{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T12:09:02Z","timestamp":1789819742687,"version":"4.0.1"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,2,2]],"date-time":"2017-02-02T00:00:00Z","timestamp":1485993600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,2,2]],"date-time":"2017-02-02T00:00:00Z","timestamp":1485993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>CVD risk prediction in diabetics is imperfect, as risk models are derived mainly from the general population. We investigate whether the addition of retinopathy and retinal vascular caliber improve CVD prediction beyond established risk factors in persons with diabetes. We recruited participants from the Singapore Malay Eye Study (SiMES, 2004\u20132006) and Singapore Prospective Study Program (SP2, 2004\u20132007), diagnosed with diabetes but no known history of CVD at baseline. Retinopathy and retinal vascular (arteriolar and venular) caliber measurements were added to risk prediction models derived from Cox regression model that included established CVD risk factors and serum biomarkers in SiMES, and validated this internally and externally in SP2. We found that the addition of retinal parameters improved discrimination compared to the addition of biochemical markers of estimated glomerular filtration rate (eGFR) and high-sensitivity C-reactive protein (hsCRP). This was even better when the retinal parameters and biomarkers were used in combination (C statistic 0.721 to 0.774, p\u2009=\u20090.013), showing improved discrimination, and overall reclassification (NRI\u2009=\u200917.0%, p\u2009=\u20090.004). External validation was consistent (C-statistics from 0.763 to 0.813, p\u2009=\u20090.045; NRI\u2009=\u200919.11%, p\u2009=\u20090.036). Our findings show that in persons with diabetes, retinopathy and retinal microvascular parameters add significant incremental value in reclassifying CVD risk, beyond established risk factors.<\/jats:p>","DOI":"10.1038\/srep41492","type":"journal-article","created":{"date-parts":[[2017,2,2]],"date-time":"2017-02-02T09:51:38Z","timestamp":1486029098000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Retinopathy Signs Improved Prediction and Reclassification of Cardiovascular Disease Risk in Diabetes: A prospective cohort study"],"prefix":"10.1038","volume":"7","author":[{"given":"Henrietta","family":"Ho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol Y.","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charumathi","family":"Sabanayagam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanfen","family":"Yip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Kamran","family":"Ikram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng Guan","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khuan Yew","family":"Chow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching Yu","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Shyong","family":"Tai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tien Yin","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,2,2]]},"reference":[{"key":"BFsrep41492_CR1","doi-asserted-by":"publisher","first-page":"945","DOI":"10.7326\/0003-4819-140-11-200406010-00035","volume":"140","author":"MM Engelgau","year":"2004","unstructured":"Engelgau, M. M., Geiss, L. S., Saaddine, J. B., Boyle, J. P., Benjamin, S. M. et al. The evolving diabetes burden in the United States. Ann Intern Med. 140, 945\u2013950 (2004).","journal-title":"Ann Intern Med"},{"key":"BFsrep41492_CR2","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1001\/archinternmed.2011.2","volume":"171","author":"SG Wannamethee","year":"2011","unstructured":"Wannamethee, S. G., Shaper, A. G., Whincup, P. H., Lennon, L. & Satter, N. Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors. Arch Intern Med. 171, 404\u2013410 (2011).","journal-title":"Arch Intern Med"},{"key":"BFsrep41492_CR3","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1007\/s11886-015-0607-7","volume":"17","author":"MO Gore","year":"2015","unstructured":"Gore, M. O., McGuire, D. K., Lingvay, I. & Rosenstock, J. Predicting cardiovascular risk in type 2 diabetes: the heterogeneity challenges. Curr Cardiol Rep. 17, 607 (2015).","journal-title":"Curr Cardiol Rep."