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1732, 1891, 2325, 2425], 'variety': [204], 'states,': [208], 'few': [209], 'meet': [210], 'appropriately': [211, 1638], 'rigorous': [212], 'criteria': [213, 1622], 'support': [215, 1768], 'routine': [216], 'measurement': [217, 315], 'prediction': [220, 564, 611, 2057], 'practice.1': [223], 'Moreover,': [224, 871, 1501, 1590], 'assessment': [226, 415], 'alone': [227], 'is': [228, 602, 954, 993, 1024, 1144, 1202, 1456, 1509, 1530, 1552, 1735], 'limited': [230, 2383], 'value': [231, 247, 595, 652, 697, 705], 'clinicians.': [233], 'To': [234], 'move': [235], 'beyond': [236], 'simple': [237], 'fortune': [238], 'telling': [239], 'take': [242], 'advantage': [243], 'potential': [246, 373, 406, 1559], 'circulating': [249, 933, 1649, 1744], 'as': [251, 443, 666, 668, 672, 797, 1321, 1339, 1502, 1753, 2399], 'modifiable': [252], 'indices': [253, 1397], 'specific': [255], 'biological': [256, 305, 420, 738, 1522], 'pathways,': [257, 1527], 'investigated.': [262], 'These': [263], 'emerging': [264, 669], 'roles': [265], 'include': [266], 'use': [268, 922, 1338, 1613, 2336], 'guide': [272], 'therapeutic': [273, 1588, 1605, 2594], 'selection': [274], 'profiling': [277, 1451, 1563, 1633], 'chronic': [279, 2463, 2504], 'course': [281], 'response': [283], 'treatment': [285, 2083], 'individual': [287], 'panels': [290], 'distinct': [292], 'markers.': [293], 'If': [294, 1620, 1731], 'selected': [297, 410], 'that': [298, 313, 437, 605, 647, 794, 824, 884, 957, 962, 1017, 1026, 1055, 1093, 1110, 1125, 1135, 1146, 1204, 1313, 1388, 1511, 1651], 'provide': [299, 587, 648, 679, 974, 1652], 'reliable': [301, 1421], 'representation': [302], 'pathway': [306, 1523], 'mediating': [307], 'risk,': [309, 1343], 'it': [310, 601, 953, 1023, 1143, 1201, 1440, 1508, 1529], 'remains': [311], 'possible': [312, 947, 956, 1025, 1145, 1203], 'changes': [317, 771, 805, 958, 1188, 1270, 1330, 1464, 1513, 1566], 'these': [319, 372, 438, 456, 460, 623, 639, 845, 1426], 'will': [321, 558, 1514, 2376, 2394], 'yield': [322, 1047], 'insight': [324], 'into': [325, 1069], 'expected': [327], 'effects': [328, 931, 1077, 1089, 1124, 1130, 1150, 1165, 1211, 1401, 1468, 1934, 2148], 'different': [330, 1526, 1604, 1729], 'therapies.Article': [331], 'see': [332], 'p': [333], '695In': [334], 'current': [336], 'issue': [337, 2360], 'Circulation,': [339], 'Sobel': [340, 1903, 2184], 'et': [341], 'al': [342], 'report': [343, 464, 607, 1224], 'findings': [344, 846, 1379, 1410, 1424, 1491], 'from': [345, 914, 943, 1225, 1723, 1769, 1774, 1784, 1792, 1894, 2200], 'combination': [347, 2275, 2302], '2': [349, 361, 1694, 1947, 2206, 2225, 2280], 'large': [350, 1062, 1683], 'substudies': [352], 'Bypass': [355, 1943], 'Angioplasty': [356, 1944], 'Revascularization': [357, 1945], 'Investigation': [358, 1946], 'Type': [360, 2639], 'Diabetes': [362, 1948], '(BARI': [363, 1949, 2208], '2D)': [364, 1950, 2209], 'trial,': [365], 'which': [367, 383, 678], 'they': [368, 384, 1160], 'consider': [369, 638, 823, 841], 'several': [370, 409, 1219], 'biomarkers.2': [377], 'In': [378, 632, 1245, 1406, 1646, 2422], 'an': [379, 800, 1175, 1222, 1346, 1673, 1690, 1703, 1936, 2062, 2315, 2359], 'ambitious': [380], 'study': [381, 718, 1293, 1316], 'performed': [385], 'serial': [386, 723], 'measurements': [387, 724], 'multiple': [389, 1603, 1664], 'reflecting': [391], 'insulin': [392], 