158 1.0565 149: 0.2667 -3.1914 -0.8092 0.1814 0.0544 0.0150 1.0490 150: 0.3028 -3.1943 -0.8090 0.1875 0.0545 0.0142 1.0617 151: 0.2473 -3.1866 -0.8163 0.1810 0.0518 0.0135 1.0601 152: 0.2443 -3.1891 -0.8214 0.1910 0.0575 0.0129 1.0446 153: 0.2659 -3.1845 -0.8110 0.2301 0.0588 0.0136 1.0371 154: 0.3238 -3.1691 -0.8017 0.2183 0.0552 0.0174 1.0558 155: 0.2942 -3.1965 -0.8044 0.2433 0.0437 0.0215 1.0303 156: 0.2904 -3.1860 -0.7860 0.1958 0.0450 0.0215 1.0280 157: 0.2851 -3.1985 -0.7937 0.1786 0.0375 0.0227 1.0421 158: 0.3207 -3.1970 -0.7840 0.1947 0.0377 0.0209 1.0186 159: 0.2959 -3.1863 -0.7957 0.1830 0.0404 0.0217 1.0202 160: 0.3243 -3.2153 -0.7835 0.2168 0.0443 0.0185 1.0208 161: 0.2858 -3.2057 -0.7993 0.1988 0.0397 0.0241 1.0050 162: 0.2951 -3.1789 -0.8091 0.2195 0.0436 0.0226 1.0214 163: 0.3340 -3.1861 -0.8086 0.1896 0.0356 0.0186 1.0286 164: 0.3346 -3.1962 -0.7978 0.1841 0.0349 0.0185 1.0376 165: 0.3306 -3.2070 -0.7862 0.1878 0.0414 0.0167 1.0553 166: 0.3483 -3.1856 -0.7808 0.2012 0.0398 0.0171 1.0427 167: 0.3149 -3.1774 -0.7863 0.1912 0.0439 0.0259 1.0600 168: 0.3247 -3.1802 -0.7929 0.1763 0.0456 0.0289 1.0460 169: 0.2849 -3.1659 -0.8165 0.1616 0.0434 0.0227 1.0580 170: 0.2989 -3.1865 -0.8125 0.1573 0.0373 0.0192 1.0323 171: 0.2680 -3.1801 -0.8207 0.1663 0.0445 0.0187 0.9920 172: 0.2594 -3.1754 -0.8223 0.1631 0.0411 0.0201 1.0083 173: 0.2691 -3.1692 -0.8323 0.1563 0.0477 0.0217 1.0213 174: 0.2795 -3.1719 -0.8121 0.1614 0.0437 0.0196 1.0340 175: 0.2828 -3.1773 -0.8219 0.2017 0.0470 0.0218 1.0045 176: 0.2505 -3.1769 -0.8146 0.1945 0.0499 0.0184 1.0329 177: 0.2929 -3.1982 -0.8010 0.2102 0.0499 0.0176 1.0293 178: 0.2900 -3.1928 -0.8011 0.2036 0.0523 0.0195 1.0206 179: 0.3106 -3.1581 -0.8042 0.2108 0.0583 0.0154 1.0441 180: 0.2707 -3.1779 -0.8084 0.1622 0.0505 0.0177 1.0597 181: 0.2641 -3.1886 -0.8381 0.1787 0.0510 0.0194 1.0409 182: 0.2292 -3.1615 -0.8415 0.1819 0.0586 0.0177 1.0594 183: 0.2450 -3.1699 -0.8373 0.1907 0.0568 0.0167 1.0385 184: 0.2559 -3.1782 -0.8280 0.1828 0.0518 0.0144 1.0493 185: 0.2477 -3.1751 -0.8276 0.1730 0.0448 0.0145 1.0272 186: 0.2413 -3.1725 -0.8312 0.1847 0.0507 0.0129 1.0386 187: 0.2537 -3.1861 -0.8200 0.1897 0.0464 0.0116 1.0416 188: 0.2563 -3.1736 -0.8261 0.2258 0.0506 0.0126 1.0401 189: 0.2633 -3.1752 -0.8162 0.1886 0.0459 0.0121 1.0519 190: 0.2663 -3.1811 -0.8145 0.1648 0.0480 0.0120 1.0482 191: 0.2574 -3.1709 -0.8175 0.1721 0.0504 0.0109 1.0555 192: 0.2476 -3.1733 -0.8177 0.1668 0.0478 0.0110 1.0821 193: 0.2955 -3.1664 -0.8109 0.1690 0.0495 0.0106 1.0521 194: 0.2584 -3.1801 -0.8252 0.1841 0.0514 0.0093 1.0593 195: 0.2602 -3.1882 -0.8294 0.1801 0.0461 0.0090 1.0397 196: 0.2251 -3.1894 -0.8292 0.1883 0.0517 0.0099 1.0391 197: 0.2500 -3.1824 -0.8078 0.2075 0.0413 0.0119 1.0704 198: 0.3072 -3.1912 -0.8139 0.2399 0.0426 0.0120 1.0404 199: 0.2987 -3.1901 -0.8029 0.2163 0.0474 0.0113 1.0580 200: 0.2746 -3.1941 -0.8078 0.1906 0.0513 0.0134 1.0351 201: 0.2662 -3.1916 -0.8064 0.1873 0.0508 0.0129 1.0285 202: 0.2753 -3.1905 -0.8066 0.1922 0.0509 0.0124 1.0420 203: 0.2852 -3.1905 -0.8076 0.2045 0.0520 0.0125 1.0432 204: 0.2897 -3.1923 -0.8072 0.2080 0.0516 0.0121 1.0417 205: 0.2898 -3.1882 -0.8068 0.2051 0.0526 0.0123 1.0395 206: 0.2896 -3.1849 -0.8066 0.2053 0.0516 0.0123 1.0439 207: 0.2879 -3.1863 -0.8066 0.2059 0.0502 0.0123 1.0453 208: 0.2851 -3.1885 -0.8067 0.2032 0.0496 0.0125 1.0422 209: 0.2873 -3.1890 -0.8076 0.2033 0.0492 0.0128 1.0399 210: 0.2889 -3.1896 -0.8079 0.2043 0.0486 0.0128 1.0393 211: 0.2905 -3.1893 -0.8072 0.2067 0.0487 0.0126 1.0364 212: 0.2918 -3.1898 -0.8065 0.2084 0.0488 0.0127 1.0353 213: 0.2934 -3.1905 -0.8059 0.2077 0.0486 0.0128 1.0356 214: 0.2939 -3.1910 -0.8059 0.2084 0.0486 0.0133 1.0339 215: 0.2934 -3.1908 -0.8055 0.2082 0.0483 0.0138 1.0337 216: 0.2955 -3.1914 -0.8055 0.2102 0.0480 0.0140 1.0351 217: 0.2964 -3.1901 -0.8056 0.2107 0.0479 0.0140 1.0337 218: 0.2966 -3.1893 -0.8062 0.2103 0.0478 0.0141 1.0337 219: 0.2972 -3.1886 -0.8070 0.2092 0.0474 0.0143 1.0330 220: 0.2957 -3.1881 -0.8072 0.2068 0.0472 0.0145 1.0329 221: 0.2943 -3.1881 -0.8073 0.2046 0.0470 0.0146 1.0323 222: 0.2949 -3.1882 -0.8071 0.2046 0.0467 0.0148 1.0328 223: 0.2954 -3.1886 -0.8070 0.2036 0.0465 0.0151 1.0327 224: 0.2960 -3.1882 -0.8068 0.2039 0.0466 0.0152 1.0322 225: 0.2961 -3.1896 -0.8060 0.2027 0.0466 0.0155 1.0336 226: 0.2956 -3.1899 -0.8060 0.2032 0.0465 0.0156 1.0343 227: 0.2947 -3.1903 -0.8057 0.2021 0.0464 0.0158 1.0345 228: 0.2938 -3.1895 -0.8062 0.2016 0.0467 0.0160 1.0347 229: 0.2934 -3.1896 -0.8062 0.2006 0.0467 0.0160 1.0348 230: 0.2941 -3.1897 -0.8062 0.2001 0.0467 0.0160 1.0346 231: 0.2942 -3.1897 -0.8058 0.1993 0.0467 0.0161 1.0344 232: 0.2932 -3.1898 -0.8055 0.1988 0.0467 0.0161 1.0339 233: 0.2932 -3.1905 -0.8049 0.1991 0.0465 0.0163 1.0340 234: 0.2925 -3.1909 -0.8044 0.1987 0.0464 0.0163 1.0340 235: 0.2927 -3.1909 -0.8045 0.1986 0.0464 0.0163 1.0340 236: 0.2922 -3.1905 -0.8051 0.1984 0.0464 0.0163 1.0342 237: 0.2925 -3.1906 -0.8052 0.1987 0.0464 0.0164 1.0342 238: 0.2928 -3.1906 -0.8052 0.1990 0.0464 0.0165 1.0352 239: 0.2928 -3.1904 -0.8052 0.1996 0.0465 0.0164 1.0359 240: 0.2926 -3.1909 -0.8051 0.1998 0.0466 0.0164 1.0354 241: 0.2932 -3.1916 -0.8046 0.2002 0.0467 0.0163 1.0348 242: 0.2927 -3.1917 -0.8047 0.2004 0.0468 0.0163 1.0350 243: 0.2917 -3.1914 -0.8048 0.2007 0.0470 0.0163 1.0350 244: 0.2910 -3.1910 -0.8048 0.1998 0.0471 0.0163 1.0354 245: 0.2911 -3.1911 -0.8048 0.1999 0.0472 0.0164 1.0364 246: 0.2911 -3.1914 -0.8048 0.1998 0.0473 0.0164 1.0366 247: 0.2910 -3.1913 -0.8046 0.2002 0.0473 0.0164 1.0367 248: 0.2907 -3.1912 -0.8047 0.2003 0.0473 0.0164 1.0371 249: 0.2902 -3.1913 -0.8046 0.1997 0.0472 0.0164 1.0372 250: 0.2906 -3.1912 -0.8045 0.2002 0.0473 0.0164 1.0369 251: 0.2905 -3.1910 -0.8043 0.2005 0.0474 0.0163 1.0370 252: 0.2906 -3.1908 -0.8041 0.2010 0.0474 0.0163 1.0374 253: 0.2899 -3.1907 -0.8043 0.2015 0.0475 0.0163 1.0374 254: 0.2893 -3.1905 -0.8043 0.2020 0.0476 0.0163 1.0371 255: 0.2890 -3.1903 -0.8041 0.2014 0.0476 0.0163 1.0374 256: 0.2891 -3.1902 -0.8042 0.2017 0.0475 0.0163 1.0371 257: 0.2888 -3.1902 -0.8044 0.2015 0.0475 0.0162 1.0373 258: 0.2885 -3.1902 -0.8046 0.2019 0.0476 0.0161 1.0375 259: 0.2878 -3.1902 -0.8048 0.2014 0.0477 0.0160 1.0377 260: 0.2873 -3.1902 -0.8047 0.2011 0.0477 0.0160 1.0370 261: 0.2875 -3.1903 -0.8044 0.2012 0.0478 0.0159 1.0368 262: 0.2881 -3.1903 -0.8042 0.2015 0.0480 0.0158 1.0370 263: 0.2884 -3.1903 -0.8042 0.2022 0.0480 0.0158 1.0368 264: 0.2883 -3.1904 -0.8043 0.2026 0.0479 0.0158 1.0372 265: 0.2885 -3.1902 -0.8043 0.2028 0.0481 0.0158 1.0375 266: 0.2886 -3.1901 -0.8042 0.2037 0.0481 0.0158 1.0371 267: 0.2890 -3.1901 -0.8042 0.2043 0.0480 0.0157 1.0372 268: 0.2893 -3.1903 -0.8042 0.2045 0.0479 0.0158 1.0368 269: 0.2899 -3.1904 -0.8040 0.2048 0.0479 0.0157 1.0369 270: 0.2903 -3.1903 -0.8040 0.2055 0.0479 0.0157 1.0363 271: 0.2904 -3.1902 -0.8041 0.2055 0.0480 0.0156 1.0364 272: 0.2904 -3.1902 -0.8041 0.2053 0.0481 0.0156 1.0368 273: 0.2906 -3.1901 -0.8040 0.2051 0.0482 0.0156 1.0369 274: 0.2904 -3.1900 -0.8040 0.2043 0.0481 0.0156 1.0372 275: 0.2903 -3.1898 -0.8041 0.2041 0.0482 0.0156 1.0371 276: 0.2904 -3.1896 -0.8039 0.2042 0.0483 0.0156 1.0376 277: 0.2902 -3.1896 -0.8037 0.2037 0.0482 0.0156 1.0378 278: 0.2901 -3.1896 -0.8036 0.2034 0.0482 0.0156 1.0381 279: 0.2900 -3.1897 -0.8037 0.2033 0.0481 0.0156 1.0382 280: 0.2897 -3.1897 -0.8036 0.2030 0.0481 0.0155 1.0378 281: 0.2893 -3.1897 -0.8036 0.2030 0.0481 0.0155 1.0376 282: 0.2894 -3.1896 -0.8035 0.2034 0.0482 0.0154 1.0377 283: 0.2901 -3.1896 -0.8034 0.2038 0.0483 0.0154 1.0384 284: 0.2901 -3.1898 -0.8033 0.2042 0.0483 0.0153 1.0384 285: 0.2901 -3.1899 -0.8034 0.2040 0.0483 0.0153 1.0383 286: 0.2899 -3.1897 -0.8035 0.2043 0.0485 0.0153 1.0383 287: 0.2899 -3.1895 -0.8036 0.2045 0.0485 0.0153 1.0384 288: 0.2899 -3.1895 -0.8037 0.2043 0.0486 0.0152 1.0386 289: 0.2901 -3.1895 -0.8037 0.2040 0.0486 0.0152 1.0388 290: 0.2902 -3.1894 -0.8037 0.2040 0.0486 0.0153 1.0390 291: 0.2906 -3.1893 -0.8036 0.2038 0.0486 0.0153 1.0385 292: 0.2905 -3.1893 -0.8036 0.2036 0.0486 0.0152 1.0382 293: 0.2901 -3.1893 -0.8037 0.2038 0.0485 0.0152 1.0381 294: 0.2897 -3.1895 -0.8039 0.2041 0.0485 0.0152 1.0378 295: 0.2898 -3.1896 -0.8039 0.2044 0.0485 0.0151 1.0376 296: 0.2898 -3.1895 -0.8040 0.2043 0.0485 0.0151 1.0378 297: 0.2899 -3.1893 -0.8041 0.2043 0.0484 0.0152 1.0377 298: 0.2900 -3.1895 -0.8041 0.2040 0.0485 0.0152 1.0375 299: 0.2898 -3.1894 -0.8042 0.2043 0.0485 0.0151 1.0376 300: 0.2897 -3.1895 -0.8043 0.2047 0.0485 0.0151 1.0377 301: 0.2897 -3.1895 -0.8043 0.2046 0.0485 0.0150 1.0377 302: 0.2895 -3.1895 -0.8044 0.2045 0.0485 0.0150 1.0376 303: 0.2893 -3.1895 -0.8045 0.2046 0.0484 0.0151 1.0372 304: 0.2893 -3.1894 -0.8046 0.2048 0.0483 0.0151 1.0373 305: 0.2892 -3.1895 -0.8046 0.2049 0.0483 0.0151 1.0373 306: 0.2890 -3.1897 -0.8047 0.2048 0.0483 0.0151 1.0373 307: 0.2891 -3.1897 -0.8048 0.2047 0.0484 0.0150 1.0376 308: 0.2889 -3.1899 -0.8049 0.2047 0.0484 0.0150 1.0379 309: 0.2886 -3.1901 -0.8050 0.2047 0.0483 0.0150 1.0379 310: 0.2885 -3.1900 -0.8052 0.2048 0.0484 0.0150 1.0378 311: 0.2885 -3.1900 -0.8052 0.2049 0.0485 0.0150 1.0378 312: 0.2883 -3.1900 -0.8053 0.2052 0.0485 0.0150 1.0377 313: 0.2882 -3.1901 -0.8054 0.2050 0.0485 0.0149 1.0378 314: 0.2881 -3.1903 -0.8053 0.2051 0.0484 0.0150 1.0378 315: 0.2881 -3.1903 -0.8053 0.2053 0.0483 0.0150 1.0379 316: 0.2882 -3.1904 -0.8053 0.2055 0.0483 0.0150 1.0379 317: 0.2884 -3.1903 -0.8053 0.2054 0.0482 0.0150 1.0380 318: 0.2885 -3.1904 -0.8053 0.2054 0.0482 0.0150 1.0379 319: 0.2884 -3.1904 -0.8053 0.2051 0.0482 0.0150 1.0380 320: 0.2881 -3.1903 -0.8054 0.2052 0.0482 0.0150 1.0383 321: 0.2878 -3.1903 -0.8056 0.2053 0.0482 0.0150 1.0383 322: 0.2877 -3.1903 -0.8058 0.2056 0.0481 0.0151 1.0383 323: 0.2872 -3.1903 -0.8059 0.2060 0.0482 0.0151 1.0383 324: 0.2874 -3.1902 -0.8058 0.2064 0.0482 0.0151 1.0381 325: 0.2873 -3.1901 -0.8059 0.2066 0.0482 0.0151 1.0379 326: 0.2873 -3.1901 -0.8061 0.2066 0.0481 0.0151 1.0378 327: 0.2874 -3.1901 -0.8061 