Abstract:
The process for the diagnosis, early detection and prognosis of the clinical development of autosomal-dominant polycystic kidney disease (ADPKD) comprises the step of determining the presence or absence or amplitude of at least three polypeptide markers in a urine sample, the polypeptide markers being selected from the markers characterized in Table 1 by values for the molecular masses and migration times.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a Continuation of copending U.S. patent application Ser. No. 13/140,106 to Mischak, which is a national stage filing of PCT application number PCT/EP2009/067430 filed on Dec. 17, 2009, which claims priority to European patent application serial number 08171983.3 filed on Dec. 17, 2008 to Mischak, which are incorporated herein by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to a process and device for the diagnosis of autosomal-dominant polycystic kidney disease. 
       BACKGROUND 
       [0003]    Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most frequent human monogenetic diseases with a prevalence of from 1:400 to 1:1000. The disease shows a progressing development and enlargement of fluid-filled vesicles or cysts in both kidneys, which substantially affects the functionality of the kidneys. About 50% of the afflicted patients become dialysis-dependent before the age of sixty. 
         [0004]    The development of the cysts is a complex process that is phenotypically similar to dedifferentiation, including high proliferation rates, increased apoptosis, altered protein sorting, altered secretory properties, and disorganization of the extracellular matrix. 
         [0005]    Although the cysts occurring in the kidney are the most prominent symptom, cyst formation also occurs outside the kidneys in the patients, especially in the liver (occasionally up to the symptoms of polycystic liver disease), and an increased frequency of other disorders, such as intercranial aneurysms. This shows that ADPKD is a systemic disease. 
         [0006]    ADPKD is the most prevalent life-threatening hereditary disease. The prevalence of ADPKD is greater than those of Huntington&#39;s disease, hemophilia, sickle-cell anemia, cystic fibrosis, myotonic dystrophy and Down syndrome taken together. 
         [0007]    In recent years, there was not only progress in the understanding of the genetic and molecular basis of ADPKD, but some diagnostic and therapeutical approaches have also been developed. 
         [0008]    In the field of genetics, the gene for PKD-1 has been located on chromosome 16 and is associated with the polycystin-1 protein, which is mutated in about 85% of all patients suffering from ADPKD. The gene for PKD-2, which is located on chromosome 4, is mutated in 15% of the ADPKD cases and is associated with the polycystin-2 protein. 
       SUMMARY OF THE INVENTION 
       [0009]    While the findings of genetics and molecular biology have induced many interesting projects of basic research, there was no relevant progress in the field of therapy. Early detection and treatment with inhibitors of the renin-angiotensin-aldosterone system has the potential to prevent the hypertrophic phenomena of the left ventricle of the heart, which often accompanies ADPKD, and to decelerate the progress of the disease. 
         [0010]    Thus, early detection of the disease is the key to an early treatment and deceleration of the course of the disease. Further, a prognosis of the course of the disease is important since the costs and side effects related to therapy should be accepted only in patients with a rapid progression. 
         [0011]    It is the object of the present invention to provide a possible diagnosis of ADPKD. This object is achieved by a process for the diagnosis of autosomal-dominant polycystic kidney disease (ADPKD) as in claim  1  comprising the step of determining the presence or absence or amplitude of at least three polypeptide markers in a urine sample, the polypeptide markers being selected from the markers characterized in Table 1 by values for the molecular masses and migration times. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 No. 
                 Mass (Da) 
                 CE_t (min) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 840.4071 
                 23.16555  
               
               
                 2 
                 884.2923 
                 43.80656  
               
               
                 3 
                 884.3214 
                 24.85187  
               
               
                 4 
                 900.4511 
                 24.99 
               
               
                 5 
                 902.4133 
                 20.84575  
               
               
                 6 
                 911.2648 
                 34.34517  
               
               
                 7 
                 923.4244 
                 22.01035  
               
               
                 8 
                 926.4665 
                 21.35563  
               
               
                 9 
                 928.3718 
                 35.46373  
               
               
                 10 
                 931.4706 
                 20.00439 
               
               
                 11 
                 935.4465 
                 23.68105  
               
               
                 12 
                 937.4612 
                 34.09575  
               
               
                 13 
                 944.5103 
                 21.24885  
               
               
                 14 
                 954.4564 
                 24.31141  
               
               
                 15 
                 956.4393 
                 20.35767  
               
               
                 16 
                 965.4274 
                 27.83332  
               
               
                 17 
                 981.5851 
                 24.79552  
               
               
                 18 
                 984.4547 
                 24.92263  
               
               
                 19 
                 988.4991 
                 21.2492 
               
               
                 20 
                 992.4164 
                 20.39667  
               
               
                 21 
                 1002.454 
                 24.41733  
               
               
                 22 
                 1013.368 
                 25.16517  
               
               
                 23 
                 1016.265  
                 35.651 
               
               
                 24 
                 1016.445 
                 25.78512  
               
               
                 25 
                 1018.462 
                 24.53558  
               
               
                 26 
                 1028.524 
                 24.83936  
               
               
                 27 
                 1032.498 
                 21.2104 
               
               
                 28 
                 1040.475 
                 25.05015  
               
               
                 29 
                 1046.427 
                 27.64366  
               
               
                 30 
                 1058.476 
                 24.89302  
               
               
                 31 
                 1068.447 
                 24.76449  
               
               
                 32 
                 1070.49 
                 36.49286  
               
               
                 33 
                 1072.5  
                 21.13634  
               
               
                 34 
                 1075.487 
                 20.61147 
               
               
                 35 
                 1082.501 
                 23.90513  
               
               
                 36 
                 1082.517 
                 21.69541  
               
               
                 37 
                 1084.428 
                 25.23275  
               
               
                 38 
                 1085.466 
                 21.93764  
               
               
                 39 
                 1096.483 
                 26.07573  
               
               
                 40 
                 1097.495 
                 21.00157  
               
               
                 41 
                 1097.498 
                 25.40513  
               
               
                 42 
                 1099.499 
                 21.67177  
               
               
                 43 
                 1100.502 
                 37.03674  
               
               
                 44 
                 1110.389  
                 33.6302 
               
               
                 45 
                 1113.511  
                 22.2623  
               
               
                 46 
                 1114.479 
                 24.21347 
               
               
                 47 
                 1116.477 
                 37.03951  
               
               
                 48 
                 1116.53  
                 20.8514  
               
               
                 49 
                 1128.394 
                 33.59201 
               
               
                 50 
                 1128.488 
                 25.64931  
               
               
                 51 
                 1130.337 
                 35.39296  
               
               
                 52 
                 1134.583 
                 23.65584  
               
               
                 53 
                 1138.468 
                 37.07027  
               
               
                 54 
                 1140.516 
                 25.38464  
               
               
                 55 
                 1141.511 
                 26.05729  
               
               
                 56 
                 1143.52 
                 36.96738  
               
               
                 57 
                 1150.561 
                 22.43054 
               
               
                 58 
                 1152.485 
                 27.84809  
               
               
                 59 
                 1153.311 
                 35.60757 
               
               
                 60 
                 1157.537 
                 37.44405  
               
               
                 61 
                 1159.603 
                 26.06505  
               
               
                 62 
                 1160.359 
                 35.60058  
               
               
                 63 
                 1162.544 
                 20.11196 
               
               
                 64 
                 1168.55 
                 20.93344  
               
               
                 65 
                 1169.566 
                 23.7134  
               
               
                 66 
                 1170.531 
                 22.38287  
               
               
                 67 
                 1173.529 
                 37.49036  
               
               
                 68 
                 1178.392 
                 20.71175  
               
               
                 69 
                 1179.523 
                 27.11006  
               
               
                 70 
                 1180.517 
                 35.69966  
               
               
                 71 
                 1182.548 
                 28.273  
               
               
                 72 
                 1186.53 
                 22.39375  
               
               
                 73 
                 1187.358 
                 35.68919 
               
               
                 74 
                 1191.517 
                 36.17672 
               
               
                 75 
                 1194.553 
                 26.70085  
               
               
                 76 
                 1196.519 
                 21.00144  
               
               
                 77 
                 1199.576  
                 21.9516  
               
               
                 78 
                 1200.537 
                 25.02658  
               
               
                 79 
                 1200.538 
                 24.14255 
               
               
                 80 
                 1208.493 
                 26.33716 
               
               
                 81 
                 1210.554 
                 20.87028 
               
               
                 82 
                 1211.542 
                 25.82128 
               
               
                 83 
                 1215.452 
                 26.87849 
               
               
                 84 
                 1216.537 
                 24.24347 
               
               
                 85 
                 1217.529 
                 35.78057 
               
               
                 86 
                 1226.525 
                 21.01619 
               
               
                 87 
                 1231.488 
                 39.56649 
               
               
                 88 
                 1244.566 
                 21.64647 
               
               
                 89 
                 1247.523 
                 22.00076 
               
               
                 90 
                 1257.443  
                 33.9189 
               
               
                 91 
                 1260.562 
                 21.82808 
               
               
                 92 
                 1266.565 
                 21.20346 
               
               
                 93 
                 1268.543  
                 21.3538 
               
               
                 94 
                 1281.585 
                 27.09018 
               
               
                 95 
                 1283.366 
                 36.12409 
               
               
                 96 
                 1287.592 
                 21.87374 
               
               
                 97 
                 1290.344 
                 30.86606 
               
               
                 98 
                 1292.393 
                 36.15933 
               
               
                 99 
                 1292.594 
                 21.41793 
               
               
                 100 
                 1295.356 
                 34.16189 
               
               
                 101 
                 1297.582 
                 27.36504 
               
               
                 102  
                 1312.622 
                 22.45504 
               
               
                 103  
                 1322.405 
                 36.37559 
               
               
                 104  
                 1326.564 
                 27.11048 
               
               
                 105 
                 1328.499 
                 26.77713 
               
               
                 106 
                 1332.416 
                 36.1259 
               
               
                 107 
                 1333.416 
                 36.10802 
               
               
                 108 
                 1337.62 
                 38.19948 
               
               
                 109 
                 1338.603 
                 23.98777 
               
               
                 110 
                 1341.578 
                 29.97724 
               
               
                 111 
                 1350.574 
                 21.26649 
               
               
                 112 
                 1351.635 
                 38.75677 
               
               
                 113  
                 1352.556 
                 29.76547 
               
               
                 114  
                 1352.779 
                 24.60145 
               
               
                 115 
                 1353.656 
                 25.63162 
               
               
                 116 
                 1354.641 
                 22.13931 
               
               
                 117 
                 1357.578 
                 30.02141 
               
               
                 118  
                 1360.627 
                 22.64544  
               
               
                 119 
                 1367.643 
                 38.88257  
               
               
                 120 
                 1368.577 
                 21.9043 
               
               
                 121  
                 1383.593 
                 27.62604  
               
               
                 122  
                 1383.637 
                 38.94024  
               
               
                 123  
                 1392.623 
                 21.75213  
               
               
                 124  
                 1399.623 
                 28.74437  
               
               
                 125 
                 1408.66 
                 39.13381  
               
               
                 126 
                 1413.55 
                 25.55998  
               
               
                 127 
                 1423.594 
                 21.90806 
               
               
                 128  
                 1424.662 
                 39.29955  
               
               
                 129  
                 1426.638 
                 22.42056  
               
               
                 130  
                 1435.659 
                 28.83627  
               
               
                 131  
                 1438.659 
                 30.20137  
               
               
                 132  
                 1439.655 
                 29.81709  
               
               
                 133  
                 1440.661 
                 39.28449  
               
               
                 134  
                 1442.626 
                 27.6328 
               
               
                 135  
                 1451.693 
                 22.55358  
               
               
                 136  
                 1466.659 
                 21.8713 
               
               
                 137  
                 1466.653 
                 28.51877  
               
               
                 138  
                 1467.795 
                 23.8873 
               
               
                 139  
                 1467.807 
                 24.68522  
               
               
                 140  
                 1469.668 
                 23.69358  
               
               
                 141  
                 1470.684 
                 21.08042  
               
               
                 142 
                 1473.63 
                 22.20617  
               
               
                 143 
                 1483.656 
                 22.58601  
               
               
                 144  
                 1486.683 
                 21.15232  
               
               
                 145  
                 1487.652 
                 29.62173  
               
               
                 146  
                 1491.739 
                 39.83392  
               
               
                 147  
                 1494.661 
                 30.3993 
               
               
                 148  
                 1496.684 
                 30.37452  
               
               
                 149 
                 1496.63 
                 22.33629  
               
               
                 150  
                 1507.738 
                 40.02385  
               
               
                 151  
                 1522.701 
                 29.40686  
               
               
                 152  
                 1523.841 
                 29.75377  
               
               
                 153 
                 1538.69 
                 29.77393 
               
               
                 154  
                 1539.735 
                 40.30862 
               
               
                 155  
                 1542.692 
                 23.96014  
               
               
                 156  
                 1556.739 
                 40.03232  
               
               
                 157 
                 1560.577 
                 21.76907  
               
               
                 158 
                 1565.688  
                 26.3032  
               
               
                 159 
                 1567.702 
                 20.19208  
               
               
                 160 
                 1576.6 
                 26.37432  
               
               
                 161  
                 1579.679 
                 23.00007  
               
               
                 162  
                 1579.713 
                 29.81744  
               
               
                 163  
                 1580.886 
                 24.84996  
               
               
                 164  
                 1580.879  
                 23.8674  
               
               
                 165  
                 1584.506 
                 37.49593  
               
               
                 166 
                 1586.738 
                 28.88186  
               
               
                 167  
                 1588.706 
                 30.15033  
               
               
                 168  
                 1591.709 
                 38.27637  
               
               
                 169  
                 1594.762 
                 40.21545  
               
               
                 170  
                 1622.722 
                 26.79132  
               
               
                 171  
                 1623.727 
                 24.12394  
               
               
                 172  
                 1630.739 
                 20.64725  
               
               
                 173 
                 1634.652 
                 37.33193  
               
               
                 174 
                 1635.76 
                 30.33571  
               
               
                 175  
                 1635.786 
                 40.44105  
               
               
                 176  
                 1638.728 
                 20.22988  
               
               
                 177 
                 1640.581 
                 23.24178  
               
               
                 178 
                 1651.79 
                 40.66166  
               
               
                 179 
                 1653.876 
                 30.38117  
               
               
                 180 
                 1660.735 
                 38.00226  
               
               
                 181 
                 1666.775 
                 30.66426  
               
               
                 182 
                 1679.947 
                 23.81762 
               
               
                 183  
                 1680.752 
                 30.02747  
               
               
                 184  
                 1684.666 
                 31.75269  
               
               
                 185  
                 1684.671 
                 30.65638  
               
               
                 186  
                 1684.709  
                 29.6453  
               
               
                 187 
                 1693.762 
                 20.50581 
               
               
                 188  
                 1703.839 
                 33.58491  
               
               
                 189 
                 1716.657 
                 20.17727 
               
               
                 190  
                 1716.773 
                 27.99784  
               
               
                 191  
                 1732.771 
                 28.17527  
               
               
                 192 
                 1746.593 
                 38.21271  
               
               
                 193 
                 1754.895 
                 31.25885  
               
               
                 194  
                 1783.791 
                 39.81519  
               
               
                 195  
                 1798.716 
                 36.94821  
               
               
                 196 
                 1806.827 
                 23.06136 
               
               
                 197 
                 1807.809 
                 20.64857 
               
               
                 198 
                 1808.793 
                 23.71763 
               
               
                 199  
                 1817.694 
                 20.23435 
               
               
                 200 
                 1818.827 
                 30.95312 
               
               
                 201  
                 1819.796 
                 23.36311 
               
               
                 202  
                 1822.735 
                 30.87417 
               
               
                 203  
                 1828.848 
                 21.20199 
               
               
                 204 
                 1834.825 
                 31.09503 
               
               
                 205 
                 1837.8 
                 30.55694 
               
               
                 206 
                 1840.836 
                 41.17953 
               
               
                 207  
                 1858.839  
                 24.2646 
               
               
                 208  
                 1860.826 
                 21.40014 
               
               
                 209  
                 1863.751 
                 19.92311 
               
               
                 210  
                 1874.831 
                 30.82379 
               
               
                 211 
                 1878.59 
                 30.77853 
               
               
                 212 
                 1884.857 
                 40.05398 
               
               
                 213  
                 1885.651 
                 38.81996 
               
               
                 214  
                 1892.973 
                 24.55813 
               
               
                 215  
                 1911.051 
                 24.98094 
               
               
                 216  
                 1936.874 
                 34.748 
               
               
                 217  
                 1947.878 
                 31.60618 
               
               
                 218 
                 1950.851 
                 35.76881 
               
               
                 219  
                 1962.875 
                 31.81242 
               
               
                 220 
                 1963.88 
                 31.74253 
               
               
                 221 
                 1969.838 
                 25.22952 
               
               
                 222  
                 1977.918 
                 32.19436 
               
               
                 223  
                 2003.939 
                 24.61864 
               
               
                 224 
                 2007.945 
                 22.10222 
               
               
                 225 
                 2008.902  
                 32.2865 
               
               
                 226 
                 2009.879 
                 32.29178 
               
               
                 227  
                 2013.893 
                 31.75577 
               
               
                 228 
                 2013.905 
                 25.19463 
               
               
                 229  
                 2014.898 
                 21.90602 
               
               
                 230  
                 2029.853 
                 20.39044 
               
               
                 231  
                 2039.129 
                 21.77864 
               
               
                 232  
                 2045.858 
                 34.17017 
               
               
                 233  
                 2058.937 
                 23.15082 
               
               
                 234  
                 2064.918 
                 24.45992 
               
               
                 235 
                 2067.818 
                 20.62077 
               
               
                 236  
                 2076.945 
                 21.77894  
               
               
                 237  
                 2077.963 
                 22.48482  
               
               
                 238  
                 2078.932 
                 26.67145  
               
               
                 239  
                 2081.936 
                 33.66116  
               
               
                 240  
                 2096.916 
                 32.9972 
               
               
                 241  
                 2109.923 
                 24.06903  
               
               
                 242  
                 2130.962 
                 32.73483  
               
               
                 243  
                 2137.942 
                 21.79294  
               
               
                 244  
                 2159.003 
                 33.19108  
               
               
                 245  
                 2235.045 
                 34.16645  
               
               
                 246  
                 2248.991 
                 25.99098  
               
               
                 247  
                 2257.869 
                 35.92739  
               
               
                 248  
                 2266.021 
                 22.1634 
               
               
                 249  
                 2280.944 
                 36.21864  
               
               
                 250  
                 2282.016 
                 22.23937  
               
               
                 251  
                 2297.011 
                 33.86518  
               
               
                 252  
                 2371.084 
                 22.7883 
               
               
                 253  
                 2380.081 
                 36.51091  
               
               
                 254  
                 2404.015 
                 20.27277  
               
               
                 255  
                 2420.998 
                 34.86081  
               
               
                 256  
                 2430.081 
                 25.69736  
               
               
                 257  
                 2446.092 
                 28.37261  
               
               
                 258  
                 2471.155 
                 34.77354  
               
               
                 259  
                 2485.125 
                 34.4072 
               
               
                 260  
                 2487.125 
                 28.27413  
               
               
                 261  
                 2501.119 
                 34.38645  
               
               
                 262  
                 2544.112 
                 26.06379  
               
               
                 263  
                 2544.128 
                 28.25992  
               
               
                 264  
                 2545.12  
                 28.20161  
               
               
                 265  
                 2547.986 
                 21.4417 
               
               
                 266  
                 2559.18  
                 19.40742  
               
               
                 267  
                 2576.124 
                 34.25753 
               
               
                 268  
                 2577.246 
                 24.66592  
               
               
                 269  
                 2589.056 
                 22.56216  
               
               
                 270  
                 2596.233 
                 34.89552  
               
               
                 271  
                 2599.19  
                 28.27509  
               
               
                 272  
                 2628.215 
                 34.96638  
               
               
                 273  
                 2642.214 
                 27.69602  
               
               
                 274 
                 2658.271 
                 19.47609  
               
               
                 275  
                 2682.143 
                 22.49183  
               
               
                 276  
                 2686.336 
                 29.34243  
               
               
                 277  
                 2742.251 
                 42.14319  
               
               
                 278  
                 2744.125 
                 35.10541  
               
               
                 279  
                 2748.788 
                 36.38231  
               
               
                 280  
                 2752.413 
                 19.8887 
               
               
                 281  
                 2767.323  
                 21.6729  
               
               
                 282  
                 2825.267  
                 24.4868  
               
               
                 283  
                 2834.187 
                 22.46729  
               
               
                 284  
                 2854.363 
                 34.86364  
               
               
                 285  
                 2914.379 
                 24.33308  
               
               
                 286  
                 2923.432 
                 36.91513  
               
               
                 287 
                 2936.536 
                 20.09721  
               
               
                 288 
                 2942.299 
                 22.23281 
               
               
                 289  
                 2973.452  
                 24.3704  
               
               
                 290  
                 2977.179 
                 19.52319  
               
               
                 291 
                 2987.348 
                 38.54569  
               
               
                 292 
                 3002.238 
                 23.80085 
               
               
                 293  
                 3011.387 
                 29.74951  
               
               
                 294  
                 3057.395 
                 29.96413  
               
               
                 295  
                 3058.378 
                 24.82364  
               
               
                 296  
                 3076.233 
                 19.57728  
               
               
                 297  
                 3132.455  
                 31.1821  
               
               
                 298  
                 3137.411 
                 30.34616  
               
               
                 299 
                 3148.277 
                 24.15522  
               
               
                 300 
                 3152.34 
                 24.55108  
               
               
                 301 
                 3166.271 
                 22.05894  
               
               
                 302  
                 3193.382 
                 22.64363  
               
               
                 303  
                 3200.423 
                 35.77416  
               
               
                 304  
                 3202.434 
                 30.60166  
               
               
                 305  
                 3205.273 
                 19.65755 
               
               
                 306 
                 3255.493 
                 30.78474 
               
               
                 307  
                 3256.527 
                 33.03419  
               
               
                 308  
                 3261.498 
                 22.19478  
               
               
                 309  
                 3264.556 
                 25.75167  
               
               
                 310  
                 3265.431 
                 36.08731  
               
               
                 311 
                 3266.484 
                 30.07129  
               
               
                 312 
                 3271.49 
                 30.70446  
               
               
                 313 
                 3282.498 
                 30.08996 
               
               
                 314  
                 3287.479 
                 30.97061 
               
               
                 315  
                 3314.431 
                 20.14047 
               
               
                 316  
                 3338.463 
                 23.58844 
               
               
                 317  
                 3350.549 
                 31.01736 
               
               
                 318  
                 3363.543 
                 30.21892 
               
               
                 319 
                 3404.619 
                 25.94028 
               
               
                 320  
                 3405.478 
                 25.96805 
               
               
                 321  
                 3416.602 
                 36.84899 
               
               
                 322  
                 3421.555 
                 25.99412 
               
               
                 323  
                 3425.605 
                 31.27027 
               
               
                 324 
                 3426.31 
                 27.69928 
               
               
                 325 
                 3441.609 
                 31.38498 
               
               
                 326 
                 3462.35 
                 19.37411 
               
               
                 327  
                 3546.672 
                 26.2234 
               
               
                 328 
                 3572.6  
                 30.6681 
               
               
                 329  
                 3582.701 
                 19.46503 
               
               
                 330  
                 3583.637 
                 41.47108 
               
               
                 331 
                 3603.678 
                 32.40852 
               
               
                 332  
                 3630.443 
                 21.77706 
               
               
                 333  
                 3681.716 
                 32.01776 
               
               
                 334 
                 3685.833 
                 22.19635 
               
               
                 335  
                 3706.721 
                 22.02471 
               
               
                 336  
                 3719.734 
                 22.49869 
               
               
                 337  
                 3774.812 
                 28.22771 
               
               
                 338 
                 3775.748 
                 25.58515 
               
               
                 339  
                 3788.818 
                 25.18606 
               
               
                 340 
                 3831.81 
                 28.48446 
               
               
                 341 
                 3839.813 
                 19.70303 
               
               
                 342  
                 3870.814 
                 33.49116 
               
               
                 343  
                 3891.752 
                 24.52856 
               
               
                 344 
                 3944.712 
                 24.55436 
               
               
                 345 
                 3984.647 
                 21.25792 
               
               
                 346 
                 3986.65 
                 20.60164 
               
               
                 347 
                 3996.658 
                 20.92089 
               
               
                 348  
                 4002.618 
                 20.65664 
               
               
                 349  
                 4043.639 
                 20.38493 
               
               
                 350  
                 4190.718 
                 20.5276 
               
               
                 351  
                 4196.749 
                 20.83785 
               
               
                 352 
                 4251.984 
                 28.76518 
               
               
                 353 
                 4368.903 
                 20.2129 
               
               
                 354 
                 4404.842 
                 20.66586 
               
               
                 355 
                 4409.888 
                 20.00095 
               
               
                 356 
                 4418.992 
                 25.74477 
               
               
                 357  
                 4467.96 
                 29.11998 
               
               
                 358 
                 4539.029 
                 26.25198 
               
               
                 359 
                 4671.824 
                 23.27783 
               
               
                 360 
                 4771.071 
                 20.19867 
               
               
                 361 
                 4799.959 
                 23.80776 
               
               
                 362 
                 5227.459 
                 27.38143 
               
               
                 363  
                 5228.26 
                 26.99815 
               
               
                 364 
                 5574.253 
                 23.20092 
               
               
                 365 
                 6055.575 
                 21.04955 
               
               
                 366 
                 6169.572 
                 24.77459 
               
               
                 367 
                 6211.741 
                 20.28513 
               
               
                 368 
                 6236.907  
                 21.066 
               
               
                 369 
                 6782.845 
                 26.57695 
               
               
                 370 
                 8176.072 
                 19.46583 
               
               
                 371  
                 8176.01 
                 20.17348 
               
               
                 372 
                 8837.408 
                 21.0634 
               
               
                 373 
                 8853.766 
                 21.09699 
               
               
                 374 
                 8917.251 
                 22.54506 
               
               
                 375 
                 9625.366 
                 20.68655 
               
               
                 376 
                 9866.536 
                 20.86863 
               
               
                 377  
                 10199.7 
                 21.11481 
               
               
                 378 
                 10341.97 
                 22.98239 
               
               
                 379 
                 10753.32 
                 19.65218 
               
               
                 380 
                 10999.91 
                 21.37191 
               
               
                 381 
                 11967.55 
                 20.46866 
               
               
                 382 
                 12716.79 
                 25.89832 
               
               
                 383 
                 14110.92 
                 21.95905 
               
               
                   
               
             
          
         
       
     
         [0012]    This method may also be used for the early detection and prognosis of the further development of the disease. 
         [0013]    Evaluation of the determined presence or absence or amplitudes of the markers may be effected by using the following reference values: 
         [0000]    
       
         
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 No. 
                 Mass [Da] 
                 CE_t [min] 
                 Freq. ADPKD 
                 Amplitude 
                 Freq. Contrl. 
                 Amplitude 
                 Freq Diff 
                 AUC 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 840.4071 
                 23.16555 
                 0.41 
                 1.67(1.53) 
                 0.48 
                 1.83(1.82) 
                 −0.06 
                 0.6091714 
               
               
                 2 
                 884.2923 
                 43.80656 
                 0.76 
                 1.68(1.63) 
                 0.12 
                 1.49(1.47) 
                 0.65 
                 0.8351573 
               
               
                 3 
                 884.3214 
                 24.85187 
                 1 
                 2.21(2.16) 
                 0.62 
                 2.06(2.10) 
                 0.38 
                 0.7611928 
               
               
                 4 
                 900.4511 
                 24.99 
                 0.59 
                 2.02(1.99) 
                 0 
                 0.00(0.00) 
                 0.59 
                 0.7941176 
               
               
                 5 
                 902.4133 
                 20.84575 
                 1 
                 2.97(3.02) 
                 0.81 
                 2.56(2.59) 
                 0.19 
                 0.8570451 
               
               
                 6 
                 911.2648 
                 34.34517 
                 1 
                 2.94(2.94) 
                 0.9 
                 2.92(2.94) 
                 0.1 
                 0.6769963 
               
               
                 7 
                 923.4244 
                 22.01035 
                 0.47 
                 1.69(1.68) 
                 0.17 
                 1.90(2.05) 
                 0.3 
                 0.7256933 
               
               
                 8 
                 926.4665 
                 21.35563 
                 0.59 
                 1.67(1.67) 
                 0.06 
                 1.58(1.50) 
                 0.53 
                 0.7698358 
               
               
                 9 
                 928.3718 
                 35.46373 
                 0.65 
                 1.72(1.77) 
                 0.29 
                 1.71(1.74) 
                 0.36 
                 0.6826265 
               
               
                 10 
                 931.4706 
                 20.00439 
                 0.76 
                 2.06(1.99) 
                 0.29 
                 2.00(2.04) 
                 0.47 
                 0.6635483 
               
               
                 11 
                 935.4465 
                 23.68105 
                 0.35 
                 1.62(1.56) 
                 0.55 
                 2.08(2.12) 
                 −0.19 
                 0.6201971 
               
               
                 12 
                 937.4612 
                 34.09575 
                 0.35 
                 1.10(1.08) 
                 0.51 
                 1.72(1.71) 
                 −0.16 
                 0.6228020 
               
               
                 13 
                 944.5103 
                 21.24885 
                 0.94 
                 2.69(2.74) 
                 0.47 
                 2.33(2.42) 
                 0.48 
                 0.7940194 
               
               
                 14 
                 954.4564 
                 24.31141 
                 0.59 
                 1.91(1.98) 
                 0.16 
                 1.74(1.67) 
                 0.43 
                 0.6769546 
               
               
                 15 
                 956.4393 
                 20.35767 
                 0.76 
                 2.41(2.46) 
                 0.49 
                 2.20(2.23) 
                 0.28 
                 0.6749081 
               
               
                 16 
                 965.4274 
                 27.83332 
                 0.76 
                 2.26(2.26) 
                 0.4 
                 2.24(2.37) 
                 0.37 
                 0.6334781 
               
               
                 17 
                 981.5851 
                 24.79552 
                 0.88 
                 2.57(2.51) 
                 0.95 
                 2.86(2.96) 
                 −0.07 
                 0.7700050 
               
               
                 18 
                 984.4547 
                 24.92263 
                 0.76 
                 2.16(2.17) 
                 0.21 
                 1.83(1.82) 
                 0.56 
                 0.7841630 
               
               
                 19 
                 988.4991 
                 21.2492 
                 0.88 
                 2.21(2.14) 
                 0.27 
                 1.94(1.94) 
                 0.61 
                 0.7307885 
               
               
                 20 
                 992.4164 
                 20.39667 
                 0.53 
                 1.86(1.88) 
                 0.15 
                 2.01(2.00) 
                 0.38 
                 0.6417892 
               
               
                 21 
                 1002.454 
                 24.41733 
                 0.59 
                 2.10(2.11) 
                 0 
                 0.00(0.00) 
                 0.59 
                 0.7941176 
               
               
                 22 
                 1013.368 
                 25.16517 
                 1 
                 3.09(3.16) 
                 0.94 
                 2.85(2.88) 
                 0.06 
                 0.8391246 
               
               
                 23 
                 1016.265 
                 35.651 
                 1 
                 2.83(2.85) 
                 0.91 
                 2.89(2.92) 
                 0.09 
                 0.5855329 
               
               
                 24 
                 1016.445 
                 25.78512 
                 1 
                 3.21(3.18) 
                 0.98 
                 3.12(3.19) 
                 0.02 
                 0.6074173 
               
               
                 25 
                 1018.462 
                 24.53558 
                 0.71 
                 2.18(2.23) 
                 0.35 
                 2.02(2.03) 
                 0.36 
                 0.6979619 
               
               
                 26 
                 1028.524 
                 24.83936 
                 0.59 
                 1.87(1.86) 
                 0.17 
                 1.78(1.87) 
                 0.41 
                 0.7130643 
               
               
                 27 
                 1032.498 
                 21.2104 
                 0.65 
                 2.86(2.83) 
                 0.58 
                 2.46(2.39) 
                 0.07 
                 0.7492482 
               
               
                 28 
                 1040.475 
                 25.05015 
                 0.35 
                 2.35(2.35) 
                 0.74 
                 2.31(2.36) 
                 −0.39 
                 0.6272970 
               
               
                 29 
                 1046.427 
                 27.64366 
                 0.53 
                 1.70(1.60) 
                 0.28 
                 1.76(1.75) 
                 0.25 
                 0.7124123 
               
               
                 30 
                 1058.476 
                 24.89302 
                 0.53 
                 3.05(3.15) 
                 0.03 
                 1.67(2.05) 
                 0.49 
                 0.7564979 
               
               
                 31 
                 1068.447 
                 24.76449 
                 1 
                 3.36(3.35) 
                 0.94 
                 3.29(3.30) 
                 0.06 
                 0.7287003 
               
               
                 32 
                 1070.49 
                 36.49286 
                 0.47 
                 1.69(1.62) 
                 0.55 
                 2.25(2.30) 
                 −0.08 
                 0.6884572 
               
               
                 33 
                 1072.5 
                 21.13634 
                 0.53 
                 2.02(2.22) 
                 0.15 
                 1.94(1.84) 
                 0.38 
                 0.6956224 
               
               
                 34 
                 1075.487 
                 20.61147 
                 0.88 
                 2.49(2.47) 
                 0.22 
                 1.94(1.92) 
                 0.66 
                 0.7434848 
               
               
                 35 
                 1082.501 
                 23.90513 
                 0.59 
                 2.46(2.59) 
                 0.47 
                 2.50(2.48) 
                 0.12 
                 0.7340461 
               
               
                 36 
                 1082.517 
                 21.69541 
                 0.76 
                 2.05(1.93) 
                 0.35 
                 1.87(1.86) 
                 0.42 
                 0.7138323 
               
               
                 37 
                 1084.428 
                 25.23275 
                 1 
                 3.12(3.19) 
                 0.93 
                 3.02(3.06) 
                 0.07 
                 0.6060192 
               