'exposure': [393], 'resistance,': [395], 'glucose': [396, 2229], 'control,': [397], 'inflammation,': [398], 'thrombosis,': [399], 'fibrinolysis,': [401], 'authors': [403, 463, 635, 792, 1260], 'evaluated': [404], 'role': [407, 432, 1677], 'improve': [413, 560, 1659], 'profile': [418], 'actions': [421], 'insulin-sensitizing': [424, 796, 1937], '(IS)': [425], 'insulin-providing': [427, 801], '(IP)': [428], 'therapies.': [429, 1730], 'This': [430, 991, 2428], 'latter': [431], 'implicitly': [433], 'suggests': [434], 'possibility': [436, 992], 'profiles': [440, 808, 1592, 1615, 1670, 1715], 'could': [441], 'function': [442], 'surrogates': [444, 1340], 'predict': [446, 1399, 1617, 1760], 'differences': [447, 1302], 'efficacy': [450], 'between': [451, 852, 1282, 1306, 1373, 1525, 1538, 1663, 1743, 2597], 'therapies.How': [453], 'well': [454, 667], 'do': [455], 'perform': [458], 'purposes?': [461], 'The': [462, 791, 1275], '"striking': [465], 'predictive': [466], 'power"': [467], 'baseline': [469, 1263, 2198], 'levels': [470, 778], 'fibrinogen,': [472], 'D-dimer,': [473], 'C-reactive': [475], 'protein': [476], '(CRP)': [477, 1016], 'terms': [479], 'subsequent': [481, 514], 'mortality': [482, 1972], 'composite': [485], 'outcome': [486], 'death,': [488], 'infarction,': [490], 'stroke,': [492], 'whereas': [493], 'plasminogen': [494, 503], 'activator': [495, 504], 'inhibitor': [496], 'type-1': [497], '(PAI-1)': [498], 'antigen': [499], 'activity,': [501], 'tissue-type': [502], '(tPA)': [505], 'antigen,': [506], 'fibrinopeptide': [508, 1183, 1412], 'A': [509, 516, 1184, 1413, 2010, 2521], 'did': [510, 636], 'not': [511, 559, 626, 637, 973, 1044, 1095, 1268, 1395, 1531, 1812, 2324, 2343, 2356, 2363], 'associate': [512], 'events.': [515, 870, 1074], 'closer': [517], 'look,': [518], 'raises': [520], 'questions': [521], 'about': [522, 1655], 'robustness': [524], 'this': [526, 556, 818, 1647, 1809], 'conclusion.': [527], 'Although': [528, 817], 'statistically': [529], 'significant,': [530], 'positive': [532], 'associations': [533, 1742], 'observed': [534, 1137, 1305], 'were': [535, 625, 860, 963, 1018, 1136], 'quantitatively': [536], 'very': [537, 847, 1061], 'modest,': [538], 'only': [540, 572, 1056, 2377], '2%': [542], 'relative': [543], 'increase': [544, 549], 'per': [547], '10%': [548], 'CRP': [551, 777], 'D-dimer.': [553], 'Associations': [554], 'range': [557], 'discrimination': [562], 'models': [565], 'likely': [568], 'result': [570, 942], 'trivial': [573], '(if': [574], 'any)': [575], 'improvements': [576], 'classification.': [579], 'Because': [580], 'measures': [581], 'association': [583, 999, 1013, 1250], 'potentially': [589], 'misleading': [590], 'overestimation': [591], 'prediction,': [600], 'now': [603], 'recommended': [604], 'more': [608, 649, 681, 713, 1420, 1546, 1637, 1675], 'complete': [609, 692, 1547], 'metrics,': [612], 'including': [613, 660, 1221, 1358, 1576], 'improvement': [614, 1050], 'receiver-operating': [617], 'characteristic': [618], 'curve,': [619], 'calibration,': [620], 'reclassification1;': [622], 'analyses': [624, 1247], 'reported': [627, 688, 1231], 'present': [630, 1140, 1315, 1506], 'publication.': [631], 'addition,': [633], 'context': [643], 'established': [645], 'robust': [650, 682], 'patients': [654, 747, 834, 1940, 2059], 'stable': [656, 1974, 2017], 'coronary': [657, 836, 906, 1975, 2018, 2067], 'artery': [658, 837, 907, 