0.2069 0.0481 0.0151 1.0376 328: 0.2874 -3.1901 -0.8061 0.2072 0.0481 0.0151 1.0374 329: 0.2875 -3.1902 -0.8059 0.2074 0.0481 0.0151 1.0375 330: 0.2873 -3.1902 -0.8059 0.2075 0.0481 0.0151 1.0376 331: 0.2873 -3.1901 -0.8059 0.2074 0.0481 0.0151 1.0374 332: 0.2871 -3.1900 -0.8059 0.2075 0.0481 0.0151 1.0377 333: 0.2869 -3.1898 -0.8061 0.2080 0.0481 0.0151 1.0379 334: 0.2866 -3.1898 -0.8064 0.2082 0.0480 0.0151 1.0380 335: 0.2865 -3.1898 -0.8066 0.2086 0.0480 0.0151 1.0378 336: 0.2862 -3.1897 -0.8067 0.2087 0.0481 0.0151 1.0378 337: 0.2859 -3.1894 -0.8069 0.2088 0.0482 0.0151 1.0378 338: 0.2859 -3.1893 -0.8069 0.2088 0.0482 0.0150 1.0376 339: 0.2856 -3.1893 -0.8070 0.2086 0.0483 0.0150 1.0376 340: 0.2854 -3.1893 -0.8070 0.2086 0.0483 0.0150 1.0374 341: 0.2855 -3.1894 -0.8070 0.2085 0.0483 0.0150 1.0374 342: 0.2853 -3.1895 -0.8070 0.2083 0.0483 0.0150 1.0373 343: 0.2851 -3.1895 -0.8070 0.2081 0.0483 0.0149 1.0371 344: 0.2851 -3.1895 -0.8070 0.2080 0.0482 0.0149 1.0371 345: 0.2851 -3.1895 -0.8069 0.2079 0.0482 0.0149 1.0369 346: 0.2852 -3.1896 -0.8070 0.2077 0.0482 0.0149 1.0370 347: 0.2853 -3.1896 -0.8071 0.2077 0.0482 0.0149 1.0373 348: 0.2850 -3.1895 -0.8072 0.2076 0.0481 0.0149 1.0373 349: 0.2849 -3.1897 -0.8072 0.2074 0.0481 0.0150 1.0373 350: 0.2846 -3.1898 -0.8073 0.2073 0.0481 0.0150 1.0373 351: 0.2844 -3.1898 -0.8074 0.2073 0.0481 0.0150 1.0372 352: 0.2839 -3.1896 -0.8074 0.2073 0.0481 0.0150 1.0374 353: 0.2839 -3.1895 -0.8075 0.2076 0.0481 0.0150 1.0374 354: 0.2839 -3.1895 -0.8076 0.2077 0.0481 0.0150 1.0373 355: 0.2839 -3.1896 -0.8077 0.2076 0.0481 0.0150 1.0373 356: 0.2837 -3.1896 -0.8077 0.2075 0.0481 0.0150 1.0374 357: 0.2838 -3.1895 -0.8078 0.2074 0.0481 0.0150 1.0375 358: 0.2837 -3.1895 -0.8077 0.2071 0.0481 0.0150 1.0374 359: 0.2837 -3.1894 -0.8077 0.2070 0.0481 0.0150 1.0374 360: 0.2835 -3.1894 -0.8078 0.2069 0.0480 0.0150 1.0373 361: 0.2832 -3.1893 -0.8080 0.2068 0.0480 0.0151 1.0372 362: 0.2833 -3.1894 -0.8080 0.2066 0.0481 0.0151 1.0371 363: 0.2832 -3.1894 -0.8081 0.2066 0.0480 0.0151 1.0368 364: 0.2832 -3.1894 -0.8081 0.2067 0.0480 0.0151 1.0369 365: 0.2831 -3.1895 -0.8081 0.2066 0.0480 0.0151 1.0368 366: 0.2832 -3.1894 -0.8082 0.2066 0.0480 0.0151 1.0369 367: 0.2833 -3.1894 -0.8082 0.2064 0.0480 0.0151 1.0370 368: 0.2834 -3.1893 -0.8082 0.2064 0.0480 0.0151 1.0370 369: 0.2833 -3.1892 -0.8083 0.2068 0.0480 0.0151 1.0370 370: 0.2833 -3.1891 -0.8083 0.2068 0.0480 0.0151 1.0370 371: 0.2828 -3.1891 -0.8085 0.2067 0.0480 0.0151 1.0370 372: 0.2825 -3.1891 -0.8087 0.2065 0.0480 0.0151 1.0371 373: 0.2823 -3.1890 -0.8088 0.2064 0.0480 0.0151 1.0373 374: 0.2822 -3.1889 -0.8089 0.2060 0.0480 0.0151 1.0374 375: 0.2818 -3.1889 -0.8090 0.2059 0.0480 0.0151 1.0376 376: 0.2816 -3.1888 -0.8091 0.2058 0.0480 0.0151 1.0375 377: 0.2814 -3.1887 -0.8091 0.2055 0.0481 0.0151 1.0375 378: 0.2810 -3.1888 -0.8092 0.2054 0.0481 0.0151 1.0375 379: 0.2808 -3.1889 -0.8092 0.2055 0.0481 0.0151 1.0376 380: 0.2806 -3.1890 -0.8093 0.2054 0.0481 0.0150 1.0375 381: 0.2803 -3.1890 -0.8094 0.2053 0.0480 0.0150 1.0374 382: 0.2801 -3.1890 -0.8095 0.2052 0.0480 0.0150 1.0374 383: 0.2803 -3.1890 -0.8094 0.2052 0.0480 0.0150 1.0373 384: 0.2802 -3.1890 -0.8095 0.2050 0.0480 0.0150 1.0372 385: 0.2801 -3.1890 -0.8095 0.2051 0.0480 0.0150 1.0372 386: 0.2802 -3.1889 -0.8095 0.2050 0.0480 0.0150 1.0372 387: 0.2803 -3.1889 -0.8094 0.2049 0.0479 0.0150 1.0371 388: 0.2804 -3.1889 -0.8093 0.2049 0.0479 0.0150 1.0371 389: 0.2804 -3.1889 -0.8093 0.2049 0.0480 0.0150 1.0372 390: 0.2803 -3.1888 -0.8094 0.2049 0.0480 0.0150 1.0370 391: 0.2804 -3.1888 -0.8094 0.2050 0.0480 0.0150 1.0370 392: 0.2805 -3.1888 -0.8094 0.2051 0.0480 0.0150 1.0370 393: 0.2804 -3.1889 -0.8095 0.2052 0.0479 0.0150 1.0369 394: 0.2803 -3.1889 -0.8095 0.2053 0.0479 0.0150 1.0369 395: 0.2805 -3.1888 -0.8095 0.2052 0.0479 0.0151 1.0370 396: 0.2807 -3.1888 -0.8094 0.2052 0.0479 0.0151 1.0369 397: 0.2809 -3.1889 -0.8093 0.2053 0.0479 0.0151 1.0369 398: 0.2809 -3.1889 -0.8092 0.2053 0.0479 0.0151 1.0368 399: 0.2811 -3.1889 -0.8091 0.2054 0.0479 0.0151 1.0367 400: 0.2813 -3.1889 -0.8091 0.2054 0.0479 0.0151 1.0369 401: 0.2814 -3.1887 -0.8091 0.2054 0.0479 0.0151 1.0369 402: 0.2816 -3.1887 -0.8090 0.2055 0.0479 0.0151 1.0370 403: 0.2819 -3.1887 -0.8091 0.2054 0.0480 0.0151 1.0371 404: 0.2822 -3.1886 -0.8091 0.2053 0.0480 0.0151 1.0371 405: 0.2822 -3.1886 -0.8091 0.2053 0.0480 0.0151 1.0371 406: 0.2823 -3.1885 -0.8091 0.2054 0.0480 0.0151 1.0372 407: 0.2824 -3.1885 -0.8090 0.2056 0.0480 0.0151 1.0371 408: 0.2824 -3.1884 -0.8090 0.2055 0.0480 0.0151 1.0373 409: 0.2824 -3.1884 -0.8091 0.2055 0.0480 0.0151 1.0372 410: 0.2823 -3.1884 -0.8092 0.2055 0.0480 0.0151 1.0373 411: 0.2824 -3.1884 -0.8092 0.2057 0.0481 0.0151 1.0374 412: 0.2823 -3.1883 -0.8093 0.2055 0.0481 0.0151 1.0376 413: 0.2821 -3.1883 -0.8094 0.2054 0.0481 0.0151 1.0377 414: 0.2817 -3.1883 -0.8095 0.2053 0.0481 0.0152 1.0377 415: 0.2817 -3.1883 -0.8095 0.2053 0.0481 0.0152 1.0377 416: 0.2818 -3.1883 -0.8096 0.2053 0.0481 0.0152 1.0376 417: 0.2818 -3.1883 -0.8096 0.2052 0.0481 0.0152 1.0375 418: 0.2817 -3.1883 -0.8096 0.2050 0.0481 0.0152 1.0375 419: 0.2816 -3.1882 -0.8096 0.2050 0.0481 0.0152 1.0374 420: 0.2816 -3.1882 -0.8095 0.2051 0.0481 0.0152 1.0373 421: 0.2816 -3.1882 -0.8095 0.2051 0.0481 0.0152 1.0373 422: 0.2818 -3.1883 -0.8094 0.2054 0.0481 0.0152 1.0373 423: 0.2819 -3.1882 -0.8094 0.2055 0.0481 0.0152 1.0373 424: 0.2819 -3.1882 -0.8095 0.2055 0.0482 0.0151 1.0373 425: 0.2820 -3.1882 -0.8095 0.2055 0.0482 0.0151 1.0373 426: 0.2821 -3.1881 -0.8095 0.2055 0.0482 0.0151 1.0373 427: 0.2820 -3.1880 -0.8096 0.2055 0.0483 0.0151 1.0371 428: 0.2818 -3.1880 -0.8096 0.2056 0.0483 0.0151 1.0371 429: 0.2818 -3.1880 -0.8096 0.2056 0.0482 0.0151 1.0371 430: 0.2816 -3.1880 -0.8096 0.2055 0.0483 0.0151 1.0370 431: 0.2814 -3.1880 -0.8097 0.2054 0.0483 0.0152 1.0369 432: 0.2812 -3.1880 -0.8097 0.2054 0.0483 0.0152 1.0368 433: 0.2812 -3.1880 -0.8096 0.2054 0.0482 0.0152 1.0368 434: 0.2811 -3.1882 -0.8096 0.2054 0.0483 0.0152 1.0367 435: 0.2811 -3.1881 -0.8096 0.2053 0.0483 0.0152 1.0367 436: 0.2811 -3.1882 -0.8095 0.2052 0.0483 0.0152 1.0368 437: 0.2810 -3.1882 -0.8096 0.2052 0.0483 0.0152 1.0368 438: 0.2808 -3.1881 -0.8097 0.2053 0.0483 0.0152 1.0368 439: 0.2807 -3.1880 -0.8097 0.2053 0.0483 0.0152 1.0368 440: 0.2806 -3.1880 -0.8097 0.2052 0.0483 0.0152 1.0368 441: 0.2807 -3.1881 -0.8097 0.2051 0.0483 0.0152 1.0368 442: 0.2806 -3.1881 -0.8096 0.2051 0.0483 0.0152 1.0368 443: 0.2807 -3.1880 -0.8097 0.2052 0.0483 0.0151 1.0369 444: 0.2807 -3.1879 -0.8098 0.2052 0.0483 0.0151 1.0369 445: 0.2807 -3.1879 -0.8098 0.2055 0.0483 0.0151 1.0370 446: 0.2806 -3.1879 -0.8098 0.2057 0.0483 0.0151 1.0370 447: 0.2807 -3.1879 -0.8099 0.2057 0.0483 0.0150 1.0370 448: 0.2808 -3.1879 -0.8098 0.2057 0.0483 0.0150 1.0369 449: 0.2808 -3.1879 -0.8097 0.2056 0.0483 0.0151 1.0368 450: 0.2808 -3.1880 -0.8096 0.2056 0.0483 0.0151 1.0368 451: 0.2809 -3.1880 -0.8096 0.2057 0.0482 0.0151 1.0368 452: 0.2808 -3.1880 -0.8097 0.2058 0.0482 0.0151 1.0368 453: 0.2808 -3.1880 -0.8097 0.2057 0.0482 0.0151 1.0367 454: 0.2808 -3.1880 -0.8097 0.2056 0.0482 0.0151 1.0366 455: 0.2808 -3.1880 -0.8098 0.2057 0.0482 0.0151 1.0366 456: 0.2807 -3.1880 -0.8098 0.2059 0.0482 0.0151 1.0365 457: 0.2807 -3.1880 -0.8098 0.2060 0.0482 0.0151 1.0364 458: 0.2807 -3.1879 -0.8098 0.2060 0.0482 0.0151 1.0363 459: 0.2807 -3.1878 -0.8098 0.2058 0.0481 0.0151 1.0363 460: 0.2808 -3.1878 -0.8098 0.2058 0.0481 0.0151 1.0362 461: 0.2807 -3.1878 -0.8098 0.2058 0.0481 0.0151 1.0362 462: 0.2807 -3.1878 -0.8097 0.2057 0.0481 0.0151 1.0362 463: 0.2807 -3.1878 -0.8097 0.2056 0.0480 0.0151 1.0363 464: 0.2807 -3.1877 -0.8097 0.2056 0.0481 0.0151 1.0362 465: 0.2808 -3.1878 -0.8097 0.2055 0.0480 0.0151 1.0363 466: 0.2809 -3.1878 -0.8097 0.2055 0.0480 0.0151 1.0363 467: 0.2809 -3.1878 -0.8097 0.2054 0.0480 0.0151 1.0362 468: 0.2810 -3.1878 -0.8096 0.2055 0.0480 0.0151 1.0361 469: 0.2811 -3.1877 -0.8096 0.2056 0.0480 0.0151 1.0361 470: 0.2811 -3.1877 -0.8096 0.2056 0.0480 0.0151 1.0361 471: 0.2809 -3.1877 -0.8097 0.2055 0.0480 0.0151 1.0361 472: 0.2807 -3.1877 -0.8097 0.2055 0.0480 0.0151 1.0360 473: 0.2806 -3.1878 -0.8097 0.2054 0.0480 0.0151 1.0360 474: 0.2805 -3.1878 -0.8097 0.2052 0.0480 0.0151 1.0360 475: 0.2805 -3.1877 -0.8097 0.2051 0.0479 0.0151 1.0360 476: 0.2805 -3.1877 -0.8098 0.2052 0.0479 0.0151 1.0360 477: 0.2805 -3.1877 -0.8098 0.2051 0.0479 0.0151 1.0359 478: 0.2804 -3.1877 -0.8098 0.2051 0.0479 0.0151 1.0359 479: 0.2805 -3.1876 -0.8098 0.2052 0.0480 0.0151 1.0359 480: 0.2805 -3.1876 -0.8098 0.2051 0.0480 0.0151 1.0360 481: 0.2805 -3.1877 -0.8097 0.2051 0.0480 0.0151 1.0360 482: 0.2805 -3.1877 -0.8098 0.2051 0.0480 0.0151 1.0360 483: 0.2805 -3.1877 -0.8098 0.2052 0.0480 0.0151 1.0360 484: 0.2804 -3.1877 -0.8098 0.2053 0.0480 0.0151 1.0359 485: 0.2805 -3.1877 -0.8098 0.2055 0.0479 0.0151 1.0360 486: 0.2805 -3.1876 -0.8098 0.2055 0.0479 0.0151 1.0360 487: 0.2806 -3.1876 -0.8098 0.2055 0.0479 0.0151 1.0359 488: 0.2806 -3.1876 -0.8098 0.2055 0.0479 0.0151 1.0357 489: 0.2807 -3.1876 -0.8098 0.2055 0.0479 0.0151 1.0356 490: 0.2808 -3.1877 -0.8097 0.2055 0.0479 0.0151 1.0356 491: 0.2809 -3.1877 -0.8097 0.2055 0.0479 0.0151 1.0355 492: 0.2810 -3.1877 -0.8096 0.2054 0.0479 0.0151 1.0355 493: 0.2810 -3.1877 -0.8096 0.2054 0.0479 0.0151 1.0355 494: 0.2811 -3.1877 -0.8096 0.2053 0.0478 0.0151 1.0354 495: 0.2813 -3.1877 -0.8095 0.2053 0.0478 0.0151 1.0353 496: 0.2815 -3.1876 -0.8095 0.2052 0.0478 0.0151 1.0353 497: 0.2815 -3.1876 -0.8095 0.2052 0.0479 0.0151 1.0353 498: 0.2816 -3.1876 -0.8096 0.2052 0.0479 0.0151 1.0353 499: 0.2816 -3.1875 -0.8096 0.2052 0.0479 0.0151 1.0352 500: 0.2816 -3.1875 -0.8097 0.2052 0.0479 0.0150 1.0352 ## Calculate ETA-based prediction and error derivatives: Calculate Jacobian...................done. Calculate sensitivities....... done. ## Calculate d(f)/d(eta) ## ... ## done ## ... ## done The model-based sensitivities have been calculated. Calculating Table Variables... done ```