               
                 38 
                 1085.466 
                 21.93764 
                 1 
                 2.62(2.64) 
                 0.76 
                 2.33(2.40) 
                 0.24 
                 0.7794437 
               
               
                 39 
                 1096.483 
                 26.07573 
                 0.76 
                 3.20(3.54) 
                 0.99 
                 3.77(3.80) 
                 −0.22 
                 0.6386569 
               
               
                 40 
                 1097.495 
                 21.00157 
                 0.53 
                 2.37(2.24) 
                 0 
                 0.00(0.00) 
                 0.53 
                 0.7647059 
               
               
                 41 
                 1097.498 
                 25.40513 
                 0.53 
                 2.86(2.79) 
                 0.07 
                 1.97(2.01) 
                 0.46 
                 0.7482900 
               
               
                 42 
                 1099.499 
                 21.67177 
                 0.94 
                 2.26(2.31) 
                 0.59 
                 2.28(2.31) 
                 0.35 
                 0.6610807 
               
               
                 43 
                 1100.502 
                 37.03674 
                 0.41 
                 2.15(2.01) 
                 0.7 
                 2.42(2.44) 
                 −0.29 
                 0.6821751 
               
               
                 44 
                 1110.389 
                 33.6302 
                 1 
                 2.56(2.57) 
                 0.58 
                 2.36(2.40) 
                 0.42 
                 0.6171901 
               
               
                 45 
                 1113.511 
                 22.2623 
                 0.59 
                 2.45(2.51) 
                 0 
                 0.00(0.00) 
                 0.59 
                 0.7941176 
               
               
                 46 
                 1114.479 
                 24.21347 
                 0.82 
                 2.21(2.14) 
                 0.4 
                 2.21(2.23) 
                 0.43 
                 0.8000752 
               
               
                 47 
                 1116.477 
                 37.03951 
                 0.24 
                 2.31(2.64) 
                 0.51 
                 2.16(2.20) 
                 −0.28 
                 0.6542825 
               
               
                 48 
                 1116.53 
                 20.8514 
                 0.71 
                 2.17(2.17) 
                 0.13 
                 1.86(1.72) 
                 0.58 
                 0.7189275 
               
               
                 49 
                 1128.394 
                 33.59201 
                 1 
                 3.12(3.06) 
                 0.92 
                 3.01(3.01) 
                 0.08 
                 0.7363014 
               
               
                 50 
                 1128.488 
                 25.64931 
                 0.65 
                 2.48(2.43) 
                 0.79 
                 2.44(2.46) 
                 −0.14 
                 0.6419980 
               
               
                 51 
                 1130.337 
                 35.39296 
                 0.88 
                 2.46(2.54) 
                 0.74 
                 2.76(2.83) 
                 0.14 
                 0.6394086 
               
               
                 52 
                 1134.583 
                 23.65584 
                 0.71 
                 2.23(2.16) 
                 0.74 
                 2.77(2.73) 
                 −0.04 
                 0.7863348 
               
               
                 53 
                 1138.468 
                 37.07027 
                 0.71 
                 2.25(2.22) 
                 0.38 
                 1.87(1.79) 
                 0.32 
                 0.7287962 
               
               
                 54 
                 1140.516 
                 25.38464 
                 0.06 
                 2.34(2.34) 
                 0.44 
                 2.35(2.42) 
                 −0.38 
                 0.7181757 
               
               
                 55 
                 1141.511 
                 26.05729 
                 0.76 
                 2.66(2.60) 
                 0.45 
                 2.05(2.03) 
                 0.31 
                 0.6506432 
               
               
                 56 
                 1143.52 
                 36.96738 
                 1 
                 2.16(2.15) 
                 0.92 
                 2.63(2.68) 
                 0.08 
                 0.7395172 
               
               
                 57 
                 1150.561 
                 22.43054 
                 0.88 
                 2.55(2.55) 
                 0.53 
                 2.21(2.24) 
                 0.35 
                 0.7982216 
               
               
                 58 
                 1152.485 
                 27.84809 
                 0.59 
                 2.10(1.97) 
                 0.15 
                 1.57(1.44) 
                 0.44 
                 0.7506840 
               
               
                 59 
                 1153.311 
                 35.60757 
                 0.94 
                 2.40(2.49) 
                 0.62 
                 2.55(2.53) 
                 0.32 
                 0.6081963 
               
               
                 60 
                 1157.537 
                 37.44405 
                 1 
                 3.02(2.95) 
                 0.99 
                 3.30(3.33) 
                 0.01 
                 0.7258934 
               
               
                 61 
                 1159.603 
                 26.06505 
                 0.76 
                 2.65(2.60) 
                 0.38 
                 2.55(2.56) 
                 0.38 
                 0.6357751 
               
               
                 62 
                 1160.359 
                 35.60058 
                 1 
                 3.03(3.09) 
                 0.97 
                 3.19(3.22) 
                 0.03 
                 0.6624206 
               
               
                 63 
                 1162.544 
                 20.11196 
                 0.59 
                 2.39(2.39) 
                 0.62 
                 2.30(2.37) 
                 −0.03 
                 0.6326428 
               
               
                 64 
                 1168.55 
                 20.93344 
                 0.59 
                 2.19(2.13) 
                 0.02 
                 1.89(1.89) 
                 0.56 
                 0.7859097 
               
               
                 65 
                 1169.566 
                 23.7134 
                 0.88 
                 2.28(2.37) 
                 0.47 
                 2.12(2.15) 
                 0.42 
                 0.6158537 
               
               
                 66 
                 1170.531 
                 22.38287 
                 0.53 
                 1.84(1.83) 
                 0.06 
                 1.97(1.83) 
                 0.47 
                 0.7325581 
               
               
                 67 
                 1173.529 
                 37.49036 
                 0.88 
                 2.18(2.12) 
                 0.81 
                 2.53(2.54) 
                 0.07 
                 0.6908678 
               
               
                 68 
                 1178.392 
                 20.71175 
                 0.59 
                 2.38(2.38) 
                 0.21 
                 2.29(2.26) 
                 0.38 
                 0.6946625 
               
               
                 69 
                 1179.523 
                 27.11006 
                 1 
                 3.09(3.11) 
                 0.86 
                 2.77(2.81) 
                 0.14 
                 0.8720930 
               
               
                 70 
                 1180.517 
                 35.69966 
                 0.47 
                 2.49(2.49) 
                 0.79 
                 2.83(2.92) 
                 −0.32 
                 0.7102406 
               
               
                 71 
                 1182.548 
                 28.273 
                 0.41 
                 1.69(1.76) 
                 0.62 
                 2.05(2.09) 
                 −0.2 
                 0.6427080 
               
               
                 72 
                 1186.53 
                 22.39375 
                 0.94 
                 2.94(2.88) 
                 0.88 
                 2.87(2.89) 
                 0.06 
                 0.7455540 
               
               
                 73 
                 1187.358 
                 35.68919 
                 0.94 
                 2.77(2.85) 
                 0.8 
                 2.88(2.93) 
                 0.14 
                 0.6713999 
               
               
                 74 
                 1191.517 
                 36.17672 
                 0.59 
                 2.17(2.16) 
                 0.85 
                 2.70(2.73) 
                 −0.26 
                 0.7734714 
               
               
                 75 
                 1194.553 
                 26.70085 
                 1 
                 3.51(3.47) 
                 0.98 
                 3.38(3.38) 
                 0.02 
                 0.5410124 
               
               
                 76 
                 1196.519 
                 21.00144 
                 0.82 
                 2.98(3.03) 
                 0.29 
                 2.70(2.79) 
                 0.53 
                 0.6886903 
               
               
                 77 
                 1199.576 
                 21.9516 
                 0.94 
                 2.49(2.45) 
                 0.59 
                 2.34(2.33) 
                 0.35 
                 0.7541040 
               
               
                 78 
                 1200.537 
                 25.02658 
                 0.53 
                 3.22(3.86) 
                 0.15 
                 2.70(2.07) 
                 0.38 
                 0.7732208 
               
               
                 79 
                 1200.538 
                 24.14255 
                 0.65 
                 3.92(3.86) 
                 0.92 
                 3.90(3.90) 
                 −0.27 
                 0.7987805 
               
               
                 80 
                 1208.493 
                 26.33716 
                 0.71 
                 2.74(2.71) 
                 0.27 
                 2.47(2.44) 
                 0.44 
                 0.7458960 
               
               
                 81 
                 1210.554 
                 20.87028 
                 0.59 
                 2.56(2.61) 
                 0.09 
                 2.10(2.03) 
                 0.5 
                 0.6727364 
               
               
                 82 
                 1211.542 
                 25.82128 
                 0.12 
                 2.45(2.45) 
                 0.59 
                 2.11(2.14) 
                 −0.48 
                 0.6394921 
               
               
                 83 
                 1215.452 
                 26.87849 
                 0.24 
                 2.67(2.76) 
                 0.29 
                 2.68(2.67) 
                 −0.06 
                 0.6974607 
               
               
                 84 
                 1216.537 
                 24.24347 
                 1 
                 3.28(3.26) 
                 0.91 
                 3.17(3.16) 
                 0.09 
                 0.6511628 
               
               
                 85 
                 1217.529 
                 35.78057 
                 0.35 
                 3.36(3.26) 
                 0.83 
                 3.57(3.66) 
                 −0.47 
                 0.8004093 
               
               
                 86 
                 1226.525 
                 21.01619 
                 0.94 
                 2.67(2.66) 
                 0.7 
                 2.60(2.65) 
                 0.24 
                 0.6538988 
               
               
                 87 
                 1231.488 
                 39.56649 
                 0.53 
                 2.22(2.30) 
                 0.1 
                 1.80(1.88) 
                 0.42 
                 0.7291382 
               
               
                 88 
                 1244.566 
                 21.64647 
                 0.59 
                 2.08(2.18) 
                 0.19 
                 1.95(2.04) 
                 0.4 
                 0.7147743 
               
               
                 89 
                 1247.523 
                 22.00076 
                 0.88 
                 3.08(3.11) 
                 0.94 
                 2.79(2.85) 
                 −0.06 
                 0.8098480 
               
               
                 90 
                 1257.443 
                 33.9189 
                 1 
                 3.40(3.39) 
                 0.97 
                 3.21(3.25) 
                 0.03 
                 0.8467257 
               
               
                 91 
                 1260.562 
                 21.82808 
                 0.65 
                 2.69(2.81) 
                 0.41 
                 2.30(2.26) 
                 0.24 
                 0.6800869 
               
               
                 92 
                 1266.565 
                 21.20346 
                 0.59 
                 2.23(2.23) 
                 0.15 
                 2.03(1.96) 
                 0.44 
                 0.7390561 
               
               
                 93 
                 1268.543 
                 21.3538 
                 0.65 
                 2.42(2.48) 
                 0.42 
                 2.35(2.42) 
                 0.23 
                 0.6291346 
               
               
                 94 
                 1281.585 
                 27.09018 
                 0.35 
                 2.59(2.74) 
                 0.69 
                 2.49(2.50) 
                 −0.33 
                 0.6627130 
               
               
                 95 
                 1283.366 
                 36.12409 
                 1 
                 2.62(2.64) 
                 0.94 
                 2.56(2.60) 
                 0.06 
                 0.6740728 
               
               
                 96 
                 1287.592 
                 21.87374 
                 0.59 
                 2.66(2.54) 
                 0.37 
                 2.50(2.51) 
                 0.22 
                 0.6125922 
               
               
                 97 
                 1290.344 
                 30.86606 
                 0.71 
                 2.32(2.21) 
                 0.21 
                 2.38(2.48) 
                 0.5 
                 0.7393981 
               
               
                 98 
                 1292.393 
                 36.15933 
                 0.29 
                 2.00(1.84) 
                 0.24 
                 2.19(2.28) 
                 0.05 
                 0.6295523 
               
               
                 99 
                 1292.594 
                 21.41793 
                 0.59 
                 2.39(2.44) 
                 0.15 
                 2.16(2.11) 
                 0.44 
                 0.7363201 
               
               
                 100 
                 1295.356 
                 34.16189 
                 0.24 
                 1.85(1.89) 
                 0.05 
                 1.72(1.68) 
                 0.19 
                 0.6740311 
               
               
                 101 
                 1297.582 
                 27.36504 
                 0.35 
                 3.23(3.26) 
                 0.8 
                 3.20(3.20) 
                 −0.45 
                 0.6459656 
               
               
                 102 
                 1312.622 
                 22.45504 
                 1 
                 3.00(3.02) 
                 0.62 
                 2.70(2.79) 
                 0.38 
                 0.6352808 
               
               
                 103 
                 1322.405 
                 36.37559 
                 0.59 
                 2.46(2.31) 
                 0.45 
                 2.48(2.55) 
                 0.13 
                 0.6366104 
               
               
                 104 
                 1326.564 
                 27.11048 
                 0.12 
                 3.05(3.05) 
                 0.64 
                 2.80(2.77) 
                 −0.52 
                 0.7488724 
               
               
                 105 
                 1328.499 
                 26.77713 
                 0.29 
                 2.06(2.12) 
                 0.23 
                 1.95(1.92) 
                 0.06 
                 0.6541096 
               
               
                 106 
                 1332.416 
                 36.1259 
                 0.65 
                 2.06(2.10) 
                 0.22 
                 1.99(1.98) 
                 0.43 
                 0.7209302 
               
               
                 107 
                 1333.416 
                 36.10802 
                 0.24 
                 2.30(2.31) 
                 0.62 
                 2.19(2.23) 
                 −0.38 
                 0.6774966 
               
               
                 108 
                 1337.62 
                 38.19948 
                 0.82 
                 2.12(2.26) 
                 0.73 
                 2.41(2.45) 
                 0.09 
                 0.6838874 
               
               
                 109 
                 1338.603 
                 23.98777 
                 0.94 
                 2.66(2.62) 
                 0.72 
                 2.49(2.52) 
                 0.22 
                 0.7031464 
               
               
                 110 
                 1341.578 
                 29.97724 
                 0.41 
                 2.30(2.39) 
                 0.33 
                 2.05(2.00) 
                 0.09 
                 0.7088623 
               
               
                 111 
                 1350.574 
                 21.26649 
                 0.71 
                 2.27(2.33) 
                 0.1 
                 2.18(2.08) 
                 0.6 
                 0.7199716 
               
               
                 112 
                 1351.635 
                 38.75677 
                 0.76 
                 2.34(2.34) 
                 0.91 
                 2.61(2.69) 
                 −0.14 
                 0.7115770 
               
               
                 113 
                 1352.556 
                 29.76547 
                 0.94 
                 2.28(2.37) 
                 0.63 
                 2.11(2.18) 
                 0.31 
                 0.6620448 
               
               
                 114 
                 1352.779 
                 24.60145 
                 0.71 
                 2.38(2.39) 
                 0.24 
                 2.09(2.08) 
                 0.46 
                 0.7698358 
               
               
                 115 
                 1353.656 
                 25.63162 
                 0.94 
                 2.53(2.48) 
                 0.94 
                 2.77(2.78) 
                 0 
                 0.7869195 
               
               
                 116 
                 1354.641 
                 22.13931 
                 0.71 
                 2.26(2.24) 
                 0.14 
                 1.77(1.78) 
                 0.57 
                 0.8283174 
               
               
                 117 
                 1357.578 
                 30.02141 
                 0.76 
                 2.25(2.33) 
                 0.5 
                 2.04(2.11) 
                 0.26 
                 0.7595640 
               
               
                 118 
                 1360.627 
                 22.64544 
                 0.59 
                 2.07(1.94) 
                 0.16 
                 1.91(2.06) 
                 0.43 
                 0.7209302 
               
               
                 119 
                 1367.643 
                 38.88257 
                 0.94 
                 2.87(2.85) 
                 0.98 
                 3.07(3.15) 
                 −0.04 
                 0.6962913 
               
               
                 120 
                 1368.577 
                 21.9043 
                 0.59 
                 2.45(2.47) 
                 0.27 
                 2.29(2.37) 
                 0.32 
                 0.7265703 
               
               
                 121 
                 1383.593 
                 27.62604 
                 1 
                 2.60(2.65) 
                 0.63 
                 2.40(2.36) 
                 0.37 
                 0.6304711 
               
               
                 122 
                 1383.637 
                 38.94024 
                 0.41 
                 1.92(2.09) 
                 0.45 
                 2.20(2.27) 
                 −0.04 
                 0.6521049 
               
               
                 123 
                 1392.623 
                 21.75213 
                 1 
                 3.53(3.49) 
                 1 
                 3.58(3.62) 
                 0 
                 0.7002269 
               
               
                 124 
                 1399.623 
                 28.74437 
                 0.35 
                 2.39(2.45) 
                 0.15 
                 2.24(2.18) 
                 0.2 
                 0.6726111 
               
               
                 125 
                 1408.66 
                 39.13381 
                 0.82 
                 2.60(2.60) 
                 0.91 
                 3.02(3.05) 
                 −0.08 
                 0.7497912 
               
               
                 126 
                 1413.55 
                 25.55998 
                 0.59 
                 2.58(2.62) 
                 0.24 
                 2.17(2.21) 
                 0.34 
                 0.7130643 
               