},{"key":"BFsrep41492_CR4","doi-asserted-by":"publisher","first-page":"162","DOI":"10.2337\/dc07-9917","volume":"30","author":"JB Buse","year":"2007","unstructured":"Buse, J. B., Ginsberg, H. N., Bakris, G. L., Clark, N. G., Costa, F. et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care. 30, 162\u2013172 (2007).","journal-title":"Diabetes Care"},{"key":"BFsrep41492_CR5","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1111\/j.1464-5491.2005.01494.x","volume":"22","author":"R Guzder","year":"2005","unstructured":"Guzder, R., Gatling, w., Mullee, M. A., Mehta, R. & Byrne, C. D. Prognostic value of the Framingham cardiovascular risk equation and the UKPDS risk engine for coronary heart disease in newly diagnosed Type 2 diabetes: results from a United Kingdom study. Diabet Med. 22, 554\u201362 (2005).","journal-title":"Diabet Med"},{"key":"BFsrep41492_CR6","doi-asserted-by":"publisher","first-page":"277","DOI":"10.2337\/diacare.27.1.277","volume":"27","author":"I Protopsaltis","year":"2004","unstructured":"Protopsaltis, I., Konstantinopoulos, P. A., Kamaratos, A. V. & Melidonis, A. I. Comparative study of prognostic value for coronary disease risk between the UK prospective diabetes study and Framingham models. Diabetes Care. 27, 277\u20138 (2004).","journal-title":"Diabetes Care"},{"key":"BFsrep41492_CR7","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1001\/jama.286.2.180","volume":"286","author":"RB D\u2019Agostino Sr","year":"2001","unstructured":"D\u2019Agostino, R. B., Sr, Grundy, S., Sullivan, L. M. & Wilson, P. CHD Risk Prediction Group. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA 286, 180\u2013187 (2001).","journal-title":"JAMA"},{"key":"BFsrep41492_CR8","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1007\/s00125-010-1681-4","volume":"53","author":"AP Kengne","year":"2010","unstructured":"Kengne, A. P., Patel, A., Colagiuri, S., Heller, S., Hamet, P. et al. The Framingham and UK Prospective Diabetes Study (UKPDS) risk equations do not reliably estimate the probability of cardiovascular events in a large ethnically diverse sample of patients with diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) Study. Diabetologia 53, 821\u2013831 (2010).","journal-title":"Diabetologia"},{"key":"BFsrep41492_CR9","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1046\/j.1365-2796.2001.00789.x","volume":"249","author":"M Laakso","year":"2001","unstructured":"Laakso, M. Cardiovascular disease in type 2 diabetes: challenge for treatment and prevention. J Intern Med. 249, 225\u2013235 (2001).","journal-title":"J Intern Med"},{"key":"BFsrep41492_CR10","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1001\/jama.293.14.1737","volume":"293","author":"M Shlipak","year":"2005","unstructured":"Shlipak, M., Fried, L. F., Cushman, M., Manolio, T. A., Peterson, D. et al. Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JAMA 293, 1737\u20131745 (2005).","journal-title":"JAMA"},{"key":"BFsrep41492_CR11","doi-asserted-by":"publisher","first-page":"2631","DOI":"10.1056\/NEJMoa055373","volume":"355","author":"TJ Wang","year":"2006","unstructured":"Wang, T. J., Gona, P., Larson, M. G., Tofler, G. H., Levy, D. et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 355, 2631\u20132639 (2006).","journal-title":"N Engl J Med"},{"key":"BFsrep41492_CR12","doi-asserted-by":"publisher","first-page":"21","DOI":"10.7326\/0003-4819-145-1-200607040-00128","volume":"145","author":"N Cook","year":"2006","unstructured":"Cook, N., Buring, J. & Ridker, P. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med. 145, 21\u201329 (2006).","journal-title":"Ann Intern Med"},{"key":"BFsrep41492_CR13","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.atherosclerosis.2009.04.020","volume":"207","author":"H Iso","year":"2009","unstructured":"Iso, H., Cui, R., Date, C., Kikuchi, S. & Tamakoshi, A. JACC Study Group. C-reactive protein levels and risk of mortality from cardiovascular disease in Japanese: the JACC Study. Atherosclerosis. 