> fit
-- nlmixr SAEM fit (ODE); OBJF calculated from FOCEi approximation -------------
     OBJF      AIC      BIC Log-likelihood Condition Number
 349.6105 363.6105 388.6422      -174.8053         176.3777

-- Time (sec; fit$time): -------------------------------------------------------
          saem setup Likelihood Calculation covariance table
elapsed 123.53 23.29                    0.1          0  0.21

-- Parameters (fit$par.fixed): -------------------------------------------------
        Parameter Estimate     SE %RSE Back-transformed(95%CI) BSV(CV%)
tka        Log Ka    0.282  0.137 48.6       1.33 (1.01, 1.73)    47.7%
tcl        Log Cl    -3.19 0.0654 2.05 0.0413 (0.0363, 0.0469)    22.2%
tv          Log V   -0.810 0.0402 4.97    0.445 (0.411, 0.482)    12.3%
add.err   add.err     1.02                             1.02            
        Shrink(SD)%
tka          1.15% 
tcl         0.881% 
tv           13.5% 
add.err      5.59% 

  No correlations in between subject variability (BSV) matrix
  Full BSV covariance (fit$omega) or correlation (fit$omega.R; diagonals=SDs)
  Distribution stats (mean/skewness/kurtosis/p-value) available in fit$shrink

-- Fit Data (object fit is a modified data.frame): -----------------------------
# A tibble: 264 x 21
  ID     TIME    DV  PRED   RES  WRES IPRED   IRES  IWRES CPRED  CRES CWRES
* <fct> <dbl> <dbl> <dbl> <dbl> <dbl> <dbl>  <dbl>  <dbl> <dbl> <dbl> <dbl>
1 1     0      0.74  0    0.74  0.727  0     0.74   0.727  0    0.74  0.727
2 1     0.25   2.84  2.52 0.323 0.226  3.50 -0.660 -0.649  2.35 0.486 0.285
3 1     0.570  6.57  4.65 1.92  1.06   6.32  0.254  0.250  4.41 2.16  0.989
# ... with 261 more rows, and 9 more variables: eta.ka <dbl>, eta.cl <dbl>,
#   eta.v <dbl>, depot <dbl>, center <dbl>, ka <dbl>, cl <dbl>, v <dbl>,
#   cp <dbl>
>

Also note that the theopyhille dataset has a different dose specification than a usual PK dataset (Issue #36).

UNCcrawler commented 6 years ago

Thank you, matt. I copied the theo_md example from the help page. I did notice "not run" on the page but ignored it :) Thanks for taking the time helping me!

On Tue, May 22, 2018 at 11:20 PM, Matthew Fidler notifications@github.com wrote:

The PNLS step is a common error in nlme. You can adjust this factor up, with the following code:

Note the theo_md is the same dataset as you specified but is included in the nlmixr packagefit <- nlme_ode(theo_md, model=ode, par_model=specs, par_trans=mypar,
             response="centr", response.scaler="V",control=nlmeControl(pnlsTol=0.1))
Also note that I don't see the lCL parameter in your ODE specification. So it really shouldn't fit very well.

If you use the unifed model structure you can specify a similar model with:

theo.mod <- function() { ini({ tka <- .5 # Log Ka tcl <- -3.2 # Log Cl tv <- -1 # Log V eta.ka ~ 1 eta.cl ~ 2 eta.v ~ 1 add.err <- 0.1 }) model({ ka <- exp(tka + eta.ka) cl <- exp(tcl + eta.cl) v <- exp(tv + eta.v) d/dt(depot) = -ka depot d/dt(center) = ka depot - cl / v * center cp = center / v cp ~ add(add.err) }) }

Then the nlme can be run by:

fit <- nlmixr(theo.mod,theo_md, calc.resid=FALSE,control=nlmeControl(pnlsTol=0.01))

**Iteration 1 LME step: Loglik: -417.1519, nlminb iterations: 1 reStruct parameters: ID1 ID2 ID3 1.086602 1.481263 2.198073 Beginning PNLS step: .. completed fit_nlme() step. PNLS step: RSS = 273.659 fixed effects: 0.2855648 -3.192379 -0.8096679 iterations: 6 Convergence crit. (must all become <= tolerance = 1e-05): fixed reStruct 0.7509161 0.3156169

**Iteration 2 LME step: Loglik: -417.3443, nlminb iterations: 1 reStruct parameters: ID1 ID2 ID3 0.8259257 1.5439870 2.1087332 Beginning PNLS step: .. completed fit_nlme() step. PNLS step: RSS = 273.659 fixed effects: 0.2855648 -3.192379 -0.8096679 iterations: 1 Convergence crit. (must all become <= tolerance = 1e-05): fixed reStruct 0.000000e+00 6.685185e-09 Warning message: In nlmixrUI.nlme.var(obj) : Initial condition for additive error ignored with nlme

fitNonlinear mixed-effects model fit by maximum likelihood Model: DV ~ (nlmixr::nlmeModList("user_fn"))(tka, tcl, tv, TIME, ID) Log-likelihood: -417.3443 Fixed: list(tka + tcl + tv ~ 1) tka tcl tv 0.2855648 -3.1923786 -0.8096679 Random effects: Formula: list(tka ~ 1, tcl ~ 1, tv ~ 1) Level: ID Structure: Diagonal tka tcl tv ResidualStdDev: 0.4457658 0.2173986 0.123592 1.018126 Number of Observations: 264Number of Groups: 12

If you want the nlmixr FOCEi-based residulas and objective function calculated you can use:

fit <- nlmixr(theo.mod,theo_md, calc.resid=TRUE,control=nlmeControl(pnlsTol=0.01))

Iteration 1LME step: Loglik: -417.1519, nlminb iterations: 1reStruct parameters: ID1 ID2 ID3 1.086602 1.481263 2.198073 Beginning PNLS step: .. completed fit_nlme() step.PNLS step: RSS = 273.659 fixed effects: 0.2855648 -3.192379 -0.8096679 iterations: 6 Convergence crit. (must all become <= tolerance = 1e-05): fixed reStruct 0.7509161 0.3156169 Iteration 2LME step: Loglik: -417.3443, nlminb iterations: 1reStruct parameters: ID1 ID2 ID3 0.8259257 1.5439870 2.1087332 Beginning PNLS step: .. completed fit_nlme() step.PNLS step: RSS = 273.659 fixed effects: 0.2855648 -3.192379 -0.8096679 iterations: 1 Convergence crit. (must all become <= tolerance = 1e-05): fixed reStruct 0.000000e+00 6.685185e-09 ## Calculate ETA-based prediction and error derivatives:Calculate Jacobian...................done.Calculate sensitivities.......done.## Calculate d(f)/d(eta) ## ...## done## ...## doneThe model-based sensitivities have been calculated.Calculating Table Variables...doneWarning message:In nlmixrUI.nlme.var(obj) : Initial condition for additive error ignored with nlme

fit-- nlmixr nlme fit by maximum likelihood (ODE; µ-ref & covs) -------------------FOCEi-based goodness of fit metrics: OBJF AIC BIC Log-likelihood Condition Number 349.5017 363.5017 388.5333 -174.7508 40.78343 nlme-based goodness of fit metrics: AIC BIC Log-likelihood 848.6887 873.7203 -417.3443 -- Time (sec; fit$time): ------------------------------------------------------- nlme setup FOCEi Evaulate covariance tableelapsed 3.02 33.93 0.11 0 0.23 -- Parameters (fit$par.fixed): ------------------------------------------------- Parameter Estimate SE %RSE Back-transformed(95%CI) BSV(CV%)tka Log Ka 0.286 0.139 48.6 1.33 (1.01, 1.75) 46.9%tcl Log Cl -3.19 0.0664 2.08 0.0411 (0.0361, 0.0468) 22.0%tv Log V -0.810 0.0438 5.41 0.445 (0.408, 0.485) 12.4%add.err add.err 1.02 1.02 Shrink(SD)%tka 1.86% tcl 0.543% tv 13.1% add.err 5.66%

No correlations in between subject variability (BSV) matrix Full BSV covariance (fit$omega) or correlation (fit$omega.R; diagonals=SDs) Distribution stats (mean/skewness/kurtosis/p-value) available in fit$shrink -- Fit Data (object fit is a modified data.frame): -----------------------------# A tibble: 264 x 21 ID TIME DV PRED RES WRES IPRED IRES IWRES CPRED CRES CWRES* 1 1 0 0.74 0 0.74 0.727 0 0.74 0.727 0 0.74 0.7272 1 0.25 2.84 2.53 0.315 0.221 3.49 -0.649 -0.637 2.37 0.471 0.2793 1 0.570 6.57 4.66 1.91 1.06 6.29 0.279 0.274 4.44 2.13 0.991# ... with 261 more rows, and 9 more variables: eta.ka , eta.cl ,# eta.v , depot , center , ka , cl , v ,# cp

The good thing about this type of model specification is you can switch estimation methods easily. For example, if you wanted to use the more precise saem algoritm you can simply change "nlme" to "saem".

fit <- nlmixr(theo.mod,theo_md, est="saem")