               
                 127 
                 1423.594 
                 21.90806 
                 0.41 
                 3.15(3.03) 
                 0.21 
                 2.93(3.13) 
                 0.2 
                 0.6637989 
               
               
                 128 
                 1424.662 
                 39.29955 
                 0.94 
                 3.34(3.29) 
                 1 
                 3.55(3.65) 
                 −0.06 
                 0.7117858 
               
               
                 129 
                 1426.638 
                 22.42056 
                 0.53 
                 1.78(1.73) 
                 0.22 
                 2.01(1.97) 
                 0.31 
                 0.6064567 
               
               
                 130 
                 1435.659 
                 28.83627 
                 1 
                 3.84(3.85) 
                 0.94 
                 3.82(3.80) 
                 0.06 
                 0.5957592 
               
               
                 131 
                 1438.659 
                 30.20137 
                 0.29 
                 2.17(2.26) 
                 0.63 
                 2.28(2.33) 
                 −0.33 
                 0.6223271 
               
               
                 132 
                 1439.655 
                 29.81709 
                 0.76 
                 2.41(2.44) 
                 0.43 
                 2.26(2.24) 
                 0.33 
                 0.6754928 
               
               
                 133 
                 1440.661 
                 39.28449 
                 0.82 
                 2.43(2.38) 
                 0.78 
                 2.89(2.96) 
                 0.04 
                 0.7286168 
               
               
                 134 
                 1442.626 
                 27.6328 
                 0.76 
                 2.83(2.88) 
                 0.1 
                 1.97(2.05) 
                 0.66 
                 0.6920314 
               
               
                 135 
                 1451.693 
                 22.55358 
                 0.71 
                 3.04(3.04) 
                 0.9 
                 3.10(3.15) 
                 −0.19 
                 0.6855997 
               
               
                 136 
                 1466.659 
                 21.8713 
                 1 
                 3.41(3.37) 
                 1 
                 3.37(3.41) 
                 0 
                 0.6834940 
               
               
                 137 
                 1466.653 
                 28.51877 
                 0.47 
                 2.19(2.16) 
                 0.67 
                 2.58(2.70) 
                 −0.2 
                 0.6686017 
               
               
                 138 
                 1467.795 
                 23.8873 
                 0.29 
                 2.74(2.55) 
                 0.64 
                 3.38(3.46) 
                 −0.35 
                 0.6645924 
               
               
                 139 
                 1467.807 
                 24.68522 
                 0.94 
                 3.19(3.20) 
                 0.56 
                 2.83(2.79) 
                 0.38 
                 0.6557005 
               
               
                 140 
                 1469.668 
                 23.69358 
                 1 
                 3.47(3.47) 
                 0.95 
                 3.38(3.44) 
                 0.05 
                 0.5601915 
               
               
                 141 
                 1470.684 
                 21.08042 
                 0.35 
                 1.89(1.84) 
                 0.58 
                 2.12(2.19) 
                 −0.23 
                 0.6760775 
               
               
                 142 
                 1473.63 
                 22.20617 
                 0.41 
                 3.00(3.15) 
                 0.31 
                 2.71(2.68) 
                 0.1 
                 0.6280905 
               
               
                 143 
                 1483.656 
                 22.58601 
                 0.47 
                 2.90(2.95) 
                 0.29 
                 2.75(2.92) 
                 0.18 
                 0.6503508 
               
               
                 144 
                 1486.683 
                 21.15232 
                 0.65 
                 2.42(2.34) 
                 0.79 
                 2.62(2.63) 
                 −0.14 
                 0.7578517 
               
               
                 145 
                 1487.652 
                 29.62173 
                 0.76 
                 2.73(2.78) 
                 0.5 
                 2.57(2.63) 
                 0.26 
                 0.6983834 
               
               
                 146 
                 1491.739 
                 39.83392 
                 1 
                 2.40(2.32) 
                 0.94 
                 2.94(2.99) 
                 0.06 
                 0.7893418 
               
               
                 147 
                 1494.661 
                 30.3993 
                 0.71 
                 2.20(2.28) 
                 0.86 
                 2.33(2.36) 
                 −0.15 
                 0.6710658 
               
               
                 148 
                 1496.684 
                 30.37452 
                 0.29 
                 1.94(1.81) 
                 0.57 
                 2.32(2.34) 
                 −0.28 
                 0.6737346 
               
               
                 149 
                 1496.63 
                 22.33629 
                 0.53 
                 2.33(2.24) 
                 0.23 
                 2.05(2.04) 
                 0.3 
                 0.6698964 
               
               
                 150 
                 1507.738 
                 40.02385 
                 0.94 
                 3.33(3.34) 
                 1 
                 3.72(3.74) 
                 −0.06 
                 0.7829937 
               
               
                 151 
                 1522.701 
                 29.40686 
                 1 
                 3.04(3.04) 
                 0.84 
                 2.86(2.88) 
                 0.16 
                 0.7599179 
               
               
                 152 
                 1523.841 
                 29.75377 
                 0.12 
                 3.21(3.21) 
                 0.8 
                 3.45(3.51) 
                 −0.68 
                 0.6491814 
               
               
                 153 
                 1538.69 
                 29.77393 
                 0.71 
                 2.34(2.34) 
                 0.84 
                 2.40(2.45) 
                 −0.13 
                 0.7183428 
               
               
                 154 
                 1539.735 
                 40.30862 
                 1 
                 3.28(3.31) 
                 0.73 
                 3.58(3.69) 
                 0.27 
                 0.7248998 
               
               
                 155 
                 1542.692 
                 23.96014 
                 0.59 
                 2.40(2.41) 
                 0.42 
                 2.36(2.39) 
                 0.17 
                 0.6599546 
               
               
                 156 
                 1556.739 
                 40.03232 
                 0.24 
                 2.05(2.03) 
                 0.59 
                 2.93(2.79) 
                 −0.36 
                 0.7356361 
               
               
                 157 
                 1560.577 
                 21.76907 
                 0.65 
                 2.61(2.70) 
                 0.44 
                 2.55(2.51) 
                 0.21 
                 0.6563649 
               
               
                 158 
                 1565.688 
                 26.3032 
                 0.71 
                 2.13(2.11) 
                 0.77 
                 2.18(2.20) 
                 −0.06 
                 0.6953725 
               
               
                 159 
                 1567.702 
                 20.19208 
                 0.88 
                 2.65(2.75) 
                 0.65 
                 2.50(2.52) 
                 0.23 
                 0.6643418 
               
               
                 160 
                 1576.6 
                 26.37432 
                 1 
                 2.93(2.98) 
                 0.84 
                 2.95(2.95) 
                 0.16 
                 0.6171901 
               
               
                 161 
                 1579.679 
                 23.00007 
                 0.94 
                 2.93(2.97) 
                 0.76 
                 2.73(2.72) 
                 0.19 
                 0.6571584 
               
               
                 162 
                 1579.713 
                 29.81744 
                 1 
                 3.41(3.40) 
                 1 
                 3.54(3.54) 
                 0 
                 0.7782189 
               
               
                 163 
                 1580.886 
                 24.84996 
                 0.71 
                 3.38(3.53) 
                 0.44 
                 2.83(2.76) 
                 0.26 
                 0.6691447 
               
               
                 164 
                 1580.879 
                 23.8674 
                 0.41 
                 2.78(2.81) 
                 0.86 
                 3.11(3.14) 
                 −0.45 
                 0.7580605 
               
               
                 165 
                 1584.506 
                 37.49593 
                 0.53 
                 2.10(2.07) 
                 0.79 
                 2.61(2.66) 
                 −0.26 
                 0.7441860 
               
               
                 166 
                 1586.738 
                 28.88186 
                 0.71 
                 2.39(2.34) 
                 0.85 
                 2.35(2.36) 
                 −0.14 
                 0.6819342 
               
               
                 167 
                 1588.706 
                 30.15033 
                 1 
                 2.88(2.90) 
                 0.5 
                 2.11(2.13) 
                 0.5 
                 0.8785499 
               
               
                 168 
                 1591.709 
                 38.27637 
                 0.06 
                 1.59(1.59) 
                 0.55 
                 2.08(2.11) 
                 −0.49 
                 0.7582246 
               
               
                 169 
                 1594.762 
                 40.21545 
                 1 
                 3.02(3.02) 
                 0.7 
                 3.28(3.27) 
                 0.3 
                 0.6005472 
               
               
                 170 
                 1622.722 
                 26.79132 
                 0.59 
                 2.38(2.42) 
                 0.69 
                 2.31(2.31) 
                 −0.1 
                 0.6237471 
               
               
                 171 
                 1623.727 
                 24.12394 
                 1 
                 3.78(3.79) 
                 0.99 
                 3.79(3.82) 
                 0.01 
                 0.5583027 
               
               
                 172 
                 1630.739 
                 20.64725 
                 0.35 
                 2.11(2.04) 
                 0.33 
                 2.28(2.25) 
                 0.03 
                 0.6211004 
               
               
                 173 
                 1634.652 
                 37.33193 
                 0.41 
                 2.37(2.34) 
                 0.55 
                 2.51(2.55) 
                 −0.13 
                 0.6727170 
               
               
                 174 
                 1635.76 
                 30.33571 
                 0.82 
                 3.04(3.33) 
                 0.71 
                 3.15(3.46) 
                 0.11 
                 0.6004845 
               
               
                 175 
                 1635.786 
                 40.44105 
                 1 
                 2.98(2.99) 
                 0.9 
                 3.16(3.24) 
                 0.1 
                 0.7440442 
               
               
                 176 
                 1638.728 
                 20.22988 
                 0.82 
                 2.71(2.76) 
                 0.56 
                 2.56(2.56) 
                 0.27 
                 0.6113014 
               
               
                 177 
                 1640.581 
                 23.24178 
                 1 
                 3.69(3.67) 
                 0.92 
                 3.62(3.66) 
                 0.08 
                 0.6668894 
               
               
                 178 
                 1651.79 
                 40.66166 
                 0.94 
                 3.52(3.54) 
                 0.98 
                 3.60(3.62) 
                 −0.04 
                 0.7731140 
               
               
                 179 
                 1653.876 
                 30.38117 
                 0.94 
                 3.16(3.18) 
                 0.65 
                 3.11(3.06) 
                 0.29 
                 0.6171066 
               
               
                 180 
                 1660.735 
                 38.00226 
                 0.41 
                 3.16(3.11) 
                 0.6 
                 3.06(3.08) 
                 −0.19 
                 0.6281906 
               
               
                 181 
                 1666.775 
                 30.66426 
                 0.65 
                 2.33(2.32) 
                 0.86 
                 2.49(2.51) 
                 −0.21 
                 0.7300368 
               
               
                 182 
                 1679.947 
                 23.81762 
                 0.94 
                 3.78(3.66) 
                 0.92 
                 4.32(4.44) 
                 0.02 
                 0.6952890 
               
               
                 183 
                 1680.752 
                 30.02747 
                 0.94 
                 3.42(3.41) 
                 0.71 
                 3.47(3.50) 
                 0.23 
                 0.5632726 
               
               
                 184 
                 1684.666 
                 31.75269 
                 0.24 
                 2.61(2.57) 
                 0.73 
                 3.10(3.17) 
                 −0.5 
                 0.7309973 
               
               
                 185 
                 1684.671 
                 30.65638 
                 0.88 
                 3.31(3.37) 
                 0.26 
                 3.29(3.30) 
                 0.63 
                 0.8144838 
               
               
                 186 
                 1684.709 
                 29.6453 
                 0.12 
                 2.20(2.20) 
                 0.57 
                 2.46(2.48) 
                 −0.45 
                 0.7523388 
               
               
                 187 
                 1693.762 
                 20.50581 
                 0.53 
                 2.19(2.19) 
                 0.65 
                 2.22(2.25) 
                 −0.12 
                 0.6432509 
               
               
                 188 
                 1703.839 
                 33.58491 
                 0.18 
                 2.17(2.15) 
                 0.58 
                 2.74(2.74) 
                 −0.4 
                 0.7291382 
               
               
                 189 
                 1716.657 
                 20.17727 
                 0.71 
                 2.56(2.60) 
                 0.55 
                 2.51(2.46) 
                 0.16 
                 0.6575342 
               
               
                 190 
                 1716.773 
                 27.99784 
                 0.71 
                 2.77(2.83) 
                 0.9 
                 2.80(2.84) 
                 −0.19 
                 0.7324173 
               
               
                 191 
                 1732.771 
                 28.17527 
                 0.94 
                 3.42(3.42) 
                 0.94 
                 3.54(3.54) 
                 0 
                 0.7753829 
               
               
                 192 
                 1746.593 
                 38.21271 
                 0.29 
                 1.61(1.56) 
                 0.55 
                 2.30(2.42) 
                 −0.25 
                 0.6781055 
               
               
                 193 
                 1754.895 
                 31.25885 
                 0.94 
                 3.53(3.46) 
                 0.67 
                 3.69(3.67) 
                 0.27 
                 0.6908620 
               
               
                 194 
                 1783.791 
                 39.81519 
                 0.71 
                 2.30(2.42) 
                 0.52 
                 2.44(2.55) 
                 0.18 
                 0.6197795 
               
               
                 195 
                 1798.716 
                 36.94821 
                 0.41 
                 2.12(2.10) 
                 0.62 
                 2.40(2.50) 
                 −0.2 
                 0.6911961 
               
               
                 196 
                 1806.827 
                 23.06136 
                 0.76 
                 2.34(2.45) 
                 0.78 
                 2.32(2.34) 
                 −0.01 
                 0.6547079 
               
               
                 197 
                 1807.809 
                 20.64857 
                 1 
                 3.25(3.24) 
                 0.91 
                 3.07(3.10) 
                 0.09 
                 0.6068326 
               
               
                 198 
                 1808.793 
                 23.71763 
                 0.35 
                 2.18(2.16) 
                 0.33 
                 2.35(2.39) 
                 0.03 
                 0.6483879 
               
               
                 199 
                 1817.694 
                 20.23435 
                 1 
                 3.32(3.41) 
                 0.94 
                 3.32(3.40) 
                 0.06 
                 0.6021550 
               
               
                 200 
                 1818.827 
                 30.95312 
                 1 
                 3.01(3.04) 
                 0.65 
                 2.31(2.35) 
                 0.35 
                 0.6579101 
               
               
                 201 
                 1819.796 
                 23.36311 
                 1 
                 3.70(3.73) 
                 0.98 
                 3.58(3.59) 
                 0.02 
                 0.5938022 
               
               
                 202 
                 1822.735 
                 30.87417 
                 0.18 
                 2.11(2.40) 
                 0.67 
                 2.59(2.60) 
                 −0.5 
                 0.7859097 
               
               
                 203 
                 1828.848 
                 21.20199 
                 0.53 
                 2.31(2.35) 
                 0.1 
                 2.12(2.17) 
                 0.42 
                 0.7222982 
               
               
                 204 
                 1834.825 
                 31.09503 
                 1 
                 3.56(3.64) 
                 0.97 
                 2.93(2.96) 
                 0.03 
                 0.8590971 
               
               
                 205 
                 1837.8 
                 30.55694 
                 0 
                 0.00(0.00) 
                 0.62 
                 2.51(2.48) 
                 −0.62 
                 0.6600401 
               
               
                 206 
                 1840.836 
                 41.17953 
                 0.35 
                 1.94(1.84) 
                 0.69 
                 2.39(2.47) 
                 −0.33 
                 0.7235216 
               
               
                 207 
                 1858.839 
                 24.2646 
                 0.12 
                 2.59(2.59) 
                 0.52 
                 2.93(2.78) 
                 −0.41 
                 0.6320581 
               
               
                 208 
                 1860.826 
                 21.40014 
                 0.47 
                 2.56(2.92) 
                 0.85 
                 2.85(2.84) 
                 −0.38 
                 0.5720013 
               
               
                 209 
                 1863.751 
                 19.92311 
                 0.29 
                 1.97(1.92) 
                 0.15 
                 2.23(2.30) 
                 0.14 
                 0.6511443 
               
               
                 210 
                 1874.831 
                 30.82379 
                 0.12 
                 2.25(2.25) 
                 0.67 
                 2.11(2.14) 
                 −0.56 
                 0.6922820 
               
               
                 211 
                 1878.59 
                 30.77853 
                 0.59 
                 2.72(2.78) 
                 0.77 
                 2.84(2.92) 
                 −0.18 
                 0.6690194 
               
               
                 212 
                 1884.857 
                 40.05398 
                 0.59 
                 2.47(2.40) 
                 0.14 
                 2.58(2.48) 
                 0.45 
                 0.7222982 
               
               
                 213 
                 1885.651 
                 38.81996 
                 0.47 
                 1.95(1.96) 
                 0.83 
                 2.18(2.25) 
                 −0.35 
                 0.5698296 
               
               
                 214 
                 1892.973 
                 24.55813 
                 0.82 
                 2.67(2.69) 
                 0.34 
                 2.47(2.50) 
                 0.49 
                 0.6457742 
               
               
                 215 
                 1911.051 
                 24.98094 
                 0.71 
                 4.94(4.95) 
                 0.93 
                 4.37(4.47) 
                 −0.22 
                 0.7079343 
               