2019], 'disease,': [659, 838], 'peptides3': [662], 'troponins,4': [665], 'biomarkers,': [670], 'such': [671, 1350, 1472, 1621], 'growth': [673], 'differentiating': [674], 'factor-15,5': [675], 'each': [676], 'substantially': [680], 'information': [684, 1654], 'than': [685, 2372], 'here.': [689], 'Certainly,': [690], 'evaluation': [693, 1884], 'new': [699], 'requires': [701], 'demonstration': [702], 'incremental': [704], 'over': [706, 761], 'best': [708], 'available': [709], 'competition.The': [710], 'larger': [711], 'novel': [714, 1886], 'goal': [715], 'was': [719, 878, 1033, 1043], 'capitalize': [721, 1556], 'compare': [729, 1728], 'impact': [731], 'IS': [733, 768, 789, 825, 853, 967, 1178, 1254, 1286, 1307], 'IP': [735, 759, 831, 855, 970, 1252, 1284, 1309], 'therapies': [736, 1213], 'pathways': [739, 1079, 1092, 1159, 1657, 2459, 2500], 'leading': [740, 910], 'atherosclerosis': [742], 'progression': [743], 'complications': [745], 'diabetes': [749, 1356, 2085, 2207, 2226, 2281], 'mellitus.': [750, 2282], 'Circulating': [751], 'tPA': [752, 1192], 'PAI-1': [754, 1190], 'increased': [755, 905], 'modestly': [756, 1057], 'arm': [760], 'time': [762], 'but': [763, 783, 1267], 'fell': [764, 779], 'significantly': [765], 'arm,': [769], 'paralleling': [770], 'plasma': [773, 1107], 'insulin.': [774], 'Fibrinogen': [775], 'both': [781, 1577], 'arms': [782], 'greater': [786], 'extent': [787], 'therapy.': [790, 1021, 1486], 'conclude': [793], '"an': [795], 'opposed': [798], 'strategy': [802, 1938], 'led': [803, 885], 'indicative': [809], 'profibrinolytic,': [812], 'antithrombotic,': [813, 1931], 'antiinflammatory': [815, 1933], 'state."2': [816], 'conclusion': [819], 'leads': [820], 'us': [821], 'therapy': [826, 832, 856, 971, 1153, 1179, 2277], 'might': [827, 1416], 'be': [828, 935, 950, 1065, 1085, 1418, 1515, 1570, 1594, 1610, 1636, 1699, 1717, 2369, 2378, 2395, 2410, 2533], 'preferable': [829], 'we': [839, 1369], 'should': [840, 1317, 2312, 2368, 2409], 'implications': [843], 'critically': [848], 'comparisons': [851], 'BARI': [858, 876, 944, 1227, 1384, 1693, 1927], '2D': [859, 877, 1228, 1385, 1928], 'null': [861, 1409, 1431], 'regard': [863], 'important': [865, 1676, 1704], 'major': [866, 1710], 'thiazolidinedione': [873], 'used': [874, 1718], 'almost': [879, 893], 'exclusively': [880], 'rosiglitazone,': [881], 'drug': [883, 1400, 1618, 1643, 1761], 'greatest': [888], 'magnitude': [889, 1036], 'change': [891, 1063], 'all': [894], 'assessed': [896], 'trial': [899, 941, 2300], 'yet': [900], 'risk,6': [909], 'its': [912, 2419], 'withdrawal': [913], 'market': [916], 'Europe': [918], 'severely': [920], 'restricted': [921], 'United': [925], 'States.7How': [926], 'can': [927, 949, 1716], 'perceived': [929], 'favorable': [930, 1076, 1129, 1164, 1187], 'reconciled': [936], 'disappointing': [939], 'overall': [940], '2D?': [945], 'Several': [946], 'explanations': [948], 'posited.': [951], 'First,': [952], 'quite': [955], 'differentially': [964], 'affected': [965], 'by': [966, 995, 1020, 1081, 1087, 1504, 2109], 'compared': [968], 'may': [972, 1064, 1084, 1111, 1126, 1185, 1207, 1295, 1474, 1635, 1658, 1671, 1750], 'clinically': [975, 1048, 1719], 'relevant': [976], 'information,': [977], 'even': [978, 1674, 1721], 'if': [979], 'some': [980, 1004], 'them': [982], 'directly': [985], 'implicated': [986], 'diabetic': [988, 1403], 'vascular': [989, 1404], 'disease.': [990, 