Compiling RxODE differential equations...done.PKG_CXXFLAGS=-Ic:/R/nlmixr/R/library/nlmixr/include -Ic:/R/nlmixr/R/library/STANHE~1/include -Ic:/R/nlmixr/R/library/Rcpp/include -Ic:/R/nlmixr/R/library/RCPPAR~1/include -Ic:/R/nlmixr/R/library/RCPPEI~1/include -Ic:/R/nlmixr/R/library/BH/includePKG_LIBS= $(BLAS_LIBS) $(LAPACK_LIBS)c:/R/nlmixr/rtools/mingw_64/bin/g++ -I"c:/R/nlmixr/R/include" -DNDEBUG -Ic:/R/nlmixr/R/library/nlmixr/include -Ic:/R/nlmixr/R/library/STANHE~1/include -Ic:/R/nlmixr/R/library/Rcpp/include -Ic:/R/nlmixr/R/library/RCPPAR~1/include -Ic:/R/nlmixr/R/library/RCPPEI~1/include -Ic:/R/nlmixr/R/library/BH/include -O2 -Wall -mtune=generic -c saem1664c61dc195x64.cpp -o saem1664c61dc195x64.oc:/R/nlmixr/rtools/mingw_64/bin/g++ -shared -s -static-libgcc -o saem1664c61dc195x64.dll tmp.def saem1664c61dc195x64.o -Lc:/R/nlmixr/R/bin/x64 -lRblas -Lc:/R/nlmixr/R/bin/x64 -lRlapack -Lc:/R/nlmixr/R/bin/x64 -lRdone.1: 0.0022 -2.9098 -0.6295 0.9500 1.9000 0.9500 9.00922: 0.0491 -3.0457 -0.8193 0.9025 1.8050 0.9025 4.61653: 0.0733 -3.1430 -0.9340 0.8574 1.7147 0.8574 2.16884: 0.0604 -3.1649 -0.9034 0.8145 1.6290 0.8145 1.78065: 0.0713 -3.1696 -0.9745 0.7738 1.5476 0.7738 1.48256: 0.0531 -3.1564 -0.9802 0.7351 1.4702 0.7351 1.32787: 0.0594 -3.1676 -0.9962 0.6983 1.3967 0.6983 1.24018: 0.0599 -3.1722 -0.9722 0.6634 1.3268 0.6634 1.15699: 0.1141 -3.1712 -0.9320 0.6302 1.2605 0.6302 1.164410: 0.0886 -3.1592 -0.9361 0.5987 1.1975 0.5987 1.202611: 0.1509 -3.1552 -0.9285 0.5688 1.1376 0.5688 1.167012: 0.1522 -3.1600 -0.9225 0.5404 1.0807 0.5404 1.170613: 0.1107 -3.1638 -0.9258 0.5133 1.0267 0.5133 1.148914: 0.1537 -3.1695 -0.9175 0.4877 0.9753 0.4877 1.138815: 0.1766 -3.1647 -0.9011 0.4633 0.9266 0.4633 1.143916: 0.1808 -3.1652 -0.8825 0.4401 0.8803 0.4401 1.109317: 0.2153 -3.1677 -0.8619 0.4547 0.8362 0.4181 1.092718: 0.2136 -3.1764 -0.8806 0.4363 0.7944 0.3972 1.123119: 0.2236 -3.1639 -0.8903 0.4314 0.7547 0.3774 1.103520: 0.2470 -3.1872 -0.8759 0.4272 0.7170 0.3585 1.055621: 0.2181 -3.1724 -0.8619 0.4058 0.6811 0.3406 1.049222: 0.2056 -3.1660 -0.8709 0.3856 0.6471 0.3235 1.060123: 0.2531 -3.1590 -0.8723 0.3663 0.6147 0.3074 1.070124: 0.2225 -3.1645 -0.8676 0.3480 0.5840 0.2920 1.058825: 0.2303 -3.1642 -0.8598 0.3499 0.5548 0.2774 1.059526: 0.2422 -3.1645 -0.8877 0.3934 0.5270 0.2635 1.065727: 0.2223 -3.1538 -0.8752 0.3737 0.5007 0.2503 1.061728: 0.2272 -3.1628 -0.8769 0.3760 0.4757 0.2378 1.051029: 0.2244 -3.1639 -0.8694 0.3572 0.4519 0.2259 1.052330: 0.2317 -3.1746 -0.8710 0.3450 0.4293 0.2146 1.036931: 0.2001 -3.1867 -0.8516 0.3278 0.4078 0.2039 1.097832: 0.1941 -3.2189 -0.8517 0.3533 0.3874 0.1937 1.073433: 0.1700 -3.2056 -0.8552 0.3550 0.3681 0.1840 1.059434: 0.2746 -3.1755 -0.8580 0.3961 0.3496 0.1748 1.028435: 0.2480 -3.1766 -0.8652 0.3919 0.3322 0.1661 1.041436: 0.2384 -3.1870 -0.8533 0.3723 0.3156 0.1578 1.055637: 0.2063 -3.1728 -0.8580 0.3814 0.2998 0.1499 1.066038: 0.3406 -3.1650 -0.8113 0.3623 0.2848 0.1424 1.067239: 0.3268 -3.1796 -0.8159 0.3442 0.2706 0.1353 1.020040: 0.2709 -3.1861 -0.7982 0.3270 0.2570 0.1285 1.075541: 0.2489 -3.2002 -0.8059 0.3106 0.2442 0.1221 1.071842: 0.2822 -3.1942 -0.8080 0.2951 0.2320 0.1160 1.042443: 0.2564 -3.1973 -0.8134 0.2804 0.2204 0.1102 1.051744: 0.2273 -3.1934 -0.8328 0.2663 0.2093 0.1047 1.053045: 0.2223 -3.1801 -0.8383 0.2530 0.1989 0.0994 1.028946: 0.2287 -3.1849 -0.8154 0.2404 0.1889 0.0945 1.058447: 0.2935 -3.2079 -0.7886 0.2284 0.1795 0.0897 1.069148: 0.3212 -3.1887 -0.7912 0.2169 0.1705 0.0853 1.065449: 0.2807 -3.1776 -0.8029 0.2061 0.1620 0.0810 1.081950: 0.3044 -3.1945 -0.7945 0.2106 0.1539 0.0769 1.053651: 0.2853 -3.1916 -0.8175 0.2096 0.1462 0.0731 1.047752: 0.3093 -3.1844 -0.8073 0.1991 0.1389 0.0694 1.015453: 0.2943 -3.2027 -0.8098 0.2028 0.1319 0.0660 1.021854: 0.2188 -3.1804 -0.8379 0.2146 0.1253 0.0627 1.056255: 0.2393 -3.1871 -0.8157 0.2039 0.1191 0.0595 1.071256: 0.2790 -3.1966 -0.8087 0.2017 0.1131 0.0566 1.080857: 0.2803 -3.2060 -0.7980 0.2143 0.1075 0.0537 1.067258: 0.2935 -3.1939 -0.8137 0.2239 0.1021 0.0510 1.033059: 0.2886 -3.1967 -0.8052 0.2127 0.0970 0.0485 1.051360: 0.2974 -3.1946 -0.8052 0.2274 0.0921 0.0461 1.012961: 0.3015 -3.1723 -0.7991 0.2458 0.0875 0.0438 1.064862: 0.2934 -3.1837 -0.7944 0.2335 0.0832 0.0416 1.040563: 0.3428 -3.2005 -0.7861 0.2218 0.0790 0.0395 1.027464: 0.3282 -3.1796 -0.7920 0.2107 0.0750 0.0375 1.015565: 0.3417 -3.1913 -0.8048 0.2059 0.0713 0.0356 1.020666: 0.2953 -3.1955 -0.8029 0.1956 0.0677 0.0339 1.015367: 0.2859 -3.2057 -0.8075 0.1859 0.0643 0.0322 1.014768: 0.2685 -3.2041 -0.7757 0.1766 0.0611 0.0306 1.060669: 0.2802 -3.2080 -0.7987 0.1745 0.0581 0.0290 1.072070: 0.2694 -3.2038 -0.7959 0.1854 0.0552 0.0276 1.052271: 0.2673 -3.1774 -0.8253 0.1810 0.0524 0.0262 1.065072: 0.2300 -3.1908 -0.8217 0.1720 0.0498 0.0252 1.029173: 0.2901 -3.1839 -0.7974 0.1634 0.0473 0.0239 1.034574: 0.2930 -3.2065 -0.7963 0.1649 0.0449 0.0227 1.037575: 0.2932 -3.2037 -0.7703 0.1744 0.0504 0.0216 1.032876: 0.3265 -3.1937 -0.7645 0.1664 0.0479 0.0205 1.066677: 0.3755 -3.1932 -0.7773 0.1647 0.0455 0.0205 1.066578: 0.3553 -3.2002 -0.7729 0.1800 0.0444 0.0195 1.030679: 0.3374 -3.1981 -0.7792 0.2168 0.0447 0.0185 1.080080: 0.3249 -3.1983 -0.7776 0.2395 0.0425 0.0176 1.095381: 0.3282 -3.2026 -0.7801 0.2275 0.0446 0.0201 1.068982: 0.3220 -3.2076 -0.7772 0.2162 0.0437 0.0201 1.055983: 0.3093 -3.1860 -0.7822 0.2054 0.0534 0.0191 1.060284: 0.2996 -3.1881 -0.8025 0.1951 0.0507 0.0182 1.029585: 0.3159 -3.1949 -0.7842 0.1960 0.0482 0.0173 1.056686: 0.3011 -3.1908 -0.7883 0.1935 0.0488 0.0183 1.020887: 0.3153 -3.2080 -0.7977 0.1838 0.0464 0.0174 1.040888: 0.2613 -3.2133 -0.7914 0.1935 0.0441 0.0189 1.033789: 0.3016 -3.2012 -0.7942 0.1869 0.0457 0.0183 1.019790: 0.2864 -3.2079 -0.8027 0.1906 0.0434 0.0174 1.033691: 0.2717 -3.2127 -0.8267 0.2040 0.0412 0.0165 1.033992: 0.2676 -3.1792 -0.8264 0.2474 0.0429 0.0187 1.041793: 0.2363 -3.1861 -0.8306 0.2435 0.0458 0.0177 1.040194: 0.2639 -3.1889 -0.8266 0.2313 0.0464 0.0168 1.019695: 0.2611 -3.1837 -0.8183 0.2355 0.0479 0.0160 1.026996: 0.2310 -3.1973 -0.8201 0.2573 0.0455 0.0152 1.028597: 0.2779 -3.1817 -0.8129 0.2444 0.0433 0.0152 1.054398: 0.2712 -3.1715 -0.8150 0.2322 0.0468 0.0147 1.050999: 0.2777 -3.1937 -0.8204 0.2206 0.0464 0.0159 1.0236100: 0.2655 -3.1876 -0.8174 0.2096 0.0445 0.0151 1.0111101: 0.2186 -3.1929 -0.8390 0.1991 0.0466 0.0144 1.0039102: 0.2120 -3.1964 -0.8456 0.1891 0.0448 0.0148 1.0349103: 0.2613 -3.1936 -0.8217 0.1842 0.0425 0.0141 1.0311104: 0.2609 -3.1718 -0.8149 0.1977 0.0426 0.0134 1.0503105: 0.2669 -3.1862 -0.8177 0.2091 0.0499 0.0127 1.0509106: 0.2685 -3.1857 -0.8191 0.2151 0.0554 0.0121 1.0484107: 0.2778 -3.1660 -0.8248 0.2169 0.0599 0.0115 1.0684108: 0.2632 -3.1839 -0.8271 0.2061 0.0569 0.0114 1.0320109: 0.2550 -3.1851 -0.8130 0.2112 0.0619 0.0109 1.0475110: 0.2679 -3.1968 -0.8267 0.2007 0.0588 0.0126 1.0203111: 0.2727 -3.1853 -0.8220 0.2046 0.0559 0.0135 1.0105112: 0.2616 -3.1902 -0.8350 0.2099 0.0583 0.0129 1.0321113: 0.2483 -3.1657 -0.8326 0.1994 0.0554 0.0122 1.0222114: 0.2539 -3.1724 -0.8313 0.1894 0.0609 0.0116 1.0113115: 0.2841 -3.1900 -0.8209 0.1816 0.0578 0.0129 1.0348116: 0.2798 -3.1897 -0.8080 0.2003 0.0549 0.0141 1.0431117: 0.2463 -3.1769 -0.8099 0.1903 0.0522 0.0137 1.0368118: 0.2754 -3.1872 -0.8202 0.1897 0.0510 0.0130 1.0143119: 0.2676 -3.1889 -0.8155 0.2215 0.0484 0.0182 1.0196120: 0.2372 -3.1957 -0.8179 0.2345 0.0460 0.0184 1.0173121: 0.2666 -3.1789 -0.8145 0.2228 0.0480 0.0185 1.0359122: 0.2810 -3.2002 -0.8033 0.2117 0.0456 0.0176 1.0317123: 0.3266 -3.1694 -0.8161 0.2210 0.0480 0.0167 1.0091124: 0.3009 -3.1621 -0.8211 0.2326 0.0497 0.0159 1.0143125: 0.3114 -3.1619 -0.8276 0.2210 0.0504 0.0151 1.0146126: 0.2727 -3.1606 -0.8359 0.2280 0.0552 0.0143 1.0277127: 0.2627 -3.1728 -0.8378 0.2166 0.0524 0.0158 1.0402128: 0.2402 -3.1735 -0.8317 0.2417 0.0540 0.0181 1.0559129: 0.2771 -3.1733 -0.8256 0.2763 0.0513 0.0172 1.0168130: 0.2887 -3.1759 -0.8254 0.2637 0.0528 0.0174 0.9922131: 0.2760 -3.1877 -0.8345 0.2506 0.0593 0.0194 1.0204132: 0.2205 -3.1712 -0.8440 0.2380 0.0563 0.0184 1.0344133: 0.2600 -3.1777 -0.8349 0.2261 0.0535 0.0196 1.0664134: 0.2856 -3.1969 -0.8045 0.2148 0.0508 0.0270 1.0303135: 0.2693 -3.1858 -0.8095 0.2113 0.0483 0.0256 1.0317136: 0.3041 -3.1913 -0.7943 0.2007 0.0459 0.0243 1.0072137: 0.3179 -3.2044 -0.7899 0.1916 0.0436 0.0231 1.0234138: 0.3144 -3.1932 -0.7891 0.1855 0.0414 0.0220 1.0134139: 0.3089 -3.1904 -0.7809 0.1927 0.0425 0.0226 1.0194140: 0.3252 -3.1830 -0.7751 0.2047 0.0408 0.0214 1.0283141: 0.3201 -3.1995 -0.7780 0.2165 0.0451 0.0204 1.0178142: 0.3393 -3.2020 -0.7754 0.2138 0.0497 0.0193 1.0307143: 0.3001 -3.1903 -0.7878 0.2031 0.0484 0.0184 1.0366144: 0.3368 -3.1932 -0.7770 0.1930 0.0460 0.0175 1.0313145: 0.3306 -3.1795 -0.8050 0.2143 0.0489 0.0166 0.9969146: 0.2796 -3.1853 -0.8019 0.2115 0.0504 0.0175 1.0293147: 0.2368 -3.1857 -0.8202 0.2010 0.0496 0.0166 1.0486148: 0.2682 -3.1926 -0.8020 0.1909 0.0471 0.0158 1.0565149: 0.2667 -3.1914 -0.8092 0.1814 0.0544 0.0150 1.0490150: 0.3028 -3.1943 -0.8090 0.1875 0.0545 0.0142 1.0617151: 0.2473 -3.1866 -0.8163 0.1810 0.0518 0.0135 1.0601152: 0.2443 -3.1891 -0.8214 0.1910 0.0575 0.0129 1.0446153: 0.2659 -3.1845 -0.8110 0.2301 0.0588 0.0136 1.0371154: 0.3238 -3.1691 -0.8017 0.2183 0.0552 0.0174 1.0558155: 0.2942 -3.1965 -0.8044 0.2433 0.0437 0.0215 1.0303156: 0.2904 -3.1860 -0.7860 0.1958 0.0450 0.0215 1.0280157: 0.2851 -3.1985 -0.7937 0.1786 0.0375 0.0227 1.0421158: 0.3207 -3.1970 -0.7840 0.1947 0.0377 0.0209 1.0186159: 0.2959 -3.1863 -0.7957 0.1830 0.0404 0.0217 1.0202160: 0.3243 -3.2153 -0.7835 0.2168 0.0443 0.0185 1.0208161: 0.2858 -3.2057 -0.7993 0.1988 0.0397 0.0241 1.0050162: 0.2951 -3.1789 -0.8091 0.2195 0.0436 0.0226 1.0214163: 0.3340 -3.1861 -0.8086 0.1896 0.0356 0.0186 1.0286164: 0.3346 -3.1962 -0.7978 0.1841 0.0349 0.0185 1.0376165: 0.3306 -3.2070 -0.7862 0.1878 0.0414 0.0167 1.0553166: 0.3483 -3.1856 -0.7808 0.2012 0.0398 0.0171 1.0427167: 0.3149 -3.1774 -0.7863 0.1912 0.0439 0.0259 1.0600168: 0.3247 -3.1802 -0.7929 0.1763 0.0456 0.0289 1.0460169: 0.2849 -3.1659 -0.8165 0.1616 0.0434 0.0227 1.0580170: 0.2989 -3.1865 -0.8125 0.1573 0.0373 0.0192 1.0323171: 0.2680 -3.1801 -0.8207 0.1663 0.0445 0.0187 0.9920172: 0.2594 -3.1754 -0.8223 0.1631 0.0411 0.0201 1.0083173: 0.2691 -3.1692 -0.8323 0.1563 0.0477 0.0217 1.0213174: 0.2795 -3.1719 -0.8121 0.1614 0.0437 0.0196 1.0340175: 0.2828 -3.1773 -0.8219 0.2017 0.0470 0.0218 1.0045176: 0.2505 -3.1769 -0.8146 0.1945 0.0499 0.0184 1.0329177: 0.2929 -3.1982 -0.8010 0.2102 0.0499 0.0176 1.0293178: 0.2900 -3.1928 -0.8011 0.2036 0.0523 0.0195 1.0206179: 0.3106 -3.1581 -0.8042 0.2108 0.0583 0.0154 1.0441180: 0.2707 -3.1779 -0.8084 0.1622 0.0505 0.0177 1.0597181: 0.2641 -3.1886 -0.8381 0.1787 0.0510 0.0194 1.0409182: 0.2292 -3.1615 -0.8415 0.1819 0.0586 0.0177 1.0594183: 0.2450 -3.1699 -0.8373 0.1907 0.0568 0.0167 1.0385184: 0.2559 -3.1782 -0.8280 0.1828 0.0518 0.0144 1.0493185: 0.2477 -3.1751 -0.8276 0.1730 0.0448 0.0145 1.0272186: 0.2413 -3.1725 -0.8312 0.1847 0.0507 0.0129 1.0386187: 0.2537 -3.1861 -0.8200 0.1897 0.0464 0.0116 1.0416188: 0.2563 -3.1736 -0.8261 0.2258 0.0506 0.0126 1.0401189: 0.2633 -3.1752 -0.8162 0.1886 0.0459 0.0121 1.0519190: 0.2663 -3.1811 -0.8145 0.1648 0.0480 0.0120 1.0482191: 0.2574 -3.1709 -0.8175 0.1721 0.0504 0.0109 1.0555192: 0.2476 -3.1733 -0.8177 0.1668 0.0478 0.0110 1.0821193: 0.2955 -3.1664 -0.8109 0.1690 0.0495 0.0106 1.0521194: 0.2584 -3.1801 -0.8252 0.1841 0.0514 0.0093 1.0593195: 0.2602 -3.1882 -0.8294 0.1801 0.0461 0.0090 1.0397196: 0.2251 -3.1894 -0.8292 0.1883 0.0517 0.0099 1.0391197: 0.2500 -3.1824 -0.8078 0.2075 0.0413 0.0119 1.0704198: 0.3072 -3.1912 -0.8139 0.2399 0.0426 0.0120 1.0404199: 0.2987 -3.1901 -0.8029 0.2163 0.0474 0.0113 1.0580200: 0.2746 -3.1941 -0.8078 0.1906 0.0513 0.0134 1.0351201: 0.2662 -3.1916 -0.8064 0.1873 0.0508 0.0129 1.0285202: 0.2753 -3.1905 -0.8066 0.1922 0.0509 0.0124 1.0420203: 0.2852 -3.1905 -0.8076 0.2045 0.0520 0.0125 1.0432204: 0.2897 -3.1923 -0.8072 0.2080 0.0516 0.0121 1.0417205: 0.2898 -3.1882 -0.8068 0.2051 0.0526 0.0123 1.0395206: 0.2896 -3.1849 -0.8066 0.2053 0.0516 0.0123 1.0439207: 0.2879 -3.1863 -0.8066 0.2059 0.0502 0.0123 1.0453208: 0.2851 -3.1885 -0.8067 0.2032 0.0496 0.0125 1.0422209: 0.2873 -3.1890 -0.8076 0.2033 0.0492 0.0128 1.0399210: 0.2889 -3.1896 -0.8079 0.2043 0.0486 0.0128 1.0393211: 0.2905 -3.1893 -0.8072 0.2067 0.0487 0.0126 1.0364212: 0.2918 -3.1898 -0.8065 0.2084 0.0488 0.0127 1.0353213: 0.2934 -3.1905 -0.8059 0.2077 0.0486 0.0128 1.0356214: 0.2939 -3.1910 -0.8059 0.2084 0.0486 0.0133 1.0339215: 0.2934 -3.1908 -0.8055 0.2082 0.0483 0.0138 1.0337216: 0.2955 -3.1914 -0.8055 0.2102 0.0480 0.0140 1.0351217: 0.2964 -3.1901 -0.8056 0.2107 0.0479 0.0140 1.0337218: 0.2966 -3.1893 -0.8062 0.2103 0.0478 0.0141 1.0337219: 0.2972 -3.1886 -0.8070 0.2092 0.0474 0.0143 1.0330220: 0.2957 -3.1881 -0.8072 0.2068 0.0472 0.0145 1.0329221: 0.2943 -3.1881 -0.8073 0.2046 0.0470 0.0146 1.0323222: 0.2949 -3.1882 -0.8071 0.2046 0.0467 0.0148 1.0328223: 0.2954 -3.1886 -0.8070 0.2036 0.0465 0.0151 1.0327224: 0.2960 -3.1882 -0.8068 0.2039 0.0466 0.0152 1.0322225: 0.2961 -3.1896 -0.8060 0.2027 0.0466 0.0155 1.0336226: 0.2956 -3.1899 -0.8060 0.2032 0.0465 0.0156 1.0343227: 0.2947 -3.1903 -0.8057 0.2021 0.0464 0.0158 1.0345228: 0.2938 -3.1895 -0.8062 0.2016 0.0467 0.0160 1.0347229: 0.2934 -3.1896 -0.8062 0.2006 0.0467 0.0160 1.0348230: 0.2941 -3.1897 -0.8062 0.2001 0.0467 0.0160 1.0346231: 0.2942 -3.1897 -0.8058 0.1993 0.0467 0.0161 1.0344232: 0.2932 -3.1898 -0.8055 0.1988 0.0467 0.0161 1.0339233: 0.2932 -3.1905 -0.8049 0.1991 0.0465 0.0163 1.0340234: 0.2925 -3.1909 -0.8044 0.1987 0.0464 0.0163 1.0340235: 0.2927 -3.1909 -0.8045 0.1986 0.0464 0.0163 1.0340236: 0.2922 -3.1905 -0.8051 0.1984 0.0464 0.0163 1.0342237: 0.2925 -3.1906 -0.8052 0.1987 0.0464 0.0164 1.0342238: 0.2928 -3.1906 -0.8052 0.1990 0.0464 0.0165 1.0352239: 0.2928 -3.1904 -0.8052 0.1996 0.0465 0.0164 1.0359240: 0.2926 -3.1909 -0.8051 0.1998 0.0466 0.0164 1.0354241: 0.2932 -3.1916 -0.8046 0.2002 0.0467 0.0163 1.0348242: 0.2927 -3.1917 -0.8047 0.2004 0.0468 0.0163 1.0350243: 0.2917 -3.1914 -0.8048 0.2007 0.0470 0.0163 1.0350244: 0.2910 -3.1910 -0.8048 0.1998 0.0471 0.0163 1.0354245: 0.2911 -3.1911 -0.8048 0.1999 0.0472 0.0164 1.0364246: 0.2911 -3.1914 -0.8048 0.1998 0.0473 0.0164 1.0366247: 0.2910 -3.1913 -0.8046 0.2002 0.0473 0.0164 1.0367248: 0.2907 -3.1912 -0.8047 0.2003 0.0473 0.0164 1.0371249: 0.2902 -3.1913 -0.8046 0.1997 0.0472 0.0164 1.0372250: 0.2906 -3.1912 -0.8045 0.2002 0.0473 0.0164 1.0369251: 0.2905 -3.1910 -0.8043 0.2005 0.0474 0.0163 1.0370252: 0.2906 -3.1908 -0.8041 0.2010 0.0474 0.0163 1.0374253: 0.2899 -3.1907 -0.8043 0.2015 0.0475 0.0163 1.0374254: 0.2893 -3.1905 -0.8043 0.2020 0.0476 0.0163 1.0371255: 0.2890 -3.1903 -0.8041 0.2014 0.0476 0.0163 1.0374256: 0.2891 -3.1902 -0.8042 0.2017 0.0475 0.0163 1.0371257: 0.2888 -3.1902 -0.8044 0.2015 0.0475 0.0162 1.0373258: 0.2885 -3.1902 -0.8046 0.2019 0.0476 0.0161 1.0375259: 0.2878 -3.1902 -0.8048 0.2014 0.0477 0.0160 1.0377260: 0.2873 -3.1902 -0.8047 0.2011 0.0477 0.0160 1.0370261: 0.2875 -3.1903 -0.8044 0.2012 0.0478 0.0159 1.0368262: 0.2881 -3.1903 -0.8042 0.2015 0.0480 0.0158 1.0370263: 0.2884 -3.1903 -0.8042 0.2022 0.0480 0.0158 1.0368264: 0.2883 -3.1904 -0.8043 0.2026 0.0479 0.0158 1.0372265: 0.2885 -3.1902 -0.8043 0.2028 0.0481 0.0158 1.0375266: 0.2886 -3.1901 -0.8042 0.2037 0.0481 0.0158 1.0371267: 0.2890 -3.1901 -0.8042 0.2043 0.0480 0.0157 1.0372268: 0.2893 -3.1903 -0.8042 0.2045 0.0479 0.0158 1.0368269: 0.2899 -3.1904 -0.8040 0.2048 0.0479 0.0157 1.0369270: 0.2903 -3.1903 -0.8040 0.2055 0.0479 0.0157 1.0363271: 0.2904 -3.1902 -0.8041 0.2055 0.0480 0.0156 1.0364272: 0.2904 -3.1902 -0.8041 0.2053 0.0481 0.0156 1.0368273: 0.2906 -3.1901 -0.8040 0.2051 0.0482 0.0156 1.0369274: 0.2904 -3.1900 -0.8040 0.2043 0.0481 0.0156 1.0372275: 0.2903 -3.1898 -0.8041 0.2041 0.0482 0.0156 1.0371276: 0.2904 -3.1896 -0.8039 0.2042 0.0483 0.0156 1.0376277: 0.2902 -3.1896 -0.8037 0.2037 0.0482 0.0156 1.0378278: 0.2901 -3.1896 -0.8036 0.2034 0.0482 0.0156 1.0381279: 0.2900 -3.1897 -0.8037 0.2033 0.0481 0.0156 1.0382280: 0.2897 -3.1897 -0.8036 0.2030 0.0481 0.0155 1.0378281: 0.2893 -3.1897 -0.8036 0.2030 0.0481 0.0155 1.0376282: 0.2894 -3.1896 -0.8035 0.2034 0.0482 0.0154 1.0377283: 0.2901 -3.1896 -0.8034 0.2038 0.0483 0.0154 1.0384284: 0.2901 -3.1898 -0.8033 0.2042 0.0483 0.0153 1.0384285: 0.2901 -3.1899 -0.8034 0.2040 0.0483 0.0153 1.0383286: 0.2899 -3.1897 -0.8035 0.2043 0.0485 0.0153 1.0383287: 0.2899 -3.1895 -0.8036 0.2045 0.0485 0.0153 1.0384288: 0.2899 -3.1895 -0.8037 0.2043 0.0486 0.0152 1.0386289: 0.2901 -3.1895 -0.8037 0.2040 0.0486 0.0152 1.0388290: 0.2902 -3.1894 -0.8037 0.2040 0.0486 0.0153 1.0390291: 0.2906 -3.1893 -0.8036 0.2038 0.0486 0.0153 1.0385292: 0.2905 -3.1893 -0.8036 0.2036 0.0486 0.0152 1.0382293: 0.2901 -3.1893 -0.8037 0.2038 0.0485 0.0152 1.0381294: 0.2897 -3.1895 -0.8039 0.2041 0.0485 0.0152 1.0378295: 0.2898 -3.1896 -0.8039 0.2044 0.0485 0.0151 1.0376296: 0.2898 -3.1895 -0.8040 0.2043 0.0485 0.0151 1.0378297: 0.2899 -3.1893 -0.8041 0.2043 0.0484 0.0152 1.0377298: 0.2900 -3.1895 -0.8041 0.2040 0.0485 0.0152 1.0375299: 0.2898 -3.1894 -0.8042 0.2043 0.0485 0.0151 1.0376300: 0.2897 -3.1895 -0.8043 0.2047 0.0485 0.0151 1.0377301: 0.2897 -3.1895 -0.8043 0.2046 0.0485 0.0150 1.0377302: 0.2895 -3.1895 -0.8044 0.2045 0.0485 0.0150 1.0376303: 0.2893 -3.1895 -0.8045 0.2046 0.0484 0.0151 1.0372304: 0.2893 -3.1894 -0.8046 0.2048 0.0483 0.0151 1.0373305: 0.2892 -3.1895 -0.8046 0.2049 0.0483 0.0151 1.0373306: 0.2890 -3.1897 -0.8047 0.2048 0.0483 0.0151 1.0373307: 0.2891 -3.1897 -0.8048 0.2047 0.0484 0.0150 1.0376308: 0.2889 -3.1899 -0.8049 0.2047 0.0484 0.0150 1.0379309: 0.2886 -3.1901 -0.8050 0.2047 0.0483 0.0150 1.0379310: 0.2885 -3.1900 -0.8052 0.2048 0.0484 0.0150 1.0378311: 0.2885 -3.1900 -0.8052 0.2049 0.0485 0.0150 1.0378312: 0.2883 -3.1900 -0.8053 0.2052 0.0485 0.0150 1.0377313: 0.2882 -3.1901 -0.8054 0.2050 0.0485 0.0149 1.0378314: 0.2881 -3.1903 -0.8053 0.2051 0.0484 0.0150 1.0378315: 0.2881 -3.1903 -0.8053 0.2053 0.0483 0.0150 1.0379316: 0.2882 -3.1904 -0.8053 0.2055 0.0483 0.0150 1.0379317: 0.2884 -3.1903 -0.8053 0.2054 0.0482 0.0150 1.0380318: 0.2885 -3.1904 -0.8053 0.2054 0.0482 0.0150 1.0379319: 0.2884 -3.1904 -0.8053 0.2051 0.0482 0.0150 1.0380320: 0.2881 -3.1903 -0.8054 0.2052 0.0482 0.0150 1.0383321: 0.2878 -3.1903 -0.8056 0.2053 0.0482 0.0150 1.0383322: 0.2877 -3.1903 -0.8058 0.2056 0.0481 0.0151 1.0383323: 0.2872 -3.1903 -0.8059 0.2060 0.0482 0.0151 1.0383324: 0.2874 -3.1902 -0.8058 0.2064 0.0482 0.0151 1.0381325: 0.2873 -3.1901 -0.8059 0.2066 0.0482 0.0151 1.0379326: 0.2873 -3.1901 -0.8061 0.2066 0.0481 0.0151 1.0378327: 0.2874 -3.1901 -0.8061 0.2069 0.0481 0.0151 1.0376328: 0.2874 -3.1901 -0.8061 0.2072 0.0481 0.0151 1.0374329: 0.2875 -3.1902 -0.8059 0.2074 0.0481 0.0151 1.0375330: 0.2873 -3.1902 -0.8059 0.2075 0.0481 0.0151 1.0376331: 0.2873 -3.1901 -0.8059 0.2074 0.0481 0.0151 1.0374332: 0.2871 -3.1900 -0.8059 0.2075 