               
                 216 
                 1936.874 
                 34.748 
                 0.59 
                 1.87(1.86) 
                 0.5 
                 1.98(2.00) 
                 0.09 
                 0.6524808 
               
               
                 217 
                 1947.878 
                 31.60618 
                 0.47 
                 2.50(2.61) 
                 0.71 
                 2.70(2.74) 
                 −0.24 
                 0.6920314 
               
               
                 218 
                 1950.851 
                 35.76881 
                 1 
                 2.80(2.80) 
                 0.91 
                 2.77(2.82) 
                 0.09 
                 0.5424077 
               
               
                 219 
                 1962.875 
                 31.81242 
                 0.76 
                 2.29(2.34) 
                 0.35 
                 2.46(2.51) 
                 0.42 
                 0.6559508 
               
               
                 220 
                 1963.88 
                 31.74253 
                 0.24 
                 2.45(2.45) 
                 0.58 
                 2.37(2.41) 
                 −0.35 
                 0.6335616 
               
               
                 221 
                 1969.838 
                 25.22952 
                 0.35 
                 2.20(2.27) 
                 0.41 
                 2.33(2.30) 
                 −0.05 
                 0.6186519 
               
               
                 222 
                 1977.918 
                 32.19436 
                 0.53 
                 2.53(2.52) 
                 0.5 
                 2.62(2.59) 
                 0.03 
                 0.6303176 
               
               
                 223 
                 2003.939 
                 24.61864 
                 0.47 
                 2.12(2.17) 
                 0.64 
                 2.19(2.23) 
                 −0.17 
                 0.6202389 
               
               
                 224 
                 2007.945 
                 22.10222 
                 1 
                 3.14(3.14) 
                 0.84 
                 2.97(3.01) 
                 0.16 
                 0.7435021 
               
               
                 225 
                 2008.902 
                 32.2865 
                 0.29 
                 2.95(2.78) 
                 0.59 
                 2.93(2.91) 
                 −0.3 
                 0.6304594 
               
               
                 226 
                 2009.879 
                 32.29178 
                 0.71 
                 2.71(2.74) 
                 0.42 
                 2.53(2.66) 
                 0.29 
                 0.6075008 
               
               
                 227 
                 2013.893 
                 31.75577 
                 0.35 
                 2.14(2.15) 
                 0.74 
                 2.04(2.11) 
                 −0.39 
                 0.6947043 
               
               
                 228 
                 2013.905 
                 25.19463 
                 1 
                 3.32(3.38) 
                 0.99 
                 3.19(3.24) 
                 0.01 
                 0.6001504 
               
               
                 229 
                 2014.898 
                 21.90602 
                 1 
                 3.61(3.64) 
                 0.98 
                 3.31(3.29) 
                 0.02 
                 0.7985717 
               
               
                 230 
                 2029.853 
                 20.39044 
                 0.47 
                 2.30(2.31) 
                 0.33 
                 2.29(2.25) 
                 0.15 
                 0.6196824 
               
               
                 231 
                 2039.129 
                 21.77864 
                 1 
                 3.14(3.26) 
                 0.76 
                 2.93(3.04) 
                 0.24 
                 0.7352941 
               
               
                 232 
                 2045.858 
                 34.17017 
                 0.29 
                 2.33(2.13) 
                 0.57 
                 2.29(2.27) 
                 −0.28 
                 0.6737096 
               
               
                 233 
                 2058.937 
                 23.15082 
                 0.65 
                 2.42(2.30) 
                 0.85 
                 2.53(2.58) 
                 −0.2 
                 0.7454895 
               
               
                 234 
                 2064.918 
                 24.45992 
                 0.65 
                 2.15(2.11) 
                 0.81 
                 2.59(2.65) 
                 −0.17 
                 0.6879803 
               
               
                 235 
                 2067.818 
                 20.62077 
                 1 
                 3.04(3.12) 
                 0.9 
                 3.09(3.16) 
                 0.1 
                 0.5916553 
               
               
                 236 
                 2076.945 
                 21.77894 
                 0.24 
                 3.17(3.13) 
                 0.76 
                 2.97(3.04) 
                 −0.52 
                 0.6145774 
               
               
                 237 
                 2077.963 
                 22.48482 
                 0.59 
                 2.38(2.35) 
                 0.24 
                 2.12(2.16) 
                 0.34 
                 0.7075923 
               
               
                 238 
                 2078.932 
                 26.67145 
                 1 
                 3.79(3.79) 
                 1 
                 3.81(3.79) 
                 0 
                 0.6163548 
               
               
                 239 
                 2081.936 
                 33.66116 
                 1 
                 2.36(2.47) 
                 0.67 
                 2.29(2.34) 
                 0.33 
                 0.6976744 
               
               
                 240 
                 2096.916 
                 32.9972 
                 0.47 
                 2.13(2.13) 
                 0.27 
                 2.06(2.05) 
                 0.2 
                 0.6861844 
               
               
                 241 
                 2109.923 
                 24.06903 
                 0.06 
                 1.54(1.54) 
                 0.62 
                 2.46(2.49) 
                 −0.56 
                 0.7423154 
               
               
                 242 
                 2130.962 
                 32.73483 
                 0.18 
                 1.85(1.89) 
                 0.55 
                 2.10(2.08) 
                 −0.37 
                 0.7093023 
               
               
                 243 
                 2137.942 
                 21.79294 
                 1 
                 2.94(2.92) 
                 0.95 
                 2.88(2.86) 
                 0.05 
                 0.6942031 
               
               
                 244 
                 2159.003 
                 33.19108 
                 1 
                 3.26(3.30) 
                 0.99 
                 3.24(3.22) 
                 0.01 
                 0.5801036 
               
               
                 245 
                 2235.045 
                 34.16645 
                 0.88 
                 2.81(2.79) 
                 0.86 
                 2.91(2.91) 
                 0.02 
                 0.6559472 
               
               
                 246 
                 2248.991 
                 25.99098 
                 0.59 
                 4.14(4.18) 
                 0.64 
                 4.25(4.26) 
                 −0.05 
                 0.6909455 
               
               
                 247 
                 2257.869 
                 35.92739 
                 0.12 
                 2.00(2.00) 
                 0.71 
                 2.99(3.03) 
                 −0.59 
                 0.6485550 
               
               
                 248 
                 2266.021 
                 22.1634 
                 1 
                 3.81(3.81) 
                 0.94 
                 3.50(3.53) 
                 0.06 
                 0.6401604 
               
               
                 249 
                 2280.944 
                 36.21864 
                 0.41 
                 2.33(2.45) 
                 0.56 
                 2.39(2.41) 
                 −0.15 
                 0.6502673 
               
               
                 250 
                 2282.016 
                 22.23937 
                 0.82 
                 2.88(2.91) 
                 0.73 
                 2.67(2.68) 
                 0.09 
                 0.6767457 
               
               
                 251 
                 2297.011 
                 33.86518 
                 0.65 
                 2.26(2.33) 
                 0.27 
                 2.26(2.30) 
                 0.38 
                 0.6860465 
               
               
                 252 
                 2371.084 
                 22.7883 
                 0.47 
                 1.95(1.93) 
                 0.5 
                 2.12(2.10) 
                 −0.03 
                 0.6227865 
               
               
                 253 
                 2380.081 
                 36.51091 
                 0.24 
                 2.08(2.07) 
                 0.6 
                 2.16(2.20) 
                 −0.37 
                 0.6928865 
               
               
                 254 
                 2404.015 
                 20.27277 
                 0.82 
                 2.44(2.41) 
                 0.74 
                 2.38(2.42) 
                 0.08 
                 0.6851403 
               
               
                 255 
                 2420.998 
                 34.86081 
                 0.29 
                 1.74(1.80) 
                 0.64 
                 2.03(2.04) 
                 −0.35 
                 0.6338540 
               
               
                 256 
                 2430.081 
                 25.69736 
                 0.24 
                 1.91(1.95) 
                 0.53 
                 2.25(2.24) 
                 −0.3 
                 0.7061826 
               
               
                 257 
                 2446.092 
                 28.37261 
                 0 
                 0.00(0.00) 
                 0.73 
                 2.33(2.31) 
                 −0.73 
                 0.7175910 
               
               
                 258 
                 2471.155 
                 34.77354 
                 1 
                 2.58(2.72) 
                 0.99 
                 2.71(2.76) 
                 0.01 
                 0.6878900 
               
               
                 259 
                 2485.125 
                 34.4072 
                 0.29 
                 2.21(2.41) 
                 0.67 
                 2.05(2.06) 
                 −0.38 
                 0.6126378 
               
               
                 260 
                 2487.125 
                 28.27413 
                 0.82 
                 2.25(2.26) 
                 0.86 
                 2.53(2.56) 
                 −0.04 
                 0.6549449 
               
               
                 261 
                 2501.119 
                 34.38645 
                 0.35 
                 2.08(2.09) 
                 0.44 
                 2.01(2.07) 
                 −0.09 
                 0.6806716 
               
               
                 262 
                 2544.112 
                 26.06379 
                 0 
                 0.00(0.00) 
                 0.56 
                 2.17(2.21) 
                 −0.56 
                 0.7790698 
               
               
                 263 
                 2544.128 
                 28.25992 
                 0.53 
                 2.04(2.25) 
                 0.63 
                 2.25(2.26) 
                 −0.1 
                 0.6398263 
               
               
                 264 
                 2545.12 
                 28.20161 
                 0.41 
                 2.26(2.28) 
                 0.17 
                 2.24(2.34) 
                 0.24 
                 0.6125961 
               
               
                 265 
                 2547.986 
                 21.4417 
                 0.71 
                 2.58(2.63) 
                 0.37 
                 2.21(2.15) 
                 0.33 
                 0.6749858 
               
               
                 266 
                 2559.18 
                 19.40742 
                 0.35 
                 3.00(2.98) 
                 0.35 
                 2.53(2.57) 
                 0 
                 0.6418037 
               
               
                 267 
                 2576.124 
                 34.25753 
                 0.12 
                 1.60(1.60) 
                 0.69 
                 2.25(2.25) 
                 −0.57 
                 0.7520464 
               
               
                 268 
                 2577.246 
                 24.66592 
                 1 
                 2.37(2.36) 
                 0.81 
                 2.38(2.38) 
                 0.19 
                 0.5902873 
               
               
                 269 
                 2589.056 
                 22.56216 
                 0.18 
                 1.73(1.49) 
                 0.55 
                 2.11(2.16) 
                 −0.37 
                 0.6570331 
               
               
                 270 
                 2596.233 
                 34.89552 
                 0.35 
                 1.73(1.70) 
                 0.65 
                 1.88(1.90) 
                 −0.3 
                 0.6398263 
               
               
                 271 
                 2599.19 
                 28.27509 
                 0.76 
                 2.27(2.30) 
                 0.88 
                 2.40(2.48) 
                 −0.12 
                 0.7089041 
               
               
                 272 
                 2628.215 
                 34.96638 
                 0.59 
                 2.73(2.72) 
                 0.52 
                 2.74(2.75) 
                 0.06 
                 0.6939875 
               
               
                 273 
                 2642.214 
                 27.69602 
                 1 
                 2.76(2.77) 
                 0.93 
                 2.69(2.70) 
                 0.07 
                 0.6374829 
               
               
                 274 
                 2658.271 
                 19.47609 
                 0.53 
                 3.28(3.48) 
                 0.4 
                 3.17(3.13) 
                 0.13 
                 0.6840962 
               
               
                 275 
                 2682.143 
                 22.49183 
                 1 
                 3.01(3.01) 
                 0.95 
                 2.98(2.95) 
                 0.05 
                 0.5851988 
               
               
                 276 
                 2686.336 
                 29.34243 
                 0.71 
                 2.36(2.40) 
                 0.38 
                 2.22(2.21) 
                 0.32 
                 0.6798363 
               
               
                 277 
                 2742.251 
                 42.14319 
                 0.94 
                 2.91(2.95) 
                 0.49 
                 2.48(2.59) 
                 0.45 
                 0.7046442 
               
               
                 278 
                 2744.125 
                 35.10541 
                 0.71 
                 2.22(2.21) 
                 0.56 
                 2.26(2.30) 
                 0.15 
                 0.6339375 
               
               
                 279 
                 2748.788 
                 36.38231 
                 0.41 
                 2.06(2.01) 
                 0.57 
                 1.91(1.92) 
                 −0.16 
                 0.6451721 
               
               
                 280 
                 2752.413 
                 19.8887 
                 0.18 
                 3.41(3.86) 
                 0.27 
                 3.20(3.15) 
                 −0.09 
                 0.6395757 
               
               
                 281 
                 2767.323 
                 21.6729 
                 0.71 
                 2.53(2.64) 
                 0.85 
                 2.65(2.68) 
                 −0.14 
                 0.6929949 
               
               
                 282 
                 2825.267 
                 24.4868 
                 1 
                 4.18(4.21) 
                 0.98 
                 4.22(4.21) 
                 0.02 
                 0.7767290 
               
               
                 283 
                 2834.187 
                 22.46729 
                 0.59 
                 2.33(2.40) 
                 0.17 
                 1.82(1.76) 
                 0.41 
                 0.7417921 
               
               
                 284 
                 2854.363 
                 34.86364 
                 1 
                 3.50(3.46) 
                 0.98 
                 3.40(3.47) 
                 0.02 
                 0.6537755 
               
               
                 285 
                 2914.379 
                 24.33308 
                 0.29 
                 2.36(2.16) 
                 0.4 
                 2.02(1.93) 
                 −0.1 
                 0.6630743 
               
               
                 286 
                 2923.432 
                 36.91513 
                 0.88 
                 2.41(2.48) 
                 0.72 
                 2.43(2.44) 
                 0.16 
                 0.6025727 
               
               
                 287 
                 2936.536 
                 20.09721 
                 0.06 
                 2.68(2.68) 
                 0 
                 0.00(0.00) 
                 0.06 
                 0.7512529 
               
               
                 288 
                 2942.299 
                 22.23281 
                 1 
                 3.58(3.67) 
                 0.97 
                 3.54(3.60) 
                 0.03 
                 0.6777481 
               
               
                 289 
                 2973.452 
                 24.3704 
                 0.76 
                 2.64(2.73) 
                 0.85 
                 2.74(2.74) 
                 −0.08 
                 0.6972490 
               
               
                 290 
                 2977.179 
                 19.52319 
                 0.59 
                 2.59(2.78) 
                 0.44 
                 2.30(2.29) 
                 0.15 
                 0.6702723 
               
               
                 291 
                 2987.348 
                 38.54569 
                 0.35 
                 2.05(2.05) 
                 0.33 
                 2.14(2.25) 
                 0.03 
                 0.6481791 
               
               
                 292 
                 3002.238 
                 23.80085 
                 0.18 
                 2.05(2.03) 
                 0.62 
                 1.95(1.91) 
                 −0.44 
                 0.6300535 
               
               
                 293 
                 3011.387 
                 29.74951 
                 0.94 
                 3.27(3.31) 
                 1 
                 3.37(3.39) 
                 −0.06 
                 0.7793534 
               
               
                 294 
                 3057.395 
                 29.96413 
                 0.24 
                 1.80(1.82) 
                 0.22 
                 1.81(1.81) 
                 0.01 
                 0.6997995 
               
               
                 295 
                 3058.378 
                 24.82364 
                 0.76 
                 2.44(2.28) 
                 0.59 
                 2.51(2.59) 
                 0.17 
                 0.6503926 
               
               
                 296 
                 3076.233 
                 19.57728 
                 0.59 
                 2.77(2.91) 
                 0.56 
                 2.49(2.51) 
                 0.03 
                 0.6693953 
               
               
                 297 
                 3132.455 
                 31.1821 
                 0.71 
                 2.26(2.25) 
                 0.36 
                 2.24(2.29) 
                 0.35 
                 0.6628801 
               
               
                 298 
                 3137.411 
                 30.34616 
                 0.94 
                 2.46(2.49) 
                 0.67 
                 2.30(2.36) 
                 0.27 
                 0.7489740 
               
               
                 299 
                 3148.277 
                 24.15522 
                 0.59 
                 2.21(2.23) 
                 0.31 
                 2.03(2.07) 
                 0.27 
                 0.6719011 
               
               
                 300 
                 3152.34 
                 24.55108 
                 0.82 
                 2.79(2.86) 
                 0.51 
                 2.52(2.52) 
                 0.31 
                 0.7217675 
               
               
                 301 
                 3166.271 
                 22.05894 
                 0.71 
                 2.77(2.85) 
                 0.28 
                 2.16(2.11) 
                 0.43 
                 0.7532994 
               
               
                 302 
                 3193.382 
                 22.64363 
                 0.76 
                 3.13(3.16) 
                 0.58 
                 3.18(3.27) 
                 0.18 
                 0.6766875 
               
               
                 303 
                 3200.423 
                 35.77416 
                 0.53 
                 2.75(2.81) 
                 0.34 
                 2.61(2.63) 
                 0.19 
                 0.6340628 
               
               
                 304 
                 3202.434 
                 30.60166 
                 0.47 
                 2.30(2.41) 
                 0.07 
                 1.99(1.99) 
                 0.4 
                 0.7820748 
               