1405, 1977, 2020], 'suggested': [994], 'absence': [997, 1173], '(PAI-1,': [1006], 'tPA,': [1007, 1240, 1389], 'fibrinogen)': [1009], 'weakness': [1011], 'others': [1015], 'influenced': [1019], 'Second,': [1022], 'directional': [1029], 'effect': [1030, 1176, 1196], 'favorable,': [1034], 'change,': [1038], 'individually': [1039], 'aggregate,': [1042], 'sufficient': [1045], 'meaningful': [1049], 'outcomes.': [1052, 1447], 'For': [1053, 1170, 1217], 'mediators': [1054], 'influence': [1058, 1234], 'outcomes,': [1059], 'required': [1066], 'translate': [1068], 'reduction': [1071], 'Third,': [1075], 'reflected': [1080], 'counterbalanced': [1086], 'unfavorable': [1088], 'other': [1091, 1167], 'captured': [1096], 'any': [1098, 1128, 1195], 'measured': [1101], 'biomarkers.': [1102, 1169, 1216], 'Rosiglitazone,': [1103], 'example,': [1105, 1171, 1218], 'causes': [1106], 'volume': [1108], 'expansion': [1109, 1118], 'adversely': [1112], 'affect': [1113], 'neurohormonal': [1114], 'balance,8': [1115], 'increases': [1116], 'fat': [1117, 2192], 'adiposity,': [1120], 'reduces': [1122], 'hematocrit,6': [1123], 'counterbalance': [1127, 1163, 1186], 'inflammation': [1132], 'thrombosis': [1134], 'study.': [1141], 'Fourth,': [1142], 'neutral': [1147], 'counterregulatory': [1149], 'redundant': [1155], '(and': [1157], 'reflect)': [1161], 'would': [1162, 1311, 1569], 'related': [1168], 'D-dimer': [1181, 1415, 1435], 'dilute': [1194], 'thrombotic': [1198, 1377], 'tendency.': [1199], 'Finally,': [1200], 'methodological': [1205], 'issues': [1206], 'exaggerated': [1209], 'studies,': [1220], 'earlier': [1223, 1640], 'investigators,9': [1229], 'strong': [1233], 'body': [1236, 1264, 1272, 1279], 'mass': [1237, 1265, 1273, 1280], 'index': [1238, 1266, 1281], 'PAI-1,': [1241, 1390], 'CRP,': [1242, 1391], 'fibrinogen.': [1244], 'their': [1246, 1337, 2091], 'drugs': [1255, 2080], 'changes,': [1258], 'account': [1261], 'index.': [1274], '0.8-kg/m2': [1276], 'difference': [1277], 'groups': [1287], 'end': [1290], 'period': [1294], 'explain,': [1296], 'part,': [1300], 'regimens.We': [1310], 'argue': [1312], 'once': [1318], 'again': [1319], 'serve': [1320], 'cautionary': [1323], 'note': [1324], 'interpretation': [1327], 'consideration': [1335, 1438], 'adding': [1344], 'increasing': [1347], 'number': [1348], 'invalidated': [1351], 'mellitus,': [1357, 2086], 'hemoglobin': [1359], 'A1C,10': [1360], 'triglycerides,11': [1361], 'recently': [1364, 2317], 'high-density': [1365], 'lipoprotein': [1366], 'cholesterol.12': [1367], 'Indeed,': [1368], 'interpret': [1370], 'disconnect': [1372], 'inflammatory': [1375], 'events': [1382], 'suggest': [1387], 'fibrinogen': [1393], 'contrast,': [1407], 'paradoxically': [1417], 'considered': [1419], 'track': [1428], 'event': [1433], 'results;': [1434], 'merits': [1436], 'also': [1441], 'independently,': [1442], 'albeit': [1443], 'modestly,': [1444], 'associates': [1445], 'Clearly,': [1448], 'embedding': [1449], 'randomized': [1454, 1485], 'fraught': [1457], 'challenges.': [1459], 'At': [1460], 'best,': [1461], 'when': [1462, 1488, 1661], 'concordant': [1466], 'events,': [1471, 1498, 1582], 'propose': [1475], 'mechanism': [1477], 'However,': [1487], 'contradictory': [1493], 'those': [1495, 1814], 'confusion': [1499], 'regions.': [1500], 'illustrated': [1503], 'study,': [1507], 'unlikely': [1510], 'uniform': [1516], 'either': [1517], 'same': [1520], 