0.0481 0.0151 1.0377333: 0.2869 -3.1898 -0.8061 0.2080 0.0481 0.0151 1.0379334: 0.2866 -3.1898 -0.8064 0.2082 0.0480 0.0151 1.0380335: 0.2865 -3.1898 -0.8066 0.2086 0.0480 0.0151 1.0378336: 0.2862 -3.1897 -0.8067 0.2087 0.0481 0.0151 1.0378337: 0.2859 -3.1894 -0.8069 0.2088 0.0482 0.0151 1.0378338: 0.2859 -3.1893 -0.8069 0.2088 0.0482 0.0150 1.0376339: 0.2856 -3.1893 -0.8070 0.2086 0.0483 0.0150 1.0376340: 0.2854 -3.1893 -0.8070 0.2086 0.0483 0.0150 1.0374341: 0.2855 -3.1894 -0.8070 0.2085 0.0483 0.0150 1.0374342: 0.2853 -3.1895 -0.8070 0.2083 0.0483 0.0150 1.0373343: 0.2851 -3.1895 -0.8070 0.2081 0.0483 0.0149 1.0371344: 0.2851 -3.1895 -0.8070 0.2080 0.0482 0.0149 1.0371345: 0.2851 -3.1895 -0.8069 0.2079 0.0482 0.0149 1.0369346: 0.2852 -3.1896 -0.8070 0.2077 0.0482 0.0149 1.0370347: 0.2853 -3.1896 -0.8071 0.2077 0.0482 0.0149 1.0373348: 0.2850 -3.1895 -0.8072 0.2076 0.0481 0.0149 1.0373349: 0.2849 -3.1897 -0.8072 0.2074 0.0481 0.0150 1.0373350: 0.2846 -3.1898 -0.8073 0.2073 0.0481 0.0150 1.0373351: 0.2844 -3.1898 -0.8074 0.2073 0.0481 0.0150 1.0372352: 0.2839 -3.1896 -0.8074 0.2073 0.0481 0.0150 1.0374353: 0.2839 -3.1895 -0.8075 0.2076 0.0481 0.0150 1.0374354: 0.2839 -3.1895 -0.8076 0.2077 0.0481 0.0150 1.0373355: 0.2839 -3.1896 -0.8077 0.2076 0.0481 0.0150 1.0373356: 0.2837 -3.1896 -0.8077 0.2075 0.0481 0.0150 1.0374357: 0.2838 -3.1895 -0.8078 0.2074 0.0481 0.0150 1.0375358: 0.2837 -3.1895 -0.8077 0.2071 0.0481 0.0150 1.0374359: 0.2837 -3.1894 -0.8077 0.2070 0.0481 0.0150 1.0374360: 0.2835 -3.1894 -0.8078 0.2069 0.0480 0.0150 1.0373361: 0.2832 -3.1893 -0.8080 0.2068 0.0480 0.0151 1.0372362: 0.2833 -3.1894 -0.8080 0.2066 0.0481 0.0151 1.0371363: 0.2832 -3.1894 -0.8081 0.2066 0.0480 0.0151 1.0368364: 0.2832 -3.1894 -0.8081 0.2067 0.0480 0.0151 1.0369365: 0.2831 -3.1895 -0.8081 0.2066 0.0480 0.0151 1.0368366: 0.2832 -3.1894 -0.8082 0.2066 0.0480 0.0151 1.0369367: 0.2833 -3.1894 -0.8082 0.2064 0.0480 0.0151 1.0370368: 0.2834 -3.1893 -0.8082 0.2064 0.0480 0.0151 1.0370369: 0.2833 -3.1892 -0.8083 0.2068 0.0480 0.0151 1.0370370: 0.2833 -3.1891 -0.8083 0.2068 0.0480 0.0151 1.0370371: 0.2828 -3.1891 -0.8085 0.2067 0.0480 0.0151 1.0370372: 0.2825 -3.1891 -0.8087 0.2065 0.0480 0.0151 1.0371373: 0.2823 -3.1890 -0.8088 0.2064 0.0480 0.0151 1.0373374: 0.2822 -3.1889 -0.8089 0.2060 0.0480 0.0151 1.0374375: 0.2818 -3.1889 -0.8090 0.2059 0.0480 0.0151 1.0376376: 0.2816 -3.1888 -0.8091 0.2058 0.0480 0.0151 1.0375377: 0.2814 -3.1887 -0.8091 0.2055 0.0481 0.0151 1.0375378: 0.2810 -3.1888 -0.8092 0.2054 0.0481 0.0151 1.0375379: 0.2808 -3.1889 -0.8092 0.2055 0.0481 0.0151 1.0376380: 0.2806 -3.1890 -0.8093 0.2054 0.0481 0.0150 1.0375381: 0.2803 -3.1890 -0.8094 0.2053 0.0480 0.0150 1.0374382: 0.2801 -3.1890 -0.8095 0.2052 0.0480 0.0150 1.0374383: 0.2803 -3.1890 -0.8094 0.2052 0.0480 0.0150 1.0373384: 0.2802 -3.1890 -0.8095 0.2050 0.0480 0.0150 1.0372385: 0.2801 -3.1890 -0.8095 0.2051 0.0480 0.0150 1.0372386: 0.2802 -3.1889 -0.8095 0.2050 0.0480 0.0150 1.0372387: 0.2803 -3.1889 -0.8094 0.2049 0.0479 0.0150 1.0371388: 0.2804 -3.1889 -0.8093 0.2049 0.0479 0.0150 1.0371389: 0.2804 -3.1889 -0.8093 0.2049 0.0480 0.0150 1.0372390: 0.2803 -3.1888 -0.8094 0.2049 0.0480 0.0150 1.0370391: 0.2804 -3.1888 -0.8094 0.2050 0.0480 0.0150 1.0370392: 0.2805 -3.1888 -0.8094 0.2051 0.0480 0.0150 1.0370393: 0.2804 -3.1889 -0.8095 0.2052 0.0479 0.0150 1.0369394: 0.2803 -3.1889 -0.8095 0.2053 0.0479 0.0150 1.0369395: 0.2805 -3.1888 -0.8095 0.2052 0.0479 0.0151 1.0370396: 0.2807 -3.1888 -0.8094 0.2052 0.0479 0.0151 1.0369397: 0.2809 -3.1889 -0.8093 0.2053 0.0479 0.0151 1.0369398: 0.2809 -3.1889 -0.8092 0.2053 0.0479 0.0151 1.0368399: 0.2811 -3.1889 -0.8091 0.2054 0.0479 0.0151 1.0367400: 0.2813 -3.1889 -0.8091 0.2054 0.0479 0.0151 1.0369401: 0.2814 -3.1887 -0.8091 0.2054 0.0479 0.0151 1.0369402: 0.2816 -3.1887 -0.8090 0.2055 0.0479 0.0151 1.0370403: 0.2819 -3.1887 -0.8091 0.2054 0.0480 0.0151 1.0371404: 0.2822 -3.1886 -0.8091 0.2053 0.0480 0.0151 1.0371405: 0.2822 -3.1886 -0.8091 0.2053 0.0480 0.0151 1.0371406: 0.2823 -3.1885 -0.8091 0.2054 0.0480 0.0151 1.0372407: 0.2824 -3.1885 -0.8090 0.2056 0.0480 0.0151 1.0371408: 0.2824 -3.1884 -0.8090 0.2055 0.0480 0.0151 1.0373409: 0.2824 -3.1884 -0.8091 0.2055 0.0480 0.0151 1.0372410: 0.2823 -3.1884 -0.8092 0.2055 0.0480 0.0151 1.0373411: 0.2824 -3.1884 -0.8092 0.2057 0.0481 0.0151 1.0374412: 0.2823 -3.1883 -0.8093 0.2055 0.0481 0.0151 1.0376413: 0.2821 -3.1883 -0.8094 0.2054 0.0481 0.0151 1.0377414: 0.2817 -3.1883 -0.8095 0.2053 0.0481 0.0152 1.0377415: 0.2817 -3.1883 -0.8095 0.2053 0.0481 0.0152 1.0377416: 0.2818 -3.1883 -0.8096 0.2053 0.0481 0.0152 1.0376417: 0.2818 -3.1883 -0.8096 0.2052 0.0481 0.0152 1.0375418: 0.2817 -3.1883 -0.8096 0.2050 0.0481 0.0152 1.0375419: 0.2816 -3.1882 -0.8096 0.2050 0.0481 0.0152 1.0374420: 0.2816 -3.1882 -0.8095 0.2051 0.0481 0.0152 1.0373421: 0.2816 -3.1882 -0.8095 0.2051 0.0481 0.0152 1.0373422: 0.2818 -3.1883 -0.8094 0.2054 0.0481 0.0152 1.0373423: 0.2819 -3.1882 -0.8094 0.2055 0.0481 0.0152 1.0373424: 0.2819 -3.1882 -0.8095 0.2055 0.0482 0.0151 1.0373425: 0.2820 -3.1882 -0.8095 0.2055 0.0482 0.0151 1.0373426: 0.2821 -3.1881 -0.8095 0.2055 0.0482 0.0151 1.0373427: 0.2820 -3.1880 -0.8096 0.2055 0.0483 0.0151 1.0371428: 0.2818 -3.1880 -0.8096 0.2056 0.0483 0.0151 1.0371429: 0.2818 -3.1880 -0.8096 0.2056 0.0482 0.0151 1.0371430: 0.2816 -3.1880 -0.8096 0.2055 0.0483 0.0151 1.0370431: 0.2814 -3.1880 -0.8097 0.2054 0.0483 0.0152 1.0369432: 0.2812 -3.1880 -0.8097 0.2054 0.0483 0.0152 1.0368433: 0.2812 -3.1880 -0.8096 0.2054 0.0482 0.0152 1.0368434: 0.2811 -3.1882 -0.8096 0.2054 0.0483 0.0152 1.0367435: 0.2811 -3.1881 -0.8096 0.2053 0.0483 0.0152 1.0367436: 0.2811 -3.1882 -0.8095 0.2052 0.0483 0.0152 1.0368437: 0.2810 -3.1882 -0.8096 0.2052 0.0483 0.0152 1.0368438: 0.2808 -3.1881 -0.8097 0.2053 0.0483 0.0152 1.0368439: 0.2807 -3.1880 -0.8097 0.2053 0.0483 0.0152 1.0368440: 0.2806 -3.1880 -0.8097 0.2052 0.0483 0.0152 1.0368441: 0.2807 -3.1881 -0.8097 0.2051 0.0483 0.0152 1.0368442: 0.2806 -3.1881 -0.8096 0.2051 0.0483 0.0152 1.0368443: 0.2807 -3.1880 -0.8097 0.2052 0.0483 0.0151 1.0369444: 0.2807 -3.1879 -0.8098 0.2052 0.0483 0.0151 1.0369445: 0.2807 -3.1879 -0.8098 0.2055 0.0483 0.0151 1.0370446: 0.2806 -3.1879 -0.8098 0.2057 0.0483 0.0151 1.0370447: 0.2807 -3.1879 -0.8099 0.2057 0.0483 0.0150 1.0370448: 0.2808 -3.1879 -0.8098 0.2057 0.0483 0.0150 1.0369449: 0.2808 -3.1879 -0.8097 0.2056 0.0483 0.0151 1.0368450: 0.2808 -3.1880 -0.8096 0.2056 0.0483 0.0151 1.0368451: 0.2809 -3.1880 -0.8096 0.2057 0.0482 0.0151 1.0368452: 0.2808 -3.1880 -0.8097 0.2058 0.0482 0.0151 1.0368453: 0.2808 -3.1880 -0.8097 0.2057 0.0482 0.0151 1.0367454: 0.2808 -3.1880 -0.8097 0.2056 0.0482 0.0151 1.0366455: 0.2808 -3.1880 -0.8098 0.2057 0.0482 0.0151 1.0366456: 0.2807 -3.1880 -0.8098 0.2059 0.0482 0.0151 1.0365457: 0.2807 -3.1880 -0.8098 0.2060 0.0482 0.0151 1.0364458: 0.2807 -3.1879 -0.8098 0.2060 0.0482 0.0151 1.0363459: 0.2807 -3.1878 -0.8098 0.2058 0.0481 0.0151 1.0363460: 0.2808 -3.1878 -0.8098 0.2058 0.0481 0.0151 1.0362461: 0.2807 -3.1878 -0.8098 0.2058 0.0481 0.0151 1.0362462: 0.2807 -3.1878 -0.8097 0.2057 0.0481 0.0151 1.0362463: 0.2807 -3.1878 -0.8097 0.2056 0.0480 0.0151 1.0363464: 0.2807 -3.1877 -0.8097 0.2056 0.0481 0.0151 1.0362465: 0.2808 -3.1878 -0.8097 0.2055 0.0480 0.0151 1.0363466: 0.2809 -3.1878 -0.8097 0.2055 0.0480 0.0151 1.0363467: 0.2809 -3.1878 -0.8097 0.2054 0.0480 0.0151 1.0362468: 0.2810 -3.1878 -0.8096 0.2055 0.0480 0.0151 1.0361469: 0.2811 -3.1877 -0.8096 0.2056 0.0480 0.0151 1.0361470: 0.2811 -3.1877 -0.8096 0.2056 0.0480 0.0151 1.0361471: 0.2809 -3.1877 -0.8097 0.2055 0.0480 0.0151 1.0361472: 0.2807 -3.1877 -0.8097 0.2055 0.0480 0.0151 1.0360473: 0.2806 -3.1878 -0.8097 0.2054 0.0480 0.0151 1.0360474: 0.2805 -3.1878 -0.8097 0.2052 0.0480 0.0151 1.0360475: 0.2805 -3.1877 -0.8097 0.2051 0.0479 0.0151 1.0360476: 0.2805 -3.1877 -0.8098 0.2052 0.0479 0.0151 1.0360477: 0.2805 -3.1877 -0.8098 0.2051 0.0479 0.0151 1.0359478: 0.2804 -3.1877 -0.8098 0.2051 0.0479 0.0151 1.0359479: 0.2805 -3.1876 -0.8098 0.2052 0.0480 0.0151 1.0359480: 0.2805 -3.1876 -0.8098 0.2051 0.0480 0.0151 1.0360481: 0.2805 -3.1877 -0.8097 0.2051 0.0480 0.0151 1.0360482: 0.2805 -3.1877 -0.8098 0.2051 0.0480 0.0151 1.0360483: 0.2805 -3.1877 -0.8098 0.2052 0.0480 0.0151 1.0360484: 0.2804 -3.1877 -0.8098 0.2053 0.0480 0.0151 1.0359485: 0.2805 -3.1877 -0.8098 0.2055 0.0479 0.0151 1.0360486: 0.2805 -3.1876 -0.8098 0.2055 0.0479 0.0151 1.0360487: 0.2806 -3.1876 -0.8098 0.2055 0.0479 0.0151 1.0359488: 0.2806 -3.1876 -0.8098 0.2055 0.0479 0.0151 1.0357489: 0.2807 -3.1876 -0.8098 0.2055 0.0479 0.0151 1.0356490: 0.2808 -3.1877 -0.8097 0.2055 0.0479 0.0151 1.0356491: 0.2809 -3.1877 -0.8097 0.2055 0.0479 0.0151 1.0355492: 0.2810 -3.1877 -0.8096 0.2054 0.0479 0.0151 1.0355493: 0.2810 -3.1877 -0.8096 0.2054 0.0479 0.0151 1.0355494: 0.2811 -3.1877 -0.8096 0.2053 0.0478 0.0151 1.0354495: 0.2813 -3.1877 -0.8095 0.2053 0.0478 0.0151 1.0353496: 0.2815 -3.1876 -0.8095 0.2052 0.0478 0.0151 1.0353497: 0.2815 -3.1876 -0.8095 0.2052 0.0479 0.0151 1.0353498: 0.2816 -3.1876 -0.8096 0.2052 0.0479 0.0151 1.0353499: 0.2816 -3.1875 -0.8096 0.2052 0.0479 0.0151 1.0352500: 0.2816 -3.1875 -0.8097 0.2052 0.0479 0.0150 1.0352## Calculate ETA-based prediction and error derivatives:Calculate Jacobian...................done.Calculate sensitivities.......done.## Calculate d(f)/d(eta) ## ...## done## ...## doneThe model-based sensitivities have been calculated.Calculating Table Variables...done

fit-- nlmixr SAEM fit (ODE); OBJF calculated from FOCEi approximation ------------- OBJF AIC BIC Log-likelihood Condition Number 349.6105 363.6105 388.6422 -174.8053 176.3777 -- Time (sec; fit$time): ------------------------------------------------------- saem setup Likelihood Calculation covariance tableelapsed 123.53 23.29 0.1 0 0.21 -- Parameters (fit$par.fixed): ------------------------------------------------- Parameter Estimate SE %RSE Back-transformed(95%CI) BSV(CV%)tka Log Ka 0.282 0.137 48.6 1.33 (1.01, 1.73) 47.7%tcl Log Cl -3.19 0.0654 2.05 0.0413 (0.0363, 0.0469) 22.2%tv Log V -0.810 0.0402 4.97 0.445 (0.411, 0.482) 12.3%add.err add.err 1.02 1.02 Shrink(SD)%tka 1.15% tcl 0.881% tv 13.5% add.err 5.59%

No correlations in between subject variability (BSV) matrix Full BSV covariance (fit$omega) or correlation (fit$omega.R; diagonals=SDs) Distribution stats (mean/skewness/kurtosis/p-value) available in fit$shrink -- Fit Data (object fit is a modified data.frame): -----------------------------# A tibble: 264 x 21 ID TIME DV PRED RES WRES IPRED IRES IWRES CPRED CRES CWRES* 1 1 0 0.74 0 0.74 0.727 0 0.74 0.727 0 0.74 0.7272 1 0.25 2.84 2.52 0.323 0.226 3.50 -0.660 -0.649 2.35 0.486 0.2853 1 0.570 6.57 4.65 1.92 1.06 6.32 0.254 0.250 4.41 2.16 0.989# ... with 261 more rows, and 9 more variables: eta.ka , eta.cl ,# eta.v , depot , center , ka , cl , v ,# cp >