               
                 305 
                 3205.273 
                 19.65755 
                 0.71 
                 2.87(3.01) 
                 0.76 
                 2.75(2.75) 
                 −0.05 
                 0.6685600 
               
               
                 306 
                 3255.493 
                 30.78474 
                 0.47 
                 2.20(2.29) 
                 0.2 
                 2.21(2.33) 
                 0.27 
                 0.6953725 
               
               
                 307 
                 3256.527 
                 33.03419 
                 0.82 
                 3.07(3.10) 
                 0.67 
                 2.60(2.69) 
                 0.15 
                 0.7700050 
               
               
                 308 
                 3261.498 
                 22.19478 
                 0.12 
                 2.34(2.34) 
                 0.51 
                 2.50(2.63) 
                 −0.39 
                 0.6969904 
               
               
                 309 
                 3264.556 
                 25.75167 
                 0.82 
                 2.88(2.90) 
                 0.94 
                 3.11(3.19) 
                 −0.12 
                 0.7183778 
               
               
                 310 
                 3265.431 
                 36.08731 
                 0.35 
                 2.30(2.46) 
                 0.76 
                 2.76(2.86) 
                 −0.4 
                 0.7746238 
               
               
                 311 
                 3266.484 
                 30.07129 
                 0.59 
                 1.95(1.95) 
                 0.4 
                 2.08(2.08) 
                 0.19 
                 0.6472603 
               
               
                 312 
                 3271.49 
                 30.70446 
                 0.35 
                 3.02(3.01) 
                 0.33 
                 3.18(3.23) 
                 0.03 
                 0.6333111 
               
               
                 313 
                 3282.498 
                 30.08996 
                 0.47 
                 1.98(2.01) 
                 0.43 
                 1.93(1.95) 
                 0.04 
                 0.6536919 
               
               
                 314 
                 3287.479 
                 30.97061 
                 0.35 
                 3.34(3.35) 
                 0.83 
                 3.42(3.42) 
                 −0.47 
                 0.6347136 
               
               
                 315 
                 3314.431 
                 20.14047 
                 0.53 
                 2.81(2.78) 
                 0.31 
                 2.61(2.77) 
                 0.22 
                 0.6507267 
               
               
                 316 
                 3338.463 
                 23.58844 
                 0.65 
                 2.90(3.04) 
                 0.56 
                 2.71(2.73) 
                 0.09 
                 0.6506014 
               
               
                 317 
                 3350.549 
                 31.01736 
                 0.41 
                 1.89(1.87) 
                 0.63 
                 2.24(2.28) 
                 −0.22 
                 0.6313103 
               
               
                 318 
                 3363.543 
                 30.21892 
                 0.35 
                 2.28(2.17) 
                 0.37 
                 2.10(2.11) 
                 −0.02 
                 0.6736552 
               
               
                 319 
                 3404.619 
                 25.94028 
                 0.59 
                 3.50(3.49) 
                 0.37 
                 3.31(3.48) 
                 0.22 
                 0.6784998 
               
               
                 320 
                 3405.478 
                 25.96805 
                 0.18 
                 3.48(3.57) 
                 0.55 
                 3.55(3.59) 
                 −0.37 
                 0.6706482 
               
               
                 321 
                 3416.602 
                 36.84899 
                 0.06 
                 1.65(1.65) 
                 0.51 
                 1.80(1.84) 
                 −0.45 
                 0.6028233 
               
               
                 322 
                 3421.555 
                 25.99412 
                 1 
                 3.11(3.12) 
                 0.88 
                 3.14(3.16) 
                 0.12 
                 0.5451052 
               
               
                 323 
                 3425.605 
                 31.27027 
                 1 
                 3.20(3.28) 
                 0.94 
                 3.31(3.34) 
                 0.06 
                 0.5608086 
               
               
                 324 
                 3426.31 
                 27.69928 
                 0.59 
                 2.11(2.15) 
                 0.33 
                 1.82(1.83) 
                 0.26 
                 0.8015787 
               
               
                 325 
                 3441.609 
                 31.38498 
                 1 
                 3.82(3.92) 
                 0.94 
                 4.03(4.07) 
                 0.06 
                 0.5699967 
               
               
                 326 
                 3462.35 
                 19.37411 
                 0.24 
                 2.54(2.51) 
                 0.15 
                 2.21(2.28) 
                 0.08 
                 0.6916973 
               
               
                 327 
                 3546.672 
                 26.2234 
                 0 
                 0.00(0.00) 
                 0.55 
                 2.64(2.72) 
                 −0.55 
                 0.7209302 
               
               
                 328 
                 3572.6 
                 30.6681 
                 0.47 
                 2.09(2.01) 
                 0.1 
                 2.11(2.22) 
                 0.37 
                 0.7309973 
               
               
                 329 
                 3582.701 
                 19.46503 
                 0.29 
                 3.25(3.22) 
                 0.44 
                 2.54(2.51) 
                 −0.15 
                 0.6397427 
               
               
                 330 
                 3583.637 
                 41.47108 
                 0.82 
                 2.44(2.46) 
                 0.45 
                 2.45(2.56) 
                 0.37 
                 0.6458403 
               
               
                 331 
                 3603.678 
                 32.40852 
                 0.12 
                 2.01(2.01) 
                 0.56 
                 2.19(2.17) 
                 −0.44 
                 0.7318741 
               
               
                 332 
                 3630.443 
                 21.77706 
                 0.71 
                 2.60(2.57) 
                 0.24 
                 2.19(2.32) 
                 0.46 
                 0.7385149 
               
               
                 333 
                 3681.716 
                 32.01776 
                 0.41 
                 1.98(1.99) 
                 0.65 
                 2.16(2.20) 
                 −0.24 
                 0.6225184 
               
               
                 334 
                 3685.833 
                 22.19635 
                 0.82 
                 3.20(3.36) 
                 0.69 
                 3.23(3.30) 
                 0.14 
                 0.6607918 
               
               
                 335 
                 3706.721 
                 22.02471 
                 0.41 
                 2.49(2.47) 
                 0.38 
                 2.72(2.80) 
                 0.03 
                 0.6143502 
               
               
                 336 
                 3719.734 
                 22.49869 
                 0.65 
                 2.67(2.69) 
                 0.55 
                 2.50(2.51) 
                 0.1 
                 0.6681006 
               
               
                 337 
                 3774.812 
                 28.22771 
                 0.24 
                 2.72(2.77) 
                 0.51 
                 2.74(2.75) 
                 −0.28 
                 0.6934203 
               
               
                 338 
                 3775.748 
                 25.58515 
                 0.76 
                 2.87(2.97) 
                 0.83 
                 2.75(2.88) 
                 −0.06 
                 0.7170899 
               
               
                 339 
                 3788.818 
                 25.18606 
                 0.18 
                 2.11(2.12) 
                 0.55 
                 2.32(2.42) 
                 −0.37 
                 0.6263782 
               
               
                 340 
                 3831.81 
                 28.48446 
                 0.53 
                 2.26(2.33) 
                 0.78 
                 3.07(3.15) 
                 −0.25 
                 0.6866021 
               
               
                 341 
                 3839.813 
                 19.70303 
                 0.82 
                 3.04(2.99) 
                 0.67 
                 3.19(3.34) 
                 0.15 
                 0.6516873 
               
               
                 342 
                 3870.814 
                 33.49116 
                 0.65 
                 2.06(2.10) 
                 0.74 
                 2.24(2.29) 
                 −0.1 
                 0.6795235 
               
               
                 343 
                 3891.752 
                 24.52856 
                 0.47 
                 2.37(2.44) 
                 0.79 
                 2.64(2.74) 
                 −0.32 
                 0.6360675 
               
               
                 344 
                 3944.712 
                 24.55436 
                 0.35 
                 2.22(2.20) 
                 0.35 
                 1.85(1.86) 
                 0 
                 0.6489308 
               
               
                 345 
                 3984.647 
                 21.25792 
                 0 
                 0.00(0.00) 
                 0.57 
                 2.79(2.85) 
                 −0.57 
                 0.7206466 
               
               
                 346 
                 3986.65 
                 20.60164 
                 1 
                 3.69(3.72) 
                 0.71 
                 3.16(3.22) 
                 0.29 
                 0.7926829 
               
               
                 347 
                 3996.658 
                 20.92089 
                 0.53 
                 3.00(2.95) 
                 0.21 
                 2.39(2.28) 
                 0.32 
                 0.7118276 
               
               
                 348 
                 4002.618 
                 20.65664 
                 0.18 
                 2.00(1.97) 
                 0.81 
                 3.02(3.24) 
                 −0.64 
                 0.6789563 
               
               
                 349 
                 4043.639 
                 20.38493 
                 0.94 
                 3.00(3.10) 
                 0.44 
                 2.75(2.70) 
                 0.5 
                 0.6801704 
               
               
                 350 
                 4190.718 
                 20.5276 
                 0.53 
                 2.25(2.25) 
                 0.09 
                 2.21(2.37) 
                 0.44 
                 0.6760775 
               
               
                 351 
                 4196.749 
                 20.83785 
                 0.71 
                 2.68(2.78) 
                 0.33 
                 2.24(2.28) 
                 0.38 
                 0.7335449 
               
               
                 352 
                 4251.984 
                 28.76518 
                 0.76 
                 2.93(2.92) 
                 0.88 
                 3.07(3.06) 
                 −0.12 
                 0.6826432 
               
               
                 353 
                 4368.903 
                 20.2129 
                 0 
                 0.00(0.00) 
                 0.64 
                 3.25(3.38) 
                 −0.64 
                 0.8197674 
               
               
                 354 
                 4404.842 
                 20.66586 
                 0.88 
                 2.97(2.94) 
                 0.45 
                 2.62(2.68) 
                 0.43 
                 0.7829519 
               
               
                 355 
                 4409.888 
                 20.00095 
                 0.82 
                 3.10(3.19) 
                 0.38 
                 2.68(2.73) 
                 0.44 
                 0.7334614 
               
               
                 356 
                 4418.992 
                 25.74477 
                 0.12 
                 2.15(2.15) 
                 0.52 
                 2.15(2.17) 
                 −0.41 
                 0.7283040 
               
               
                 357 
                 4467.96 
                 29.11998 
                 0.29 
                 2.34(2.47) 
                 0.71 
                 2.67(2.74) 
                 −0.42 
                 0.7564979 
               
               
                 358 
                 4539.029 
                 26.25198 
                 0.24 
                 1.72(1.80) 
                 0.51 
                 2.32(2.30) 
                 −0.28 
                 0.7010777 
               
               
                 359 
                 4671.824 
                 23.27783 
                 0.82 
                 2.57(2.65) 
                 0.66 
                 2.40(2.45) 
                 0.16 
                 0.7878383 
               
               
                 360 
                 4771.071 
                 20.19867 
                 0.76 
                 3.11(3.08) 
                 0.3 
                 2.56(2.51) 
                 0.46 
                 0.7571834 
               
               
                 361 
                 4799.959 
                 23.80776 
                 1 
                 3.48(3.53) 
                 0.87 
                 3.26(3.24) 
                 0.13 
                 0.8591714 
               
               
                 362 
                 5227.459 
                 27.38143 
                 0.47 
                 2.93(2.91) 
                 0.14 
                 2.44(2.28) 
                 0.33 
                 0.6736552 
               
               
                 363 
                 5228.26 
                 26.99815 
                 0.18 
                 2.49(2.43) 
                 0.56 
                 2.64(2.84) 
                 −0.38 
                 0.6406693 
               
               
                 364 
                 5574.253 
                 23.20092 
                 0.88 
                 2.74(2.81) 
                 0.79 
                 2.63(2.67) 
                 0.09 
                 0.7053959 
               
               
                 365 
                 6055.575 
                 21.04955 
                 0.29 
                 2.56(2.41) 
                 0.29 
                 2.36(2.39) 
                 0 
                 0.7641163 
               
               
                 366 
                 6169.572 
                 24.77459 
                 0.76 
                 3.21(3.11) 
                 0.17 
                 2.52(2.63) 
                 0.59 
                 0.7647010 
               
               
                 367 
                 6211.741 
                 20.28513 
                 0.76 
                 3.00(2.95) 
                 0.45 
                 2.70(2.71) 
                 0.31 
                 0.7373461 
               
               
                 368 
                 6236.907 
                 21.066 
                 0.47 
                 2.88(2.93) 
                 0.52 
                 2.67(2.66) 
                 −0.05 
                 0.7427330 
               
               
                 369 
                 6782.845 
                 26.57695 
                 0.59 
                 2.70(2.73) 
                 0.33 
                 2.63(2.62) 
                 0.26 
                 0.6318775 
               
               
                 370 
                 8176.072 
                 19.46583 
                 0.18 
                 4.01(4.01) 
                 0.71 
                 3.16(3.23) 
                 −0.53 
                 0.7161423 
               
               
                 371 
                 8176.01 
                 20.17348 
                 0.59 
                 3.79(3.91) 
                 0.03 
                 3.37(3.48) 
                 0.55 
                 0.7828317 
               
               
                 372 
                 8837.408 
                 21.0634 
                 1 
                 3.48(3.68) 
                 0.41 
                 2.81(2.85) 
                 0.59 
                 0.8829769 
               
               
                 373 
                 8853.766 
                 21.09699 
                 0.18 
                 2.41(2.69) 
                 0.76 
                 3.03(3.04) 
                 −0.58 
                 0.6331440 
               
               
                 374 
                 8917.251 
                 22.54506 
                 0.82 
                 2.62(2.75) 
                 0.24 
                 2.23(2.24) 
                 0.58 
                 0.8127297 
               
               
                 375 
                 9625.366 
                 20.68655 
                 0.65 
                 2.58(2.60) 
                 0.26 
                 2.27(2.31) 
                 0.39 
                 0.6497661 
               
               
                 376 
                 9866.536 
                 20.86863 
                 0.76 
                 3.28(3.26) 
                 0.5 
                 2.89(2.90) 
                 0.26 
                 0.6806716 
               
               
                 377 
                 10199.7 
                 21.11481 
                 0.59 
                 2.41(2.52) 
                 0.26 
                 2.45(2.45) 
                 0.33 
                 0.6714417 
               
               
                 378 
                 10341.97 
                 22.98239 
                 0.76 
                 2.98(3.08) 
                 0.08 
                 2.76(2.68) 
                 0.68 
                 0.7283662 
               
               
                 379 
                 10753.32 
                 19.65218 
                 0.47 
                 2.90(2.68) 
                 0.19 
                 2.42(2.39) 
                 0.28 
                 0.7113264 
               
               
                 380 
                 10999.91 
                 21.37191 
                 0.53 
                 3.36(3.21) 
                 0.19 
                 3.27(3.46) 
                 0.34 
                 0.6348981 
               
               
                 381 
                 11967.55 
                 20.46866 
                 0.53 
                 2.53(2.57) 
                 0.28 
                 2.20(2.06) 
                 0.25 
                 0.7801537 
               
               
                 382 
                 12716.79 
                 25.89832 
                 0.59 
                 2.50(2.61) 
                 0.06 
                 2.51(2.49) 
                 0.53 
                 0.7691518 
               
               
                 383 
                 14110.92 
                 21.95905 
                 0.76 
                 2.89(2.85) 
                 0.26 
                 2.45(2.52) 
                 0.51 
                 0.6982960 
               
               
                   
               
             
          
         
       
     
