Abstract
Type 1 diabetes (T1D) is characterized by pancreatic beta cell dysfunction and insulin depletion. Over 40% of people with T1D manage their glucose through multiple injections of long-acting basal and short-acting bolus insulin, so-called multiple daily injections (MDI)1,2. Errors in dosing can lead to life-threatening hypoglycaemia events (<70 mg dl−1) and hyperglycaemia (>180 mg dl−1), increasing the risk of retinopathy, neuropathy, and nephropathy. Machine learning (artificial intelligence) approaches are being harnessed to incorporate decision support into many medical specialties. Here, we report an algorithm that provides weekly insulin dosage recommendations to adults with T1D using MDI therapy. We employ a unique virtual platform3 to generate over 50,000 glucose observations to train a k-nearest neighbours4 decision support system (KNN-DSS) to identify causes of hyperglycaemia or hypoglycaemia and determine necessary insulin adjustments from a set of 12 potential recommendations. The KNN-DSS algorithm achieves an overall agreement with board-certified endocrinologists of 67.9% when validated on real-world human data, and delivers safe recommendations, per endocrinologist review. A comparison of inter-physician-recommended adjustments to insulin pump therapy indicates full agreement of 41.2% among endocrinologists, which is consistent with previous measures of inter-physician agreement (41–45%)5. In silico3,6 benchmarking using a platform accepted by the United States Food and Drug Administration for evaluation of artificial pancreas technologies indicates substantial improvement in glycaemic outcomes after 12 weeks of KNN-DSS use. Our data indicate that the KNN-DSS allows for early identification of dangerous insulin regimens and may be used to improve glycaemic outcomes and prevent life-threatening complications in people with T1D.
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Data availability
The data generated in silico during this study and the code used for analysis is available from the corresponding author on reasonable request. Access to human participant data was granted for the current study, and further human data usage or sharing is subject to restrictions and is not publicly available. Requests for restricted, de-identified data on human participants can be submitted to the corresponding authors at OHSU. Requests will be assessed on a case-by-case basis, and are subject to a formal Repository Sharing Agreement. Additional reported outcomes of human participants can be found at https://clinicaltrials.gov under registration number NCT03443713.
Code availability
The code used to generate in silico data for this study, the OHSU virtual patient population simulator code, is available at https://github.com/petejacobs/T1D_VPP. Access to the licensed software for the UVA–Padova virtual population was granted for the current study and it can be requested from the developers of this software directly at the University of Padova.
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Acknowledgements
The guarantor of this research is Peter G. Jacobs who takes responsibility for the contents of the article. Correspondence and requests for materials can be addressed to Nichole S. Tyler and Peter G. Jacobs. The authors thank Gavin Young for his contributions to algorithm methodology. The authors disclose receipt of the following financial support for the research, authorship, and/or publication of the article: this work was supported by The Leona M. and Harry B. Helmsley Charitable Trust (grant 2018PG-T1D001), the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (grant 1 R01DK120367-01) and a Dexcom grant.
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N.S.T., C.M.M.-L., R.H.D. and P.G.J. contributed to the design of the published decision support engine algorithm. N.S.T. and C.M.M.-L. performed the additional evaluations of decision support engine performance. N.S.T., C.M.M.-L., R.H.D., W.W.H. and P.G.J. designed and discussed strategies for engine evaluation and outcomes metrics. L.M.W., J.R.C. and J.E.Y. served as physicians collecting human clinical trial data, contributed to the design of the quality control algorithm, and performed a safety evaluation of the algorithm. D.L.B., V.B.G. and F.H.G. collected and managed the human data used to evaluate the decision support engine.
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The authors declare the following competing interests regarding research, authorship and publication of this article: J.R.C. and P.G.J. have financial interest in Pacific Diabetes Technologies Inc. (PDT), a company with potential commercial interests in the results and research of this technology. J.R.C. and P.G.J. are founders and shareholders in PDT and P.G.J. is a board member of PDT. Neither J.R.C. nor P.G.J. receive any financial compensation from PDT as consultants or otherwise, beyond shares in the company. J.R.C. and P.G.J. have received honoraria for consulting and research support from Dexcom. Although the methods on the algorithm were disclosed to the OHSU Technology Transfer Office, there has not yet been a patent filed on the algorithm and PDT does not have any rights to any of the technology described in the paper. N.S.T., C.M.M., R.H.D., L.M.W., D.L.B., V.B.G., F.H.G., W.W.H. and J.E.Y. declare no competing interests.
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Extended data
Extended Data Fig. 1 Quality control algorithm to assess need for insulin titration.
Quality control algorithm to assess need for insulin titration. User data and glycemic outcomes are loaded and compared against metrics for percent time in hypoglycaemia, percent time in target range, and percent time in serious hypoglycaemia. If users meet all metrics, recommendations for insulin titration are not required.
Extended Data Fig. 2 Quality control algorithm to assess increasing basal insulin dosage.
Quality control algorithm to assess increasing basal insulin dosage. User features and glycemic outcomes are loaded by the algorithm and assessed for physician-informed metrics of nocturnal hypoglycaemia, near hypoglycaemia episodes, subject time in target range, subject adherence, and insulin formulation-dependent requirements.
Extended Data Fig. 3 Quality control algorithm to assess decreasing basal insulin dosage.
Quality control algorithm to assess decreasing basal insulin dosage. User features and glycemic outcomes are loaded by the algorithm and assessed for subject adherence, and insulin formulation-dependent requirements.
Extended Data Fig. 4 Quality control algorithm to assess increasing meal bolus insulin dosage.
Quality control algorithm to assess increasing meal bolus insulin dosage. User features and glycemic outcomes are loaded by the algorithm and assessed for physician-informed metrics of postprandial hypoglycaemia, subject adherence, and factors returned by the ALPHA algorithm.
Extended Data Fig. 5 Quality control algorithm to assess decreasing meal bolus insulin dosage.
Quality control algorithm to assess decreasing meal bolus insulin dosage. User features and glycemic outcomes are loaded by the algorithm and assessed for physician-informed metrics of postprandial severe hyperglycaemia, subject adherence, and factors returned by the ALPHA algorithm.
Extended Data Fig. 6 Quality control algorithm to assess increasing correction bolus insulin dosage.
Quality control algorithm to assess increasing correction bolus insulin dosage. User features and glycemic outcomes are loaded by the algorithm and assessed for physician-informed metrics of postprandial and correction-related hypoglycaemia, subject adherence, and factors returned by the ALPHA algorithm.
Extended Data Fig. 7 Quality control algorithm to assess decreasing correction bolus insulin dosage.
Quality control algorithm to assess decreasing correction bolus insulin dosage. User features and glycemic outcomes are loaded by the algorithm and assessed for physician-informed metrics of subject adherence, postprandial and correction-related hypoglycaemia, and factors returned by the ALPHA algorithm.
Extended Data Fig. 8 KNN-DSS engine performance in improving subject outcomes in an independent virtual patient population.
KNN-DSS engine performance in improving subject outcomes in an independent virtual patient population. