Abstract
Aims/hypothesis: Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP. Methods: Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard. Results: Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity. Conclusions/interpretation: We established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.
| Original language | English |
|---|---|
| Pages (from-to) | 1856-1861 |
| Number of pages | 6 |
| Journal | Diabetologia |
| Volume | 61 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 1 Aug 2018 |
| Externally published | Yes |
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In: Diabetologia, Vol. 61, No. 8, 01.08.2018, p. 1856-1861.
Research output: Contribution to journal › Review article › peer-review
TY - JOUR
T1 - Corneal confocal microscopy for identification of diabetic sensorimotor polyneuropathy
T2 - a pooled multinational consortium study
AU - Perkins, Bruce A.
AU - Lovblom, Leif E.
AU - Bril, Vera
AU - Scarr, Daniel
AU - Ostrovski, Ilia
AU - Orszag, Andrej
AU - Edwards, Katie
AU - Pritchard, Nicola
AU - Russell, Anthony
AU - Dehghani, Cirous
AU - Pacaud, Danièle
AU - Romanchuk, Kenneth
AU - Mah, Jean K.
AU - Jeziorska, Maria
AU - Marshall, Andrew
AU - Shtein, Roni M.
AU - Pop-Busui, Rodica
AU - Lentz, Stephen I.
AU - Boulton, Andrew J.M.
AU - Tavakoli, Mitra
AU - Efron, Nathan
AU - Malik, Rayaz A.
N1 - Funding Information: Funding This report was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH (grant no. 1DP3DK104386-01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Initially, four of the study centres were funded by JDRF (Brisbane, Calgary, Manchester, Toronto) and one by a Michigan Diabetes Research and Training Center grant (Michigan P30DK020572). Some aspects of the Toronto project were funded by a Diabetes Canada (formerly the Canadian Diabetes Association) operating grant; other aspects of the Manchester projects have received funding from NIH (5RO1-NS46259-03, R01DK077903-01A1 NINDS). We acknowledge the contributions of the Steven and Ofra Menkes Fund for supporting aspects of this research in Toronto. The funding sources played no role in study design, in the collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the paper for publication. Funding Information: Duality of interest BAP reports grants from CIHR, NIH and JDRF, speaker honoraria from Medtronic, Johnson & Johnson, Insulet, Abbott, Novo Nordisk and Sanofi and research grant support from Medtronic and Boehringer Ingelheim and serves as a consultant for Boehringer Ingelheim, Insulet and Novo Nordisk. NE reports grants from JDRF and NHMRC during the conduct of the study. DP reports grants from NIH RFA DK-13-027 and grants from JDRF during the conduct of the study. JKM has received research grants from Eli Lilly, Pfizer, Bristol-Myers Squibb, PTC Therapeutics, Sanofi Genzyme, Novartis, ReveraGen Pharma and Biogen. SIL reports grants from NIH-DHHS-US through a consortium with Mount Sinai Hospital and grants from NIH-NIDDK Michigan Diabetes Research Center Diabetes Interdisciplinary Study Grant during the conduct of the study. All other authors declare that there is no duality of interest associated with their contribution to this manuscript. Funding Information: We acknowledge the generous support of Randy and Jenny Frisch and The Harvey and Annice Frisch Family Fund and the contributions of the Steven and Ofra Menkes Fund, who supported work at the University of Toronto. Parts of this study were presented in abstract form at the following meetings: the American Diabetes Association 77th Scientific Sessions, San Diego, CA, USA, June 2017; the Canadian Diabetes Association and the Canadian Society of Endocrinology and Metabolism 19th Annual Professional Conference and Annual Meetings, Ottawa, ON, Canada, October 2016 and 26th Annual Meeting of the Diabetic Neuropathy Study Group of the EASD (NEURODIAB), Bucharest, Romania, September 2016. All authors participated in data acquisition and interpretation, reviewed the manuscript for scholarly content and accuracy and gave approval for the final draft. BAP, NE and RAM designed the study. BAP, LEL and RAM contributed to data interpretation and wrote the first draft of the manuscript. LEL was responsible for statistical analysis, with contributions from DS and IO. BAP had full access to all the data in the study and had final responsibility for the decision to submit for publication. Bruce A. Perkins and Leif E. Lovblom are co-primary authors. BAP reports grants from CIHR, NIH and JDRF, speaker honoraria from Medtronic, Johnson & Johnson, Insulet, Abbott, Novo Nordisk and Sanofi and research grant support from Medtronic and Boehringer Ingelheim and serves as a consultant for Boehringer Ingelheim, Insulet and Novo Nordisk. NE reports grants from JDRF and NHMRC during the conduct of the study. DP reports grants from NIH RFA DK-13-027 and grants from JDRF during the conduct of the study. JKM has received research grants from Eli Lilly, Pfizer, Bristol-Myers Squibb, PTC Therapeutics, Sanofi Genzyme, Novartis, ReveraGen Pharma and Biogen. SIL reports grants from NIH-DHHS-US through a consortium with Mount Sinai Hospital and grants from NIH-NIDDK Michigan Diabetes Research Center Diabetes Interdisciplinary Study Grant during the conduct of the study. All other authors declare that there is no duality of interest associated with their contribution to this manuscript. Funding Information: Acknowledgements We acknowledge the generous support of Randy and Jenny Frisch and The Harvey and Annice Frisch Family Fund and the contributions of the Steven and Ofra Menkes Fund, who supported work at the University of Toronto. Parts of this study were presented in abstract form at the following meetings: the American Diabetes Association 77th Scientific Sessions, San Diego, CA, USA, June 2017; the Canadian Diabetes Association and the Canadian Society of Endocrinology and Metabolism 19th Annual Professional Conference and Annual Meetings, Ottawa, ON, Canada, October 2016 and 26th Annual Meeting of the Diabetic Neuropathy Study Group of the EASD (NEURODIAB), Bucharest, Romania, September 2016. Publisher Copyright: © 2018, The Author(s). Funding Information: Funding This report was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH (grant no. 1DP3DK104386-01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Initially, four of the study centres were funded by JDRF (Brisbane, Calgary, Manchester, Toronto) and one by a Michigan Diabetes Research and Training Center grant (Michigan P30DK020572). Some aspects of the Toronto project were funded by a Diabetes Canada (formerly the Canadian Diabetes Association) operating grant; other aspects of the Manchester projects have received funding from NIH (5RO1-NS46259-03, R01DK077903-01A1 NINDS). We acknowledge the contributions of the Steven and Ofra Menkes Fund for supporting aspects of this research in Toronto. The funding sources played no role in study design, in the collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the paper for publication. Funding Information: We acknowledge the generous support of Randy and Jenny Frisch and The Harvey and Annice Frisch Family Fund and the contributions of the Steven and Ofra Menkes Fund, who supported work at the University of Toronto. Parts of this study were presented in abstract form at the following meetings: the American Diabetes Association 77th Scientific Sessions, San Diego, CA, USA, June 2017; the Canadian Diabetes Association and the Canadian Society of Endocrinology and Metabolism 19th Annual Professional Conference and Annual Meetings, Ottawa, ON, Canada, October 2016 and 26th Annual Meeting of the Diabetic Neuropathy Study Group of the EASD (NEURODIAB), Bucharest, Romania, September 2016. All authors participated in data acquisition and interpretation, reviewed the manuscript for scholarly content and accuracy and gave approval for the final draft. BAP, NE and RAM designed the study. BAP, LEL and RAM contributed to data interpretation and wrote the first draft of the manuscript. LEL was responsible for statistical analysis, with contributions from DS and IO. BAP had full access to all the data in the study and had final responsibility for the decision to submit for publication. Bruce A. Perkins and Leif E. Lovblom are co-primary authors. BAP reports grants from CIHR, NIH and JDRF, speaker honoraria from Medtronic, Johnson & Johnson, Insulet, Abbott, Novo Nordisk and Sanofi and research grant support from Medtronic and Boehringer Ingelheim and serves as a consultant for Boehringer Ingelheim, Insulet and Novo Nordisk. NE reports grants from JDRF and NHMRC during the conduct of the study. DP reports grants from NIH RFA DK-13-027 and grants from JDRF during the conduct of the study. JKM has received research grants from Eli Lilly, Pfizer, Bristol-Myers Squibb, PTC Therapeutics, Sanofi Genzyme, Novartis, ReveraGen Pharma and Biogen. SIL reports grants from NIH-DHHS-US through a consortium with Mount Sinai Hospital and grants from NIH-NIDDK Michigan Diabetes Research Center Diabetes Interdisciplinary Study Grant during the conduct of the study. All other authors declare that there is no duality of interest associated with their contribution to this manuscript. Funding Information: Acknowledgements We acknowledge the generous support of Randy and Jenny Frisch and The Harvey and Annice Frisch Family Fund and the contributions of the Steven and Ofra Menkes Fund, who supported work at the University of Toronto. Parts of this study were presented in abstract form at the following meetings: the American Diabetes Association 77th Scientific Sessions, San Diego, CA, USA, June 2017; the Canadian Diabetes Association and the Canadian Society of Endocrinology and Metabolism 19th Annual Professional Conference and Annual Meetings, Ottawa, ON, Canada, October 2016 and 26th Annual Meeting of the Diabetic Neuropathy Study Group of the EASD (NEURODIAB), Bucharest, Romania, September 2016. Publisher Copyright: © 2018, The Author(s).
PY - 2018/8/1
Y1 - 2018/8/1
N2 - Aims/hypothesis: Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP. Methods: Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard. Results: Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity. Conclusions/interpretation: We established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.
AB - Aims/hypothesis: Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP. Methods: Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard. Results: Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity. Conclusions/interpretation: We established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.
KW - Corneal confocal microscopy
KW - Corneal nerves
KW - Diabetic neuropathy
KW - Diabetic sensorimotor polyneuropathy
KW - Small nerve fibre morphology
UR - http://www.scopus.com/inward/record.url?scp=85048000979&partnerID=8YFLogxK
U2 - 10.1007/s00125-018-4653-8
DO - 10.1007/s00125-018-4653-8
M3 - Review article
C2 - 29869146
AN - SCOPUS:85048000979
SN - 0012-186X
VL - 61
SP - 1856
EP - 1861
JO - Diabetologia
JF - Diabetologia
IS - 8
ER -