         [0014]    It is preferred if at least five, at least six, at least eight, at least ten, at least 20 or at least 50 polypeptide markers as defined in Table 1 are used. 
         [0015]    Preferably, the urine sample is a midstream urine sample. The use of a human urine sample is preferred. 
         [0016]    The measurement of the amplitudes and/or presence or absence can be effected by a variety of methods. Suitable methods include capillary electrophoresis, HPLC, gas-phase ion spectrometry and/or mass spectrometry. 
         [0017]    In a preferred embodiment, a capillary electrophoresis is performed before the molecular masses of the polypeptide markers are measured. 
         [0018]    Mass spectrometry is particularly suitable for measuring the amplitude or presence or absence of the polypeptide marker or markers. 
         [0019]    According to the invention, the process preferably has a sensitivity of at least 60% and a specificity of at least 60%. Preferably, the sensitivity is at least 70% or at least 80%, and the specificity is at least 70% or at least 80%. 
         [0020]    In one embodiment of the invention, the sample is first separated into at least three, preferably at least 5 or 10 subsamples. This is followed by the analysis of at least three, preferably at least 5 or 10, subsamples for determining the presence or absence or amplitude of at least one polypeptide marker in the sample, wherein said polypeptide marker is selected from the markers of Table 1, which are characterized by their molecular masses and migration times (CE times). 
         [0021]    The CE times stated in the Tables relate to a glass capillary of 90 cm in length and with an inner diameter (ID) of 50 μm at an applied voltage of 25 kV, and 20% acetonitrile, 0.25% formic acid in water is used as the mobile solvent. Details can be found in the experimental part. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0022]      FIGS. 1A and 1B  show the summed-up data from urine samples from control patients and ADPKD patients. 
           [0023]      FIGS. 2A-2D  show the “receiver operating characteristic” curves for the training and the test set. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0024]    Specificity is defined as the number of actually negative samples divided by the sum of the numbers of the actually negative and false positive samples. A specificity of 100% means that a test recognizes all healthy persons as being healthy, i.e., no healthy subject is identified as being ill. This says nothing about how reliably the test recognizes sick patients. 
         [0025]    Sensitivity is defined as the number of actually positive samples divided by the sum of the numbers of the actually positive and false negative samples. A sensitivity of 100% means that the test recognizes all sick persons. This says nothing about how reliably the test recognizes healthy patients. 
         [0026]    By the markers according to the invention, it is possible to achieve a specificity of at least 60%, preferably at least 70%, more preferably at least 80%, even more preferably at least 90% and most preferably at least 95% for the stated disease for which a diagnosis is desired. 
         [0027]    By the markers according to the invention, it is possible to achieve a sensitivity of at least 60%, preferably at least 70%, more preferably at least 80%, even more preferably at least 90% and most preferably at least 95% for the stated disease for which a diagnosis is desired. 
         [0028]    The migration time is determined by capillary electrophoresis (CE), for example, as set forth in the Example under item 2. In this Example, a glass capillary of 90 cm in length and with an inner diameter (ID) of 50 μm and an outer diameter (OD) of 360 μm is operated at an applied voltage of 30 kV. 
         [0029]    As the mobile solvent, 30% methanol, 0.5% formic acid in water may be used, for example. 
         [0030]    In principle, higher formic acid contents, for example, 0.25%, 0.5%, 0.75% or 1%, may also be employed. 
         [0031]    It is known that the CE migration times may vary. Nevertheless, the order in which the polypeptide markers are eluted is typically the same under the stated conditions for each CE system employed. In order to balance any differences in the migration time that may nevertheless occur, the system can be normalized using standards for which the migration times are exactly known. These standards may be, for example, the polypeptides stated in the Examples (see the Examples). 
         [0032]    The characterization of the polypeptides shown in the Tables was determined by means of capillary electrophoresis-mass spectrometry (CE-MS), a method which has been described in detail, for example, by Neuhoff et al. (Rapid communications in mass spectrometry, 2004, Vol. 20, pages 149-156). The variation of the molecular masses between individual measurements or between different mass spectrometers is relatively small when the calibration is exact, typically within a range of ±0.01% or ±0.005%. 
         [0033]    The polypeptide markers according to the invention are proteins or peptides or degradation products of proteins or peptides. They may be chemically modified, for example, by posttranslational modifications, such as glycosylation, phosphorylation, alkylation or disulfide bridges, or by other reactions, for example, within the scope of degradation. In addition, the polypeptide markers may also be chemically altered, for example, oxidized, in the course of the purification of the samples. 
         [0034]    Proceeding from the parameters that determine the polypeptide markers (molecular weight and migration time), it is possible to identify the sequence of the corresponding polypeptides by methods known in the prior art. 
         [0035]    The polypeptides according to the invention are used to diagnose ADPKD. 
         [0036]    “Diagnosis” means the process of knowledge gaining by assigning symptoms or phenomena to a disease or injury. In the present case, the presence or absence of particular polypeptide markers is also used for differential diagnosis. The presence or absence of a polypeptide marker can be measured by any method known in the prior art. Methods which may be used are exemplified below. 
         [0037]    A polypeptide marker is considered present if its measured value is at least as high as its threshold value. If the measured value is lower, then the polypeptide marker is considered absent. The threshold value can be determined either by the sensitivity of the measuring method (detection limit) or defined from experience. 
         [0038]    In the context of the present invention, the threshold value is considered to be exceeded preferably if the measured value of the sample for a certain molecular mass is at least twice as high as that of a blank sample (for example, only buffer or solvent). 
         [0039]    The polypeptide marker or markers is/are used in such a way that its/their presence or absence is measured, wherein the presence or absence is indicative of ADPKD. Thus, there are polypeptide markers which are typically present in patients with ADPKD, but do not or less frequently occur in subjects with no ADPKD. Further, there are polypeptide markers which are present in subjects with ADPKD, but do not or less frequently occur in subjects with no ADPKD. 
         [0040]    In addition or also alternatively to the frequency markers (determination of presence or absence), amplitude markers may also be used for diagnosis. Amplitude markers are used in such a way that the presence or absence is not critical, but the height of the signal (the amplitude) is decisive if the signal is present in both groups. In the Tables, the mean amplitudes of the corresponding signals (characterized by mass and migration time) averaged over all samples measured are stated. To achieve comparability between differently concentrated samples or different measuring methods, two normalization methods are possible. In the first approach, all peptide signals of a sample are normalized to a total amplitude of 1 million counts. Therefore, the respective mean amplitudes of the individual markers are stated as parts per million (ppm). 
         [0041]    In addition, it is possible to define further amplitude markers by an alternative normalization method: In this case, all peptide signals of one sample are scaled with a common normalization factor, as set forth, for example, in Theodorescu et al. Electrophoresis, 26: 2797-808 (2005). Thus, a linear regression is formed between the peptide amplitudes of the individual samples and the reference values of all known polypeptides. The slope of the regression line just corresponds to the relative concentration and is used as a normalization factor for this sample. 
         [0042]    All the groups employed consist of at least 20 individual patient or control samples in order to obtain a reliable mean amplitude. The decision for a diagnosis is made as a function of how high the amplitude of the respective polypeptide markers in the patient sample is in comparison with the mean amplitudes in the control groups or the “ill” group. If the value is in the vicinity of the mean amplitude of the “ill” group, the existence of ADPKD is to be considered, and if it rather corresponds to the mean amplitudes of the control group, the non-existence of ADPKD is to be considered. The distance from the mean amplitude can be interpreted as a probability of the sample&#39;s belonging to a certain group. 
         [0043]    Alternatively, the distance between the measured value and the mean amplitude may be considered a probability of the sample&#39;s belonging to a certain group. 
         [0044]    A frequency marker is a variant of an amplitude marker in which the amplitude is low in some samples. It is possible to convert such frequency markers to amplitude markers by including the corresponding samples in which the marker is not found into the calculation of the amplitude with a very small amplitude, on the order of the detection limit. 
         [0045]    The subject from which the sample in which the presence or absence of one or more polypeptide markers is determined is derived may be any subject which is capable of suffering from ADPKD. Preferably, the subject is a mammal, and most preferably, it is a human. 
         [0046]    In a preferred embodiment of the invention, not just three polypeptide markers, but a larger combination of markers are used to enable differential diagnosis. By comparing a plurality of polypeptide markers, a bias in the overall result due to a few individual deviations from the typical presence probability in the individual can be reduced or avoided. 
         [0047]    The sample in which the presence or absence of the peptide marker or markers according to the invention is measured may be any sample which is obtained from the body of the subject. The sample is a sample which has a polypeptide composition suitable for providing information about the state of the subject. For example, it may be blood, urine, a synovial fluid, a tissue fluid, a body secretion, sweat, cerebrospinal fluid, lymph, intestinal, gastric or pancreatic juice, bile, lacrimal fluid, a tissue sample, sperm, vaginal fluid or a feces sample. Preferably, it is a liquid sample. 
         [0048]    In a preferred embodiment, the sample is a urine sample. 
         [0049]    Urine samples can be taken as preferred in the prior art. Preferably, a midstream urine sample is used in the context of the present invention. For example, the urine sample may be taken by means of a catheter or also by means of an urination apparatus as described in WO 01/74275. 
         [0050]    The presence or absence of a polypeptide marker in the sample may be determined by any method known in the prior art that is suitable for measuring polypeptide markers. Such methods are known to the skilled person. In principle, the presence or absence of a polypeptide marker can be determined by direct methods, such as mass spectrometry, or indirect methods, for example, by means of ligands. 
         [0051]    If required or desirable, the sample from the subject, for example, the urine sample, may be pretreated by any suitable means and, for example, purified or separated before the presence or absence of the polypeptide marker or markers is measured. The treatment may comprise, for example, purification, separation, dilution or concentration. The methods may be, for example, centrifugation, filtration, ultrafiltration, dialysis, precipitation or chromatographic methods, such as affinity separation or separation by means of ion-exchange chromatography, or electrophoretic separation. Particular examples thereof are gel electrophoresis, two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), capillary electrophoresis, metal affinity chromatography, immobilized metal affinity chromatography (IMAC), lectin-based affinity chromatography, liquid chromatography, high-performance liquid chromatography (HPLC), normal and reverse-phase HPLC, cation-exchange chromatography and selective binding to surfaces. All these methods are well known to the skilled person, and the skilled person will be able to select the method as a function of the sample employed and the method for determining the presence or absence of the polypeptide marker or markers. 
         [0052]    In one embodiment of the invention, the sample, before being measured is separated by capillary electrophoresis, purified by ultracentrifugation and/or divided by ultrafiltration into fractions which contain polypeptide markers of a particular molecular size. 
         [0053]    Preferably, a mass-spectrometric method is used to determine the presence or absence of a polypeptide marker, wherein a purification or separation of the sample may be performed upstream from such method. As compared to the currently employed methods, mass-spectrometric analysis has the advantage that the concentration of many (&gt;100) polypeptides of a sample can be determined by a single analysis. Any type of mass spectrometer may be employed. By means of mass spectrometry, it is possible to measure 10 fmol of a polypeptide marker, i.e., 0.1 ng of a 10 kD protein, as a matter of routine with a measuring accuracy of about ±0.01% in a complex mixture. In mass spectrometers, an ion-forming unit is coupled with a suitable analytic device. For example, electrosprayionization (ESI) interfaces are mostly used to measure ions in liquid samples, whereas MALDI (matrix-assisted laser desorption/ionization) technique is used for measuring ions from a sample crystallized in a matrix. To analyze the ions formed, quadrupoles, ion traps or time-of-flight (TOF) analyzers may be used, for example. 
         [0054]    In electrospray ionization (ESI), the molecules present in solution are atomized, inter alia, under the influence of high voltage (e.g., 1-8 kV), which forms charged droplets that become smaller from the evaporation of the solvent. Finally, so-called Coulomb explosions result in the formation of free ions, which can then be analyzed and detected. 
         [0055]    In the analysis of the ions by means of TOF, a particular acceleration voltage is applied which confers an equal amount of kinetic energy to the ions. Thereafter, the time that the respective ions take to travel a particular drifting distance through the flying tube is measured very accurately. Since with equal amounts of kinetic energy, the velocity of the ions depends on their mass, the latter can thus be determined. TOF analyzers have a very high scanning speed and reach a very good resolution. 
         [0056]    Preferred methods for the determination of the presence or absence of polypeptide markers include gas-phase ion spectrometry, such as laser desorption/ionization mass spectrometry, MALDITOF MS, SELDI-TOF MS (surface-enhanced laser desorption/ionization), LC MS (liquid chromatography/mass spectrometry), 2D-PAGE/MS and capillary electrophoresis-mass spectrometry (CE-MS). All the methods mentioned are known to the skilled person. 
         [0057]    A particularly preferred method is CE-MS, in which capillary electrophoresis is coupled with mass spectrometry. This method has been described in some detail, for example, in the German Patent Application DE 10021737, in Kaiser et al. (J. Chromatogr A, 2003, Vol. 1013: 157-171, and Electrophoresis, 2004, 25: 2044-2055) and in Wittke et al. (J. Chromatogr. A, 2003, 1013: 173-181). The CE-MS technology allows to determine the presence of some hundreds of polypeptide markers of a sample simultaneously within a short time and in a small volume with high sensitivity. After a sample has been measured, a pattern of the measured polypeptide markers is prepared, and this pattern can be compared with reference patterns of sick or healthy subjects. In most cases, it is sufficient to use a limited number of polypeptide markers for the diagnosis of UAS. A CE-MS method which includes CE coupled on-line to an ESI-TOF MS is further preferred. 
         [0058]    For CE-MS, the use of volatile solvents is preferred, and it is best to work under essentially salt-free conditions. Examples of suitable solvents include acetonitrile, methanol and the like. The solvents can be diluted with water or an acid (e.g., 0.1% to 1% formic acid) in order to protonate the analyte, preferably the polypeptides. 
         [0059]    By means of capillary electrophoresis, it is possible to separate molecules by their charge and size. Neutral particles will migrate at the speed of the electro-osmotic flow upon application of a current, while cations are accelerated towards the cathode, and anions are delayed. The advantage of capillaries in electrophoresis resides in the favorable ratio of surface to volume, which enables a good dissipation of the Joule heat generated during the current flow. This in turn allows high voltages (usually up to 30 kV) to be applied and thus a high separating performance and short times of analysis. 
         [0060]    In capillary electrophoresis, silica glass capillaries having inner diameters of typically from 50 to 75 μm are usually employed. The lengths employed are 30-100 cm. In addition, the capillaries are usually made of plastic-coated silica glass. The capillaries may be either untreated, i.e., expose their hydrophilic groups on the interior surface, or coated on the interior surface. A hydrophobic coating may be used to improve the resolution. In addition to the voltage, a pressure may also be applied, which typically is within a range of from 0 to 1 psi. The pressure may also be applied only during the separation or altered meanwhile. 
         [0061]    In a preferred method for measuring polypeptide markers, the markers of the sample are separated by capillary electrophoresis, then directly ionized and transferred on-line into a coupled mass spectrometer for detection. 
         [0062]    In the method according to the invention, it is advantageous to use several polypeptide markers for the diagnosis. 
         [0063]    The use of at least 5, 6, 8 or 10 markers is preferred. 
         [0064]    In one embodiment, from 20 to 50 markers are used. 
         [0065]    In order to determine the probability of the existence of a disease when several markers are used, statistic methods known to the skilled person may be used. For example, the Random Forests method described by Weis singer et al. (Kidney Int., 2004, 65: 2426-2434) may be used by using a computer program such as S-Plus, or the support vector machines as described in the same publication. Another possibility is the linear combination of individual signals as described, for example, in Rossing et al., J Am Soc Nephrol. (2008) 19(7): 1283-90. 
       Example 
     1. Sample Preparation 
       [0066]    For detecting the polypeptide markers for the diagnosis, urine was employed. Urine was collected from healthy donors (control group), from patients suffering from a chronic kidney disease or a renal or bladder carcinoma (“diseases control”) as well as from patients suffering from ADPKD. 
         [0067]    For the subsequent CE-MS measurement, the proteins which are also contained in the urine of patients in an elevated concentration, such as albumin and immunoglobulins, had to be separated off by ultrafiltration. Thus, 700 μl of urine was collected and admixed with 700 μl of filtration buffer (2 M urea, 10 mM ammonia, 0.02% SDS). This 1.4 ml of sample volume was ultrafiltrated (20 kDa, Sartorius, Gottingen, Germany). The ultrafiltration was performed at 3000 rpm in a centrifuge until 1.1 ml of ultrafiltrate was obtained. 
         [0068]    The 1.1 ml of filtrate obtained was then applied to a PD 10 column (Amersham Bioscience, Uppsala, Sweden) and desalted against 2.5 ml of 0.01% NH 4 OH, and lyophilized. For the CE-MS measurement, the polypeptides were then resuspended with 20 μl of water (HPLC grade, Merck). 
       2. CE-MS Measurement 
       [0069]    The CE-MS measurements were performed with a Beckman Coulter capillary electrophoresis system (P/ACE MDQ System; Beckman Coulter Inc., Fullerton, Calif., USA) and a Bruker ESITOF mass spectrometer (micro-TOF MS, Bruker Daltonik, Bremen, Germany). 
         [0070]    The CE capillaries were supplied by Beckman Coulter and had an ID/OD of 50/360 μm and a length of 90 cm. The mobile phase for the CE separation consisted of 20% acetonitrile and 0.25% formic acid in water. For the “sheath flow” on the MS, 30% isopropanol with 0.5% formic acid was used, here at a flow rate of 2 μl/min. The coupling of CE and MS was realized by a CE-ESI-MS Sprayer Kit (Agilent Technologies, Waldbronn, Germany). 
         [0071]    For injecting the sample, a pressure of from 1 to a maximum of 6 psi was applied, and the duration of the injection was 99 seconds. With these parameters, about 150 nl of the sample was injected into the capillary, which corresponds to about 10% of the capillary volume. A stacking technique was used to concentrate the sample in the capillary. Thus, before the sample was injected, a 1 M NH 3  solution was injected for 7 seconds (at 1 psi), and after the sample was injected, a 2 M formic acid solution was injected for 5 seconds. When the separation voltage (30 kV) was applied, the analytes were automatically concentrated between these solutions. 
         [0072]    The subsequent CE separation was performed with a pressure method: 40 minutes at 0 psi, then 0.1 psi for 2 min, 0.2 psi for 2 min, 0.3 psi for 2 min, 0.4 psi for 2 min, and finally 0.5 psi for 17 min. The total duration of a separation run was thus 65 minutes. 
         [0073]    In order to obtain as good a signal intensity as possible on the side of the MS, the nebulizer gas was turned to the lowest possible value. The voltage applied to the spray needle for generating the electrospray was 3700-4100 V. The remaining settings at the mass spectrometer were optimized for peptide detection according to the manufacturer&#39;s instructions. The spectra were recorded over a mass range of m/z 400 to m/z 3000 and accumulated every 3 seconds. 
       3. Standards for the CE Measurement 
       [0074]    For checking and standardizing the CE measurement, the following proteins or polypeptides which are characterized by the stated CE migration times under the chosen conditions were employed: 
         [0000]    
       