207, 291\u2013297 (2009).","journal-title":"Atherosclerosis"},{"key":"BFsrep41492_CR14","doi-asserted-by":"crossref","unstructured":"Adler, A. I., Stevens, R. J., Manley, S. E., Bilous, R. W., Cull, C. A. et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 63, 225\u2013232.","DOI":"10.1046\/j.1523-1755.2003.00712.x"},{"key":"BFsrep41492_CR15","doi-asserted-by":"publisher","first-page":"164","DOI":"10.2337\/diacare.28.1.164","volume":"28","author":"JL Gross","year":"2005","unstructured":"Gross, J. L., de Azevedo, M. J., Silveiro, S. P., Canani, L. H., Caramori, M. L. et al. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 28, 164\u2013176 (2005).","journal-title":"Diabetes Care"},{"key":"BFsrep41492_CR16","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/S0039-6257(01)00234-X","volume":"46","author":"T Wong","year":"2001","unstructured":"Wong, T., Klein, R., Klein, B. E., Tielsch, J. M., Hubbard, L. et al. Retinal microvascular abnormalities and their relationship with hypertension, cardiovascular disease, and mortality. Surv Ophthalmol. 46, 59\u201380 (2001).","journal-title":"Surv Ophthalmol"},{"key":"BFsrep41492_CR17","doi-asserted-by":"publisher","first-page":"2402","DOI":"10.1161\/STROKEAHA.113.001738","volume":"44","author":"CY Cheung","year":"2013","unstructured":"Cheung, C. Y., Tay, W. T., Ikram, M. K., Ong, Y. T., De Silva, D. A. et al. Retinal microvascular changes and risk of stroke: the Singapore Malay Eye Study. Stroke. 44, 2402\u20132408 (2013).","journal-title":"Stroke"},{"key":"BFsrep41492_CR18","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1007\/s00125-015-3511-1","volume":"58","author":"C Cheung","year":"2015","unstructured":"Cheung, C., Ikram, M. K., Klein, R. & Wong, T. Y. The clinical implications of recent studies on the structure and function of the retinal microvasculature in diabetes. Diabetologia. 58, 871\u2013885 (2015).","journal-title":"Diabetologia"},{"key":"BFsrep41492_CR19","doi-asserted-by":"publisher","first-page":"750","DOI":"10.2337\/dc12-1554","volume":"36","author":"M Ikram","year":"2013","unstructured":"Ikram, M., Cheung, C. Y., Lorenzi, M., Klein, R., Jones, T. L. et al. Retinal vascular caliber as a biomarker for diabetes microvascular complications. Diabetes Care. 36, 750\u2013759 (2013).","journal-title":"Diabetes Care"},{"key":"BFsrep41492_CR20","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.amjcard.2008.02.094","volume":"102","author":"K McGeechan","year":"2008","unstructured":"McGeechan, K., Liew, G., Macaskill, P., Irwig, L., Klein, R. et al. Risk prediction of coronary heart disease based on retinal vascular caliber (from the Atherosclerosis Risk In Communities [ARIC] Study). Am J Cardiol. 102, 58\u201363 (2008).","journal-title":"Am J Cardiol"},{"key":"BFsrep41492_CR21","doi-asserted-by":"publisher","first-page":"2388","DOI":"10.1001\/archinte.166.21.2388","volume":"166","author":"T Wong","year":"2006","unstructured":"Wong, T., Kamineni, A., Klein, R., Sharrett, A. R., Klein, B. E. et al. Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study. Arch Intern Med. 166, 2388\u20132394 (2006).","journal-title":"Arch Intern Med"},{"key":"BFsrep41492_CR22","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.2337\/diacare.28.6.1383","volume":"28","author":"MV van Hecke","year":"2005","unstructured":"van Hecke, M. V., Dekker, J. M., Stehouwer, C. D., Polak, B. C., Fuller, J. H. et al. Diabetic retinopathy is associated with mortality and cardiovascular disease incidence: the EURODIAB prospective complications study. Diabetes Care. 28, 1383\u20131389 (2005).","journal-title":"Diabetes Care"},{"key":"BFsrep41492_CR23","doi-asserted-by":"publisher","first-page":"1917","DOI":"10.1001\/archinte.164.17.1917","volume":"164","author":"BE Klein","year":"2004","unstructured":"Klein, B. E., Klein, R., McBride, P. E., Cruickshanks, K. J., Palta, M. et al. Cardiovascular disease, mortality, and retinal microvascular characteristics in type 1 diabetes: Wisconsin epidemiologic study of diabetic retinopathy. Arch Intern Med. 164, 1917\u20131924 (2004).","journal-title":"Arch Intern Med"},{"key":"BFsrep41492_CR24","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1111\/j.1469-7580.2005.00395.x","volume":"206","author":"N Patton","year":"2005","unstructured":"Patton, N., Aslam, T., Macgillivray, T., Pattie, A., Deary, I. J. et al. Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J Anat. 206, 319\u2013348 (2005).","journal-title":"J Anat"},{"key":"BFsrep41492_CR25","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/BF00281542","volume":"21","author":"SE Smith","year":"1981","unstructured":"Smith, S. E., Smith, S. A. & Brown, P. M. Cardiac autonomic dysfunction in patients with diabetic retinopathy. Diabetologia. 21, 525\u2013528 (1981).","journal-title":"Diabetologia"},{"key":"BFsrep41492_CR26","doi-asserted-by":"publisher","first-page":"2540","DOI":"10.2337\/diacare.27.10.2540","volume":"27","author":"DS Fong","year":"2004","unstructured":"Fong, D. S., Aiello, L. P., Ferris, F. L., 3rd & Klein, R. Diabetic retinopathy. Diabetes Care. 27, 2540\u20132553 (2004).","journal-title":"Diabetes Care"},{"key":"BFsrep41492_CR27","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1111\/j.1464-5491.2007.02217.x","volume":"24","author":"AM Spijkerman","year":"2007","unstructured":"Spijkerman, A. M., Fall, M. A., Tarnow, L., Twisk, J. W., Lauritzen, E. et al. Endothelial dysfunction and low-grade inflammation and the progression of retinopathy in Type 2 diabetes. Diabet Med. 24, 969\u2013976 (2007).","journal-title":"Diabet Med"},{"key":"BFsrep41492_CR28","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1016\/j.jacc.2014.04.089","volume":"64","author":"BM Everett","year":"2014","unstructured":"Everett, B. M., Berger, J. S., Manson, J. E., Ridker, P. M. & Cook, N. R. B-type natriuretic pepetides improve cardiovascular disease risk prediction in a cohort of women. J Am Coll Cardiol. 64, 1789\u20131797 (2014).","journal-title":"J Am Coll Cardiol"},{"key":"BFsrep41492_CR29","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1093\/aje\/kwh101","volume":"159","author":"MS Pepe","year":"2004","unstructured":"Pepe, M. S., Janes, H., Longton, F., Leisenring, W. & Newcomb, P. Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. Am J Epidemiol. 159, 882\u2013890 (2004).","journal-title":"Am J Epidemiol"},{"key":"BFsrep41492_CR30","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1007\/s00125-009-1454-0","volume":"52","author":"P Chamnan","year":"2009","unstructured":"Chamnan, P., Simmons, R. K., Sharp, S. J., Griffin, S. J. & Wareham, N. J. Cardiovascular risk assessment scores for people with diabetes: a systematic review. Diabetologia. 52, 2001\u20132014 (2009).","journal-title":"Diabetologia"},{"key":"BFsrep41492_CR31","doi-asserted-by":"publisher","first-page":"e4215","DOI":"10.1136\/bmj.e4215","volume":"344","author":"C McGorrian","year":"2012","unstructured":"McGorrian, C. & Blake, G. J. The risks in risk prediction. BMJ. 344, e4215 (2012).","journal-title":"BMJ"},{"key":"BFsrep41492_CR32","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1097\/EDE.0000000000000018","volume":"25","author":"KF Kerr","year":"2014","unstructured":"Kerr, K. F., Wang, Z., Janes, H., McClelland, R. L., Psaty, B. M. et al. Net reclassification indices for evaluating risk-prediction instruments: a critical review. Epidemiology. 25, 114\u2013121 (2014).","journal-title":"Epidemiology"},{"key":"BFsrep41492_CR33","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1080\/09286580600878844","volume":"14","author":"AW Foong","year":"2007","unstructured":"Foong, A. W., Saw, S. M., Loo, J. L., Shen, S., Loon, S. C. et al. Rationale and methodology for a population-based study of eye diseases in Malay people: The Singapore Malay eye study (SiMES). Ophthalmic Epidemiol. 