Also note that the theopyhille dataset has a different dose specification than a usual PK dataset (Issue #36 https://github.com/nlmixrdevelopment/nlmixr/issues/36). You can either change the dataset or the model (a model change is below)

theo.mod2 <- function() {+ ini({+ tka <- .5 # Log Ka+ tcl <- -3.2 # Log Cl+ tv <- -1 # Log V+ eta.ka ~ 1+ eta.cl ~ 2+ eta.v ~ 1+ add.err <- 0.1+ })+ model({+ ka <- exp(tka + eta.ka)+ cl <- exp(tcl + eta.cl)+ v <- exp(tv + eta.v)+ d/dt(depot) = -ka depot+ d/dt(center) = ka depot - cl / v center+ cp = (center / v) wt+ cp ~ add(add.err)+ })+ }> fit <- nlmixr(theo.mod2,theo_md, est="saem")

Compiling RxODE differential equations...done.PKG_CXXFLAGS=-Ic:/R/nlmixr/R/library/nlmixr/include -Ic:/R/nlmixr/R/library/STANHE~1/include -Ic:/R/nlmixr/R/library/Rcpp/include -Ic:/R/nlmixr/R/library/RCPPAR~1/include -Ic:/R/nlmixr/R/library/RCPPEI~1/include -Ic:/R/nlmixr/R/library/BH/includePKG_LIBS= $(BLAS_LIBS) $(LAPACK_LIBS)c:/R/nlmixr/rtools/mingw_64/bin/g++ -I"c:/R/nlmixr/R/include" -DNDEBUG -Ic:/R/nlmixr/R/library/nlmixr/include -Ic:/R/nlmixr/R/library/STANHE~1/include -Ic:/R/nlmixr/R/library/Rcpp/include -Ic:/R/nlmixr/R/library/RCPPAR~1/include -Ic:/R/nlmixr/R/library/RCPPEI~1/include -Ic:/R/nlmixr/R/library/BH/include -O2 -Wall -mtune=generic -c saem1664c353f4abfx64.cpp -o saem1664c353f4abfx64.oc:/R/nlmixr/rtools/mingw_64/bin/g++ -shared -s -static-libgcc -o saem1664c353f4abfx64.dll tmp.def saem1664c353f4abfx64.o -Lc:/R/nlmixr/R/bin/x64 -lRblas -Lc:/R/nlmixr/R/bin/x64 -lRlapack -Lc:/R/nlmixr/R/bin/x64 -lRdone.1: -1.7977 1.4233 -0.1387 1.3452 1.9000 1.4159 13.20842: -2.2817 1.3197 0.2501 1.2779 1.8050 1.3451 6.44933: -2.3148 1.2611 0.4194 1.2140 1.7147 1.2778 4.29864: -2.3550 1.1285 0.6010 1.1533 1.6290 1.2139 2.58935: -2.3248 1.0990 0.6004 1.0956 1.5476 1.1532 2.29086: -2.3291 1.1026 0.6744 1.0409 1.4702 1.0956 1.96887: -2.3756 1.0764 0.6518 0.9888 1.3967 1.0408 1.75308: -2.4391 1.0224 0.6822 0.9394 1.3268 0.9887 1.43399: -2.4114 1.0209 0.6896 0.8924 1.2605 0.9393 1.334310: -2.3754 1.0516 0.7340 0.8478 1.1975 0.8923 1.306211: -2.3471 1.0531 0.8311 0.8054 1.1376 0.8477 1.186512: -2.3485 1.0611 0.8142 0.7651 1.0807 0.8053 1.192313: -2.3463 1.0636 0.7774 0.7269 1.0267 0.7651 1.208114: -2.3168 1.0735 0.8358 0.6905 0.9753 0.7268 1.155715: -2.3361 1.0723 0.7969 0.6560 0.9266 0.6905 1.096616: -2.3307 1.0764 0.7972 0.6232 0.8803 0.6560 1.107817: -2.3507 1.0746 0.7832 0.5920 0.8362 0.6232 1.082618: -2.3444 1.0735 0.7930 0.5624 0.7944 0.5920 1.085719: -2.3470 1.0781 0.7889 0.5343 0.7547 0.5624 1.072120: -2.3425 1.0586 0.7958 0.5076 0.7170 0.5343 1.056521: -2.3423 1.0564 0.8241 0.4822 0.6811 0.5076 1.063822: -2.3620 1.0495 0.8127 0.4581 0.6471 0.4822 1.037523: -2.3451 1.0557 0.7758 0.4352 0.6147 0.4581 1.059724: -2.3525 1.0586 0.7655 0.4134 0.5840 0.4352 1.027625: -2.3453 1.0593 0.7786 0.3928 0.5548 0.4134 1.041926: -2.3436 1.0639 0.7779 0.3731 0.5270 0.3927 1.030427: -2.3654 1.0556 0.7589 0.3545 0.5007 0.3731 1.033328: -2.3866 1.0541 0.7364 0.3368 0.4757 0.3545 1.044629: -2.4054 1.0588 0.7041 0.3199 0.4519 0.3367 1.054230: -2.3965 1.0514 0.7243 0.3039 0.4293 0.3199 1.073831: -2.4197 1.0438 0.7216 0.2887 0.4078 0.3039 1.068432: -2.4165 1.0290 0.7334 0.2743 0.3874 0.2887 1.062133: -2.4166 1.0415 0.6976 0.2606 0.3681 0.2743 1.060934: -2.3981 1.0426 0.7126 0.2475 0.3496 0.2606 1.066135: -2.4137 1.0391 0.7062 0.2352 0.3322 0.2475 1.065536: -2.4044 1.0272 0.7079 0.2234 0.3156 0.2361 1.064337: -2.4105 1.0408 0.7294 0.2122 0.2998 0.2281 1.061238: -2.3889 1.0496 0.7202 0.2016 0.2848 0.2327 1.041639: -2.3832 1.0581 0.7379 0.1915 0.2706 0.2210 1.046940: -2.3794 1.0600 0.7518 0.1820 0.2570 0.2100 1.041341: -2.3838 1.0596 0.7571 0.1729 0.2442 0.1995 1.024442: -2.3713 1.0453 0.7563 0.1642 0.2320 0.1895 1.035743: -2.3745 1.0450 0.7373 0.1560 0.2204 0.1800 1.043044: -2.3990 1.0536 0.7140 0.1482 0.2093 0.1710 1.047445: -2.3934 1.0488 0.7028 0.1408 0.1989 0.1865 1.041146: -2.3936 1.0450 0.7219 0.1338 0.1889 0.1856 1.043247: -2.4088 1.0363 0.6819 0.1271 0.1795 0.2068 1.072748: -2.4073 1.0403 0.7106 0.1207 0.1705 0.1964 1.061249: -2.4116 1.0350 0.7190 0.1147 0.1620 0.1866 1.079450: -2.4108 1.0300 0.7200 0.1090 0.1539 0.1773 1.066151: -2.3926 1.0484 0.6926 0.1035 0.1462 0.1684 1.050852: -2.3817 1.0459 0.7297 0.0983 0.1389 0.1600 1.037653: -2.3751 1.0544 0.7575 0.0934 0.1319 0.1520 1.042954: -2.4026 1.0439 0.7456 0.0887 0.1253 0.1444 1.043355: -2.4146 1.0330 0.7404 0.0843 0.1191 0.1372 1.065656: -2.4012 1.0267 0.7417 0.0801 0.1131 0.1340 1.061257: -2.4092 1.0411 0.7463 0.0761 0.1075 0.1273 1.047158: -2.4040 1.0359 0.7204 0.0723 0.1021 0.1392 1.035959: -2.4048 1.0367 0.7377 0.0687 0.0970 0.1323 1.041460: -2.3998 1.0355 0.7608 0.0652 0.0921 0.1256 1.048461: -2.3835 1.0463 0.7761 0.0620 0.0875 0.1194 1.054562: -2.3739 1.0476 0.7848 0.0589 0.0832 0.1232 1.050163: -2.3716 1.0405 0.7717 0.0559 0.0790 0.1277 1.049764: -2.3648 1.0584 0.7662 0.0531 0.0750 0.1213 1.041765: -2.3539 1.0522 0.7683 0.0505 0.0713 0.1152 1.067166: -2.3984 1.0449 0.7667 0.0480 0.0677 0.1095 1.037267: -2.4077 1.0177 0.7484 0.0456 0.0643 0.1204 1.050368: -2.4189 1.0294 0.7575 0.0433 0.0611 0.1144 1.067269: -2.4134 1.0332 0.7252 0.0411 0.0581 0.1521 1.056370: -2.4173 1.0357 0.7165 0.0391 0.0552 0.1537 1.039171: -2.4242 1.0371 0.6887 0.0371 0.0524 0.1507 1.038572: -2.4412 1.0195 0.6808 0.0352 0.0498 0.1563 1.044873: -2.4254 1.0336 0.7386 0.0335 0.0473 0.1711 1.033574: -2.4279 1.0293 0.7195 0.0318 0.0449 0.1626 1.016175: -2.4205 1.0242 0.7765 0.0302 0.0427 0.1544 1.032176: -2.4030 1.0344 0.7867 0.0287 0.0406 0.1716 1.066577: -2.3913 1.0316 0.7569 0.0273 0.0385 0.1754 1.015178: -2.3946 1.0378 0.7464 0.0259 0.0422 0.1666 1.020779: -2.3983 1.0453 0.7407 0.0246 0.0431 0.1583 1.041680: -2.3911 1.0582 0.7447 0.0234 0.0476 0.1836 1.052181: -2.3875 1.0447 0.7367 0.0222 0.0452 0.1744 1.010282: -2.3722 1.0362 0.7672 0.0211 0.0429 0.1657 1.017383: -2.3892 1.0381 0.7524 0.0200 0.0443 0.1574 1.042084: -2.4174 1.0246 0.7031 0.0190 0.0421 0.1672 1.015585: -2.4340 1.0206 0.7161 0.0181 0.0399 0.1702 1.045486: -2.4257 1.0307 0.6851 0.0172 0.0380 0.1734 1.017587: -2.4285 1.0250 0.6788 0.0163 0.0376 0.1648 1.030588: -2.4337 1.0170 0.7209 0.0155 0.0358 0.1565 1.040389: -2.4350 1.0260 0.6938 0.0147 0.0340 0.1487 1.045090: -2.4309 1.0207 0.7002 0.0140 0.0355 0.1413 1.041991: -2.4434 1.0123 0.6764 0.0133 0.0357 0.1391 1.032392: -2.4437 1.0249 0.6884 0.0126 0.0445 0.1577 1.030493: -2.4590 1.0123 0.6792 0.0120 0.0423 0.1670 1.024894: -2.4437 1.0303 0.6606 0.0114 0.0437 0.1586 1.050295: -2.4264 1.0289 0.7145 0.0108 0.0430 0.1507 1.027896: -2.4173 1.0275 0.7264 0.0103 0.0409 0.1432 1.026397: -2.4084 1.0338 0.7123 0.0098 0.0388 0.1360 1.033598: -2.4190 1.0386 0.7435 0.0093 0.0395 0.1441 1.038199: -2.4216 1.0194 0.6931 0.0088 0.0375 0.1671 1.0210100: -2.4308 1.0208 0.7311 0.0084 0.0357 0.1588 1.0312101: -2.4427 1.0032 0.6918 0.0080 0.0339 0.1508 1.0373102: -2.4617 1.0011 0.6699 0.0076 0.0322 0.1545 1.0685103: -2.4469 1.0082 0.7087 0.0072 0.0314 0.1645 1.0632104: -2.4276 1.0173 0.7390 0.0068 0.0317 0.1766 1.0551105: -2.4252 1.0230 0.7171 0.0077 0.0328 0.1678 1.0456106: -2.4162 1.0252 0.7093 0.0080 0.0373 0.1594 1.0295107: -2.3911 1.0446 0.7528 0.0099 0.0355 0.1674 1.0634108: -2.3938 1.0331 0.7495 0.0094 0.0356 0.1620 1.0375109: -2.3988 1.0387 0.7636 0.0089 0.0377 0.1718 1.0404110: -2.4060 1.0306 0.7270 0.0089 0.0375 0.1632 1.0121111: -2.4125 1.0393 0.7181 0.0084 0.0389 0.1550 1.0263112: -2.4228 1.0249 0.6734 0.0095 0.0417 0.1499 1.0244113: -2.4147 1.0446 0.7272 0.0090 0.0396 0.1455 1.0108114: -2.3971 1.0380 0.7377 0.0085 0.0419 0.1382 1.0469115: -2.3895 1.0321 0.7166 0.0089 0.0401 0.1571 1.0553116: -2.4044 1.0375 0.7305 0.0085 0.0381 0.1783 1.0413117: -2.4140 1.0388 0.7499 0.0081 0.0362 0.1694 1.0546118: -2.4126 1.0184 0.7322 0.0077 0.0396 0.1609 1.0295119: -2.4191 1.0222 0.7369 0.0073 0.0376 0.1978 1.0222120: -2.4241 1.0222 0.7297 0.0070 0.0368 0.1879 1.0216121: -2.4305 1.0274 0.7071 0.0066 0.0349 0.1809 1.0497122: -2.4211 1.0188 0.7251 0.0068 0.0355 0.1747 1.0343123: -2.4097 1.0321 0.7142 0.0064 0.0382 0.1791 1.0235124: -2.4032 1.0432 0.7258 0.0061 0.0370 0.1903 1.0386125: -2.3936 1.0452 0.7153 0.0058 0.0351 0.1808 1.0449126: -2.4105 1.0382 0.6908 0.0055 0.0334 0.1749 1.0373127: -2.4092 1.0333 0.6748 0.0052 0.0333 0.1834 1.0407128: -2.4116 1.0356 0.7135 0.0050 0.0317 0.1742 1.0629129: -2.4084 1.0385 0.7157 0.0047 0.0390 0.1655 1.0542130: -2.3920 1.0380 0.7317 0.0045 0.0371 0.1572 1.0198131: -2.4034 1.0289 0.7102 0.0043 0.0353 0.1493 1.0494132: -2.4153 1.0342 0.6777 0.0041 0.0335 0.1449 1.0546133: -2.4175 1.0220 0.6869 0.0039 0.0319 0.1666 1.0600134: -2.4177 1.0173 0.7401 0.0037 0.0363 0.1583 1.0415135: -2.4256 1.0231 0.7301 0.0036 0.0367 0.1641 1.0420136: -2.4283 1.0292 0.7071 0.0034 0.0348 0.1871 1.0312137: -2.4207 1.0236 0.7029 0.0038 0.0331 0.1777 1.0428138: -2.4122 1.0291 0.6963 0.0038 0.0347 0.1877 1.0238139: -2.4114 1.0382 0.7356 0.0045 0.0349 0.1879 1.0157140: -2.4058 1.0331 0.7272 0.0044 0.0349 0.1785 1.0364141: -2.4107 1.0225 0.7407 0.0042 0.0383 0.1696 1.0264142: -2.4144 1.0179 0.7384 0.0044 0.0364 0.1611 1.0151143: -2.4130 1.0339 0.7221 0.0042 0.0346 0.1530 1.0386144: -2.4020 1.0352 0.7330 0.0039 0.0363 0.1588 1.0264145: -2.4039 1.0404 0.7026 0.0042 0.0366 0.1508 1.0298146: -2.4074 1.0397 0.7359 0.0049 0.0387 0.1531 1.0264147: -2.4160 1.0277 0.7125 0.0052 0.0368 0.1579 1.0379148: -2.4138 1.0262 0.7282 0.0050 0.0349 0.1714 1.0244149: -2.4113 1.0251 0.7415 0.0047 0.0401 0.1757 1.0320150: -2.4138 1.0220 0.7153 0.0045 0.0381 0.1732 1.0050151: -2.4244 1.0326 0.7182 0.0043 0.0366 0.1729 1.0340152: -2.4247 1.0377 0.6833 0.0041 0.0386 0.1492 1.0344153: -2.4312 1.0248 0.7148 0.0044 0.0347 0.1907 1.0574154: -2.4258 1.0260 0.7198 0.0041 0.0352 0.1901 1.0527155: -2.4336 1.0189 0.7007 0.0028 0.0331 0.1802 1.0568156: -2.4278 1.0230 0.6979 0.0030 0.0343 0.1659 1.0444157: -2.4241 1.0118 0.7457 0.0024 0.0300 0.1446 1.0778158: -2.4157 1.0302 0.7276 0.0025 0.0278 0.1325 1.0586159: -2.4199 1.0275 0.7342 0.0025 0.0315 0.1453 1.0501160: -2.4121 1.0255 0.7294 0.0027 0.0370 0.1482 1.0750161: -2.4143 1.0213 0.7164 0.0029 0.0329 0.1414 1.1157162: -2.4069 1.0399 0.7014 0.0033 0.0325 0.1208 1.1035163: -2.4047 1.0335 0.6819 0.0035 0.0311 0.1266 1.0933164: -2.4139 1.0365 0.6750 0.0028 0.0291 0.1277 1.1088165: -2.4112 1.0302 0.7020 0.0025 0.0271 0.1454 1.0751166: -2.4039 1.0361 0.7133 0.0023 0.0271 0.1828 1.0590167: -2.4063 1.0479 0.7222 0.0027 0.0328 0.1854 1.0564168: -2.4029 1.0400 0.7401 0.0029 0.0339 0.1960 1.0323169: -2.4024 1.0413 0.7340 0.0034 0.0353 0.1683 1.0300170: -2.3989 1.0381 0.7328 0.0026 0.0338 0.1546 1.0581171: -2.4045 1.0322 0.7217 0.0029 0.0304 0.1487 1.0336172: -2.4130 1.0365 0.7215 0.0032 0.0336 0.1717 1.0211173: -2.4081 1.0357 0.7082 0.0023 0.0336 0.1506 1.0428174: -2.4085 1.0339 0.7283 0.0019 0.0304 0.1628 1.0426175: -2.4105 1.0444 0.6982 0.0025 0.0321 0.1836 1.0513176: -2.4106 1.0332 0.7533 0.0030 0.0321 0.2033 1.0371177: -2.4037 1.0324 0.7673 0.0026 0.0330 0.1870 1.0720178: -2.4063 1.0349 0.7272 0.0026 0.0364 0.1804 1.0302179: -2.3995 1.0475 0.7193 0.0027 0.0391 0.2016 1.0394180: -2.3964 1.0328 0.7272 0.0024 0.0355 0.2208 1.0350181: -2.3945 1.0406 0.7117 0.0022 0.0331 0.2045 1.0451182: -2.4031 1.0358 0.6929 0.0026 0.0386 0.1996 1.0434183: -2.4068 1.0319 0.7231 0.0025 0.0408 0.1878 1.0417184: -2.4065 1.0346 0.7378 0.0026 0.0361 0.1728 1.0343185: -2.4009 1.0361 0.7231 0.0025 0.0324 0.1769 1.0607186: -2.4036 1.0426 0.7263 0.0027 0.0306 0.2023 1.0892187: -2.4031 1.0387 0.7376 0.0040 0.0326 0.1533 1.0502188: -2.4035 1.0383 0.7323 0.0053 0.0360 0.1546 1.0734189: -2.3998 1.0390 0.7952 0.0043 0.0371 0.1573 1.0717190: -2.4115 1.0264 0.7628 0.0052 0.0384 0.1616 1.0307191: -2.4249 1.0279 0.7239 0.0038 0.0359 0.1487 1.0469192: -2.4189 1.0393 0.7140 0.0031 0.0338 0.1654 1.0180193: -2.4163 1.0418 0.7164 0.0035 0.0356 0.1740 1.0204194: -2.4211 1.0256 0.6637 0.0036 0.0312 0.1439 1.0558195: -2.4254 1.0270 0.6582 0.0034 0.0330 0.1627 1.0546196: -2.4236 1.0314 0.6928 0.0035 0.0326 0.1469 1.0708197: -2.4290 1.0228 0.7287 0.0031 0.0339 0.1609 1.0776198: -2.4214 1.0138 0.7226 0.0028 0.0345 0.1436 1.0651199: -2.4255 1.0274 0.6921 0.0033 0.0368 0.1630 1.0677200: -2.4284 1.0330 0.7191 0.0040 0.0332 0.1671 1.0718201: -2.4262 1.0314 0.7230 0.0037 0.0340 0.1507 1.0716202: -2.4237 1.0330 0.7131 0.0038 0.0328 0.1507 1.0728203: -2.4211 1.0337 0.7085 0.0039 0.0326 0.1509 1.0691204: -2.4188 1.0337 0.7103 0.0039 0.0327 0.1549 1.0704205: -2.4175 1.0360 0.7153 0.0043 0.0327 0.1595 1.0683206: -2.4167 1.0366 0.7199 0.0044 0.0323 0.1610 1.0701207: -2.4158 1.0352 0.7199 0.0045 0.0320 0.1631 1.0644208: -2.4149 1.0347 0.7223 0.0047 0.0320 0.1631 1.0630209: -2.4137 1.0329 0.7235 0.0047 0.0318 0.1612 1.0644210: -2.4127 1.0319 0.7275 0.0047 0.0316 0.1595 1.0616211: -2.4123 1.0315 0.7307 0.0047 0.0317 0.1587 1.0610212: -2.4121 1.0311 0.7326 0.0046 0.0318 0.1568 1.0617213: -2.4118 1.0309 0.7307 0.0046 0.0320 0.1577 1.0620214: -2.4127 1.0301 0.7293 0.0045 0.0324 0.1575 1.0595215: -2.4131 1.0300 0.7284 0.0044 0.0326 0.1573 1.0593216: -2.4136 1.0291 0.7272 0.0045 0.0327 0.1575 1.0592217: -2.4136 1.0295 0.7254 0.0045 0.0328 0.1564 1.0585218: -2.4137 1.0296 0.7234 0.0045 0.0328 0.1556 1.0588219: -2.4140 1.0291 0.7224 0.0045 0.0327 0.1574 1.0575220: -2.4145 1.0290 0.7226 0.0045 0.0327 0.1588 1.0559221: -2.4149 1.0291 0.7223 0.0044 0.0327 0.1592 1.0544222: -2.4153 1.0289 0.7211 0.0045 0.0327 0.1599 1.0527223: -2.4150 1.0288 0.7211 0.0045 0.0328 0.1591 1.0514224: -2.4145 1.0292 0.7217 0.0045 0.0329 0.1585 1.0497225: -2.4139 1.0289 0.7241 0.0045 0.0330 0.1585 1.0496226: -2.4137 1.0286 0.7238 0.0045 0.0331 0.1573 1.0489227: -2.4136 1.0287 0.7246 0.0046 0.0332 0.1568 1.0481228: -2.4134 1.0288 0.7235 0.0046 0.0331 0.1559 1.0482229: -2.4135 1.0290 0.7226 0.0046 0.0331 0.1547 1.0481230: -2.4136 1.0287 0.7221 0.0046 0.0332 0.1542 1.0483231: -2.4139 1.0285 0.7222 0.0046 0.0333 0.1543 1.0476232: -2.4145 1.0281 0.7221 0.0046 0.0333 0.1556 1.0466233: -2.4149 1.0278 0.7221 0.0046 0.0333 0.1566 1.0465234: -2.4152 1.0278 0.7221 0.0046 0.0333 0.1570 1.0461235: -2.4155 1.0276 0.7211 0.0045 0.0334 0.1578 1.0461236: -2.4158 1.0277 0.7197 0.0045 0.0335 0.1589 1.0464237: -2.4160 1.0277 0.7189 0.0045 0.0334 0.1597 1.0468238: -2.4163 1.0274 0.7186 0.0046 0.0333 0.1602 1.0473239: -2.4161 1.0278 0.7176 0.0046 0.0334 0.1598 1.0474240: -2.4160 1.0278 0.7179 0.0046 0.0334 0.1600 1.0475241: -2.4158 1.0276 0.7180 0.0046 0.0334 0.1599 1.0475242: -2.4159 1.0273 0.7178 0.0046 0.0334 0.1598 1.0483243: -2.4161 1.0275 0.7179 0.0046 0.0335 0.1605 1.0490244: -2.4161 1.0276 0.7179 0.0046 0.0336 0.1608 1.0492245: -2.4160 1.0276 0.7178 0.0047 0.0336 0.1613 1.0492246: -2.4159 1.0276 0.7181 0.0047 0.0337 0.1618 1.0493247: -2.4161 1.0276 0.7184 0.0047 0.0338 0.1621 1.0496248: -2.4161 1.0275 0.7181 0.0047 0.0339 0.1620 1.0495249: -2.4161 1.0278 0.7179 0.0047 0.0338 0.1621 1.0494250: -2.4160 1.0279 0.7185 0.0046 0.0338 0.1623 1.0494251: -2.4159 1.0279 0.7190 0.0046 0.0339 0.1630 1.0492252: -2.4157 1.0281 0.7198 0.0046 0.0339 0.1634 1.0486253: -2.4156 1.0282 0.7202 0.0046 0.0339 0.1638 1.0481254: -2.4156 1.0283 0.7207 0.0046 0.0340 0.1643 1.0478255: -2.4156 1.0283 0.7210 0.0046 0.0340 0.1646 1.0478256: -2.4157 1.0281 0.7205 0.0046 0.0340 0.1647 1.0480257: -2.4160 1.0279 0.7199 0.0046 0.0340 0.1648 1.0479258: -2.4161 1.0279 0.7195 0.0046 0.0341 0.1647 1.0479259: -2.4162 1.0278 0.7191 0.0046 0.0341 0.1650 1.0481260: -2.4166 1.0276 0.7192 0.0046 0.0341 0.1654 1.0479261: -2.4168 1.0273 0.7190 0.0046 0.0341 0.1655 1.0478262: -2.4170 1.0272 0.7191 0.0046 0.0342 0.1659 1.0478263: -2.4171 1.0271 0.7189 0.0046 0.0342 0.1659 1.0480264: -2.4172 1.0271 0.7182 0.0046 0.0343 0.1657 1.0484265: -2.4172 1.0272 0.7179 0.0046 0.0343 0.1658 1.0483266: -2.4170 1.0273 0.7176 0.0046 0.0344 0.1655 1.0485267: -2.4169 1.0273 0.7179 0.0046 0.0343 0.1651 1.0483268: -2.4168 1.0274 0.7178 0.0046 0.0343 0.1646 1.0483269: -2.4166 1.0275 0.7183 0.0046 0.0343 0.1644 1.0484270: -2.4164 1.0277 0.7181 0.0046 0.0344 0.1644 1.0483271: -2.4161 1.0279 0.7175 0.0046 0.0344 0.1642 1.0482272: -2.4159 1.0279 0.7174 0.0046 0.0345 0.1644 1.0482273: -2.4159 1.0281 0.7174 0.0046 0.0346 0.1643 1.0483274: -2.4161 1.0281 0.7173 0.0046 0.0346 0.1643 1.0485275: -2.4161 1.0282 0.7168 0.0046 0.0346 0.1642 1.0485276: -2.4162 1.0284 0.7168 0.0046 0.0347 0.1644 1.0485277: -2.4161 1.0286 0.7171 0.0046 0.0347 0.1642 1.0488278: -2.4162 1.0286 0.7173 0.0046 0.0347 0.1639 1.0487279: -2.4163 1.0285 0.7171 0.0046 0.0347 0.1643 1.0488280: -2.4163 1.0286 0.7171 0.0046 0.0347 0.1637 1.0486281: -2.4163 1.0287 0.7171 0.0046 0.0348 0.1632 1.0486282: -2.4163 1.0287 0.7172 0.0046 0.0348 0.1630 1.0485283: -2.4161 1.0288 0.7175 0.0046 0.0348 0.1629 1.0485284: -2.4160 1.0289 0.7179 0.0046 0.0347 0.1627 1.0482285: -2.4159 1.0290 0.7176 0.0046 0.0347 0.1628 1.0480286: -2.4158 1.0292 0.7174 0.0046 0.0347 0.1629 1.0476287: -2.4156 1.0294 0.7172 0.0046 0.0348 0.1629 1.0475288: -2.4153 1.0295 0.7174 0.0046 0.0348 0.1626 1.0476289: -2.4152 1.0295 0.7174 0.0046 0.0348 0.1627 1.0473290: -2.4152 1.0295 0.7176 0.0046 0.0348 0.1627 1.0472291: -2.4152 1.0297 0.7177 0.0046 0.0349 0.1627 1.0467292: -2.4151 1.0298 0.7178 0.0046 0.0349 0.1625 1.0464293: -2.4151 1.0298 0.7174 0.0046 0.0349 0.1626 1.0464294: -2.4153 1.0296 0.7171 0.0046 0.0350 0.1623 1.0461295: -2.4155 1.0294 0.7172 0.0046 0.0350 0.1624 1.0457296: -2.4156 1.0294 0.7170 0.0046 0.0350 0.1622 1.0456297: -2.4157 1.0294 0.7172 0.0046 0.0350 0.1620 1.0455298: -2.4157 1.0293 0.7174 0.0046 0.0350 0.1617 1.0456299: -2.4157 1.0293 0.7174 0.0046 0.0350 0.1615 1.0455300: -2.4158 1.0291 0.7178 0.0046 0.0349 0.1612 1.0457301: -2.4158 1.0290 0.7176 0.0046 0.0349 0.1609 1.0457302: -2.4157 1.0290 0.7176 0.0046 0.0349 0.1610 1.0454303: -2.4157

mattfidler commented 6 years ago

If so, the theo_md example needs to be modified.

mattfidler commented 6 years ago

Ah. My mistake. Volume isn't estimated, rather both KE and CL are estimated.

mattfidler commented 6 years ago

I updated the example with the pnlsTol option; Thanks for bringing this to our attention.

nlmixrdevelopment / nlmixr

nlme_ode running error #50

Note the theo_md is the same dataset as you specified but is included in the nlmixr packagefit <- nlme_ode(theo_md, model=ode, par_model=specs, par_trans=mypar,