         
               
               
             
           
               
                   
               
               
                 Protein/polypeptide 
                 Migration time 
               
               
                   
               
             
             
               
                 Aprotinin (SIGMA, Taufkirchen, DE, Cat. # A1153) 
                  19.3 min 
               
               
                 Ribonuclease, SIGMA, Taufkirchen, DE, Cat. # R4875 
                 19.55 min 
               
               
                 Lysozyme, SIGMA, Taufkirchen, DE, Cat. # L7651 
                 19.28 min 
               
               
                 “REV”, Sequence: REVQSKIGYGRQIIS 
                 20.95 min 
               
               
                 “ELM”, Sequence: ELMTGELPYSHINNRDQIIFMVGR 
                 23.49 min 
               
               
                 “KINCON”, Sequence: TGSLPYSHIGSRDQIIFMVGR 
                 22.62 min 
               
               
                 “GIVLY” Sequence: GIVLYELMTGELPYSHIN 
                  32.2 min 
               
               
                   
               
             
          
         
       
     
         [0075]    The proteins/polypeptides were employed at a concentration of 10 pmol/μl each in water. “REV”, “ELM, “KINCON” and “GIVLY” are synthetic peptides. 
         [0076]    In principle, it is known to the skilled person that slight variations of the migration times may occur in separations by capillary electrophoresis. However, under the conditions described, the order of migration will not change. For the skilled person who knows the stated masses and CE times, it is possible without difficulty to assign their own measurements to the polypeptide markers according to the invention. For example, they may proceed as follows: At first, they select one of the polypeptides found in their measurement (peptide 1) and try to find one or more identical masses within a time slot of the stated CE time (for example, ±5 min). If only one identical mass is found within this interval, the assignment is completed. If several matching masses are found, a decision about the assignment is still to be made. Thus, another peptide (peptide 2) from the measurement is selected, and it is tried to identify an appropriate polypeptide marker, again taking a corresponding time slot into account. 
         [0077]    Again, if several markers can be found with a corresponding mass, the most probable assignment is that in which there is a substantially linear relationship between the shift for peptide 1 and that for peptide 2. 
         [0078]    Depending on the complexity of the assignment problem, it suggests itself to the skilled person to optionally use further proteins from their sample for assignment, for example, ten proteins. Typically, the migration times are either extended or shortened by particular absolute values, or compressions or expansions of the whole course occur. However, comigrating peptides will also comigrate under such conditions. 
         [0079]    In addition, the skilled person can make use of the migration patterns described by Zuerbig et al. in Electrophoresis 27 (2006), pp. 2111-2125. If they plot their measurement in the form of m/z versus migration time by means of a simple diagram (e.g., with MS Excel), the line patterns described also become visible. Now, a simple assignment of the individual polypeptides is possible by counting the lines. 
         [0080]    Other approaches of assignment are also possible. Basically, the skilled person could also use the peptides mentioned above as internal standards for assigning their CE measurements. 
       Testing the Markers 
       [0081]    Urine samples from 17 patients with ADPKD were first compared with 86 samples from control patients rated to be healthy. The summed-up data are shown in  FIG. 1 . The identification of 383 biomarkers that show statistically significant differences between the groups was achieved. 
         [0082]    In a test model for evaluation, a discrimination could be achieved with 100% sensitivity and 98.8% specificity. 
         [0083]    To evaluate the markers, 150 further samples were examined and tested with the established model. The sensitivity was 87.5%, and the specificity was 97.5%.  FIG. 2  shows the ROC curves for the training and test sets. 
         [0084]    In order to test the specificity of the biomarkers for ADPKD, further controls were included. A specificity of 93% was found with healthy controls, a 95% specificity was found for patients with other chronic kidney diseases, 85% specificity for bladder cancer, and 83% specificity for kidney tumors. 
         [0085]    In addition, a group of healthy subjects of &gt;60 years of age was included. In this case, a specificity of only 69% was found. 
         [0086]    For some of the 383 potential biomarkers, it was possible to establish sequence information. In an analysis that was based only on the 75 sequenced peptides, a sensitivity of 100% and a specificity of 95.5% were found in the training set. Upon cross-validation, a sensitivity of 94.1% and a specificity of 94.2% were obtained. This model ewas again tested against a test set. The sensitivity was 66.7%, and the specificity was 99.1%. It is found that the additional biomarkers not yet sequenced further increase the performance of the diagnostic method. 
         [0087]    However, 75 biomarkers already showed an AUC of 0.89 and are thus excellently suitable. The sequence information obtained thereby is stated in Table 3. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 No. 
                 Sequence 
                 Name 
                 Start_AA 
                 Stop_AA 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 KGDTGPpGP 
                 Collagen alpha-1 (III) chain 
                 629 
                 637 
               
               
                   
               
               
                 17 
                 VLNLGPITR 
                 Uromodulin 
                 598 
                 606 
               
               
                   
               
               
                 19 
                 YQTNKAKH 
                 Cystatin-B 
                 85 
                 92 
               
               
                   
               
               
                 24 
                 ApGDKGESGPS 
                 Collagen alpha-1 (I) chain 
                 777 
                 787 
               
               
                   
               
               
                 28 
                 SpGPDGKTGPp 
                 Collagen alpha-1 (I) chain 
                 546 
                 556 
               
               
                   
               
               
                 39 
                 ApGDRGEpGPp 
                 Collagen alpha-1 (I) chain 
                 798 
                 808 
               
               
                   
               
               
                 60 
                 GPPGppGpPGPPS 
                 Collagen alpha-1 (I) chain 
                 1181 
                 1193 
               
               
                   
               
               
                 61 
                 MIEQNTKSPL 
                 Alpha-1-antitrypsin 
                 398 
                 407 
               
               
                   
               
               
                 72 
                 DDGEAGKpGRpG 
                 Collagen alpha-1 (I) chain 
                 231 
                 242 
               
               
                   
               
               
                 75 
                 SpGPDGKTGPPGp 
                 Collagen alpha-1 (I) chain 
                 546 
                 558 
               
               
                   
               
               
                 82 
                 GPpGEAGKpGEQG 
                 Collagen alpha-1 (I) chain 
                 650 
                 662 
               
               
                   
               
               
                 89 
                 DKGETGEQGDRG 
                 Collagen alpha-1 (I) chain 
                 10 
                 1106 
               
               
                   
               
               
                 101 
                 SpGSpGPDGKTGPp 
                 Collagen alpha-1 (I) chain 
                 543 
                 556 
               
               
                   
               
               
                 113 
                 DSGSSEEQGGSSRA 
                 Polymeric-immunoglobulin receptor 
                 626 
                 639 
               
               
                   
               
               
                 121 
                 GSpGGpGSDGKpGPpG 
                 Collagen alpha-1 (III) chain 
                 540 
                 555 
               
               
                   
               
               
                 128 
                 GLPGPpGPpGSFLSN 
                 Collagen alpha-1 (XVII) chain 
                 885 
                 899 
               
               
                   
               
               
                 129 
                 PpGKNGDDGEAGKpG 
                 Collagen alpha-1 (I) chain 
                 225 
                 239 
               
               
                   
               
               
                 130 
                 SpGSPGPDGKTGPpGP 
                 Collagen alpha-1 (I) chain 
                 543 
                 558 
               
               
                   
               
               
                 131 
                 GLpGTGGPpGENGKpG 
                 Collagen alpha-1 (III) chain 
                 642 
                 657 
               
               
                   
               
               
                 132 
                 TIDEKGTEAAGAMF 
                 Alpha-1-antitrypsin 
                 363 
                 376 
               
               
                   
               
               
                 135 
                 ApGKNGERGGpGGpGP 
                 Collagen alpha-1 (III) chain 
                 589 
                 604 
               
               
                   
               
               
                 138 
                 DQSRVLNLGPITR 
                 Uromodulin 
                 594 
                 606 
               
               
                   
               
               
                 140 
                 DGQPGAKGEpGDAGAK 
                 Collagen alpha-1 (I) chain 
                 820 
                 835 
               
               
                   
               
               
                 143 
                 GPpGKNGDDGEAGKpG 
                 Collagen alpha-1 (I) chain 
                 224 
                 239 
               
               
                   
               
               
                 146 
                 VGPpGpPGPPGPPGPPS 
                 Collagen alpha-1 (I) chain 
                 1174 
                 1190 
               
               
                   
               
               
                 151 
                 SpGSpGPDGKTGPPGpA 
                 Collagen alpha-1 (I) chain 
                 543 
                 559 
               
               
                   
               
               
                 152 
                 VIDQSRVLNLGPIT 
                 Uromodulin 
                 592 
                 605 
               
               
                   
               
               
                 153 
                 PpGEAGKpGEQGVpGD 
                 Collagen alpha-1 (I) chain 
                 651 
                 666 
               
               
                   
               
               
                 155 
                 DGQpGAKGEpGDAGAKG 
                 Collagen alpha-1 (I) chain 
                 820 
                 836 
               
               
                   
               
               
                 159 
                 GSEADHEGTHSTKRG 
                 Fibrinogen alpha chain 
                 608 
                 622 
               
               
                   
               
               
                 162 
                 SpGSpGPDGKTGPPGpAG 
                 Collagen alpha-1 (I) chain 
                 543 
                 560 
               
               
                   
               
               
                 164 
                 IDQSRVLNLGPITR 
                 Uromodulin 
                 593 
                 606 
               
               
                   
               
               
                 167 
                 TGLSMDGGGSPKGDVDP 
                 NA/K-ATPase gamma chain 
                 2 
                 18 
               
               
                   
               
               
                 171 
                 DGApGKNGERGGpGGpGP 
                 Collagen alpha-1 (III) chain 
                 587 
                 604 
               
               
                   
               
               
                 172 
                 EGSpGRDGSpGAKGDRG 
                 Collagen alpha-1 (I) chain 
                 1021 
                 1037 
               
               
                   
               
               
                 175 
                 VGPpGPpGPpGPPGPPSAG 
                 Collagen alpha-1 (I) chain 
                 1177 
                 1195 
               
               
                   
               
               
                 176 
                 AGSEADHEGTHSTKRG 
                 Fibrinogen alpha chain 
                 607 
                 622 
               
               
                   
               
               
                 179 
                 SGSVIDQSRVLNLGPI 
                 Uromodulin 
                 589 
                 604 
               
               
                   
               
               
                 181 
                 KpGEQGVpGDLGApGPSG 
                 Collagen alpha-1 (I) chain 
                 657 
                 674 
               
               
                   
               
               
                 182 
                 VIDQSRVLNLGPITR 
                 Uromodulin 
                 592 
                 606 
               
               
                   
               
               
                 183 
                 GLpGTGGPpGENGKpGEp 
                 Collagen alpha-1 (III) chain 
                 642 
                 659 
               
               
                   
               
               
                 188 
                 DHDVGSELPPEGVLGAL 
                 ProSAAS 
                 223 
                 239 
               
               
                   
               
               
                 200 
                 GLpGTGGPpGENGKPGEPGp 
                 Collagen alpha-1 (III) chain 
                 642 
                 661 
               
               
                   
               
               
                 204 
                 GLpGTGGPpGENGKpGEPGp 
                 Collagen alpha-1 (III) chain 
                 642 
                 661 
               
               
                   
               
               
                 208 
                 EGSpGRDGSpGAKGDRGET 
                 Collagen alpha-1 (I) chain 
                 1021 
                 1039 
               
               
                   
               
               
                 215 
                 SGSVIDQSRVLNLGPITR 
                 Uromodulin 
                 589 
                 606 
               
               
                   
               
               
                 224 
                 DGESGRPGRPGERGLPGPPG 
                 Collagen alpha-1 (III) chain 
                 230 
                 249 
               
               
                   
               
               
                 227 
                 AGpPGPPGppGTSGHpGSpGSpG 
                 Collagen alpha-1 (III) chain 
                 176 
                 198 
               
               
                   
               
               
                 228 
                 NSGEpGApGSKGDTGAKGEpGP 
                 Collagen alpha-1 (I) chain 
                 432 
                 453 
               
               
                   
               
               
                 229 
                 EGSpGRDGSpGAKGDRGETGP 
                 Collagen alpha-1 (I) chain 
                 1021 
                 1041 
               
               
                   
               
               
                 231 
                 SGSVIDQSRVLNLGPITRK 
                 Uromodulin 
                 589 
                 607 
               
               
                   
               
               
                 238 
                 DAGApGApGGKGDAGApGERGPpG 
                 Collagen alpha-1 (III) chain 
                 586 
                 604 
               
               
                   
               
               
                 240 
                 GAPGNDGAKGDAGAPGAPGSQGAPG 
                 Collagen alpha-1 (I) chain 
                 701 
                 725 
               
               
                   
               
               
                 243 
                 NGEpGGKGERGApGEKGEGGpPG 
                 Collagen alpha-1 (III) chain 
                 818 
                 840 
               
               
                   
               
               
                 244 
                 AGPpGEAGKpGEQGVpGDLGAPGP 
                 Collagen alpha-1 (I) chain 
                 646 
                 669 
               
               
                   
               
               
                 245 
                 GRTGDAGPVGPPGPpGppGpPGPPS 
                 Collagen alpha-1 (I) chain 
                 1169 
                 1193 
               
               
                   
               
               
                 248 
                 QNGEpGGKGERGAPGEKGEGGppG 
                 Collagen alpha-1 (III) chain 
                 817 
                 840 
               
               
                   
               
               
                 257 
                 ADGQpGAKGEpGDAGAKGDAGpPGPAGP 
                 Collagen alpha-1 (I) chain 
                 819 
                 846 
               
               
                   
               
               
                 258 
                 TGPIGPpGPAGApGDKGESGPSGPAGPTG 
                 Collagen alpha-1 (I) chain 
                 766 
                 794 
               
               
                   
               
               
                 264 
                 GPpGADGQpGAKGEpGDAGAKGDAGpPGP 
                 Collagen alpha-1 (I) chain 
                 815 
                 843 
               
               
                   
               
               
                 266 
                 DEAGSEADHEGTHSTKRGHAKSRP 
                 Fibrinogen alpha chain 
                 605 
                 628 
               
               
                   
               
               
                 268 
                 DDILASPPRLPEPQPYPGAPHHSS 
                 Collagen alpha-1 (XVIII) chain 
                 1296 
                 1319 
               
               
                   
               
               
                 271 
                 AGPpGApGApGApGPVGPAGKSGDRGETGP 
                 Collagen alpha-1 (I) chain 
                 1042 
                 1071 
               
               
                   
               
               
                 273 
                 QGpPGPSGEEGKRGPNGEAGSAGPPGppG 
                 Collagen alpha-2 (I) chain 
                 369 
                 397 
               
               
                   
               
               
                 280 
                 DAHKSEVAHRFKDLGEENFKALVL 
                 Serum albumin; N-term. 
                 25 
                 48 
               
               
                   
               
               
                 281 
                 KEGGKGPRGETGPAGRpGEVGpPGPpGPAG 
                 Collagen alpha-1 (I) chain 
                 903 
                 932 
               
               
                   
               
               
                 282 
                 ERGEAGIpGVpGAKGEDGKDGSpGEpGANG 
                 Collagen alpha-1 (III) chain 
                 448 
                 477 
               
               
                   
               
               
                 288 
                 ESGREGApGAEGSpGRDGSpGAKGDRGETGP 
                 Collagen alpha-1 (I) chain 
                 1011 
                 1041 
               
               
                   
               
               
                 293 
                 LTGSpGSpGpDGKTGPPGPAGQDGRPGPpGppG 
                 Collagen alpha-1 (I) chain 
                 537 
                 569 
               
               
                   
               
               
                 302 
                 PpGESGREGAPGAEGSpGRDGSpGAKGDRGETGP 
                 Collagen alpha-1 (I) chain 
                 1008 
                 1041 
               
               
                   
               
               
                 312 
                 NTGApGSpGVSGpKGDAGQpGEKGSPGAQGPP- 
                 Collagen alpha-1 (III) chain 
                 910 
                 946 
               
               
                   
                 GAPGp 
               
               
                   
               
               
                 316 
                 EEKAVADTRDQADGSRASVDSGSSEEQGGSSRA 
                 Polymeric-immunoglobulin receptor 
                 607 
                 639 
               
               
                   
               
               
                 320 
                 ARGNDGARGSDGQPGPpGppGTAGFpG- 
                 Collagen alpha-1 (III) chain 
                 319 
                 355 
               
               
                   
                 SpGAKGEVGP 
               
               
                   
               
               
                 325 
                 NTGAPGSpGVSGpKGDAGQpGEKGSpGA- 
                 Collagen alpha-1 (III) chain 
                 910 
                 948 
               
               
                   
                 QGpPGAPGPLG 
               
               
                   
               
               
                 334 
                 GRPEAQPPPLSSEHKEPVAGDAVPGPKDGSAPEVR 
                 Neurosecretory protein VGF 
                 26 
                 62 
               
               
                   
                 GA