14, 25\u201335 (2007).","journal-title":"Ophthalmic Epidemiol"},{"key":"BFsrep41492_CR34","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1136\/jech.44.1.29","volume":"44","author":"K Hughes","year":"1990","unstructured":"Hughes, K., Yeo, P. P., Lun, K. C., Thai, A. C., Sothy, S. P. et al. Cardiovascular diseases in Chinese, Malays, and Indians in Singapore. II. Differences in risk factor levels. J Epidemiol Community Health. 44, 29\u201335 (1990).","journal-title":"J Epidemiol Community Health"},{"key":"BFsrep41492_CR35","doi-asserted-by":"publisher","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","volume":"150","author":"AS Levey","year":"2009","unstructured":"Levey, A. S., Stevens, L. A., Schmid, C. H., Zhang, Y. L., Castro, A. F., 3rd et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 150, 604\u2013612 (2009).","journal-title":"Ann Intern Med"},{"key":"BFsrep41492_CR36","doi-asserted-by":"publisher","first-page":"892","DOI":"10.7326\/0003-4819-151-12-200912150-00014","volume":"151","author":"C Sabanyagam","year":"2009","unstructured":"Sabanyagam, C., Wong, T. Y. & Tai, E. S. The CKD-EPI equation and MDRD study equation find similar prevalence of chronic kidney disease in Asian populations. Ann Intern Med. 151, 892\u2013893 (2009).","journal-title":"Ann Intern Med"},{"key":"BFsrep41492_CR37","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1016\/j.ophtha.2008.05.014","volume":"115","author":"T Wong","year":"2008","unstructured":"Wong, T., Cheung, N., Tay, W. T., Wang, J. J., Aung, T. et al. Prevalence and risk factors for diabetic retinopathy: the Singapore Malay Eye Study. Ophthalmology. 115, 1869\u20131875 (2008).","journal-title":"Ophthalmology"},{"key":"BFsrep41492_CR38","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1016\/j.ophtha.2003.09.039","volume":"111","author":"T Wong","year":"2004","unstructured":"Wong, T., Knudtson, M. D., Klein, R., Klein, B. E., Meur, S. M. et al. Computer-assisted measurement of retinal vessel diameters in the Beaver Dam Eye Study: methodology, correlation between eyes, and effect of refractive errors. Ophthalmology. 111, 1183\u20131190 (2004).","journal-title":"Ophthalmology"},{"key":"BFsrep41492_CR39","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1161\/CIRCULATIONAHA.107.699579","volume":"117","author":"RB D\u2019Agostino Sr","year":"2008","unstructured":"D\u2019Agostino, R. B., Sr, Vasan, R. S., Pencina, M. J., Wolf, P. A., Cobain, M. et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 117, 745\u2013753 (2008).","journal-title":"Circulation"},{"key":"BFsrep41492_CR40","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1002\/sim.4780030207","volume":"3","author":"FE Harrell Jr","year":"1984","unstructured":"Harrell, F. E., Jr, Lee, K. L., Califf, R. M., Pryor, D. B. & Rosati, R. A. Regression modelling strategies for improved prognostic prediction. Stat Med. 3, 143\u2013152 (1984).","journal-title":"Stat Med"},{"key":"BFsrep41492_CR41","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1002\/sim.2929","volume":"27","author":"MJ Pencina","year":"2008","unstructured":"Pencina, M. J., D\u2019Agostino, R. B., Sr, D\u2019Agostino, R. B., Jr & Vasan, R. S. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 27, 157\u2013172 (2008).","journal-title":"Stat Med"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep41492.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep41492","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep41492.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,24]],"date-time":"2022-12-24T00:29:58Z","timestamp":1671841798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep41492"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,2]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,2,20]]}},"alternative-id":["BFsrep41492"],"URL":"https:\/\/doi.org\/10.1038\/srep41492","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,2]]},"assertion":[{"value":"3 August 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 December 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"41492"}}