'clear': [1532], 'how': [1533], 'weigh': [1535], 'inconsistent': [1536], 'results': [1537, 2199], 'various': [1544], 'pathways.A': [1545], 'understanding': [1548], 'biomarker/phenotype': [1550], 'correlations': [1551], 'needed': [1553], 'fully': [1555], 'Ideally,': [1565], 'validated': [1571, 1626, 1653], 'against': [1572], 'precise': [1573], 'phenotypes,': [1575, 1748], 'imaging-based': [1578], 'phenotypes': [1579, 1601], 'before': [1583, 1682, 1713], 'being': [1584], 'tested': [1585], 'large-scale': [1587], 'must': [1593], 'shown': [1595], 'correlate': [1597], 'similarly': [1598], 'classes': [1606], 'order': [1608], 'able': [1611], 'response.': [1619], 'met': [1624], 'processes': [1630], 'identified,': [1632], 'positioned': [1639], 'development': [1644], 'process.': [1645], 'context,': [1648], 'efficiency': [1660], 'selecting': [1662], 'candidate': [1665], 'compounds': [1666], 'and/or': [1667], 'dosages.': [1668], 'Biomarker': [1669], 'play': [1672], 'identifying': [1679, 1740], 'safety': [1680], 'signals': [1681], 'numbers': [1684], 'individuals': [1686], 'exposed': [1688], 'experimental': [1691], 'agent.The': [1692], 'D': [1695], 'investigators': [1696], 'congratulated': [1700], 'tackling': [1702], 'question': [1706], 'highlighting': [1708], 'challenges': [1711], 'ahead': [1712], 'reliably': [1722], 'standpoint': [1726], 'stronger': [1733], 'foundation': [1734], 'built': [1736], 'through': [1737], 'translational': [1738], 'research,': [1739], 'consistent': [1741], 'indeed': [1751], 'emerge': [1752], 'tools': [1754], 'monitor': [1756], 'response.DisclosuresDr': [1762], 'received': [1766, 1789], 'grant': [1767], 'Roche': [1770], 'Diagnostics;': [1771], 'consulting': [1772, 1790], 'income': [1773, 1791], 'Tethys': [1775, 1801], 'Bioscience,': [1776, 1802], 'AstraZeneca,': [1777], 'Daiichi': [1779, 1797], 'Sankyo;': [1780], 'lecture': [1782], 'honoraria': [1783], 'BMS/Sanofi-Aventis.': [1785], 'Dr': [1786], 'F.': [1793], 'Hoffmann': [1794], 'LaRoche,': [1795], 'Genentech,': [1796], 'Sankyo,': [1798], 'Novo': [1799], 'Nordisk,': [1800], 'Ipsen': [1804], 'Pharmaceutical.FootnotesThe': [1805], 'opinions': [1806], 'expressed': [1807], 'article': [1810, 2316, 2389], 'necessarily': [1813], 'editors': [1817], 'American': [1821, 1896, 2569, 2620], 'Heart': [1822, 1897, 2163, 2469, 2508, 2621, 2637], 'Association.Correspondence': [1823], 'Lemos,': [1828], 'MD,': [1829], 'UT': [1830], '5909': [1834], 'Harry': [1835], 'Hines': [1836], 'Blvd,': [1837], 'HA': [1838], '9.133,': [1839], 'Dallas,': [1840], 'TX': [1841], '75390-9047.': [1842], 'E-mail': [1843], 'james.[email': [1844], 'protected]eduReferences1.': [1845], 'Hlatky': [1846], 'MA,': [1847, 2007], 'Greenland': [1848], 'P,': [1849, 1963, 2047, 2250], 'Arnett': [1850], 'DK,': [1851, 2076, 2124], 'Ballantyne': [1852], 'CM,': [1853, 1871], 'Criqui': [1854], 'MH,': [1855, 2138, 2179], 'Elkind': [1856], 'MS,': [1857, 1991], 'Go': [1858], 'AS,': [1859], 'Harrell': [1860], 'FE,': [1861], 'Hong': [1862], 'Y,': [1863], 'Howard': [1864, 1866], 'BV,': [1865], 'VJ,': [1867], 'Hsue': [1868], 'PY,': [1869], 'Kramer': [1870], 'McConnell': [1872], 'JP,': [1873], 'Normand': [1874], 'SL,': [1875], "O'Donnell": [1876], 'CJ,': [1877], 'Smith': [1878], 'SC,': [1879], 'Wilson': [1880], 'PW.': [1881], 'Criteria': [1882], 'risk:': [1890], 'scientific': [1892], 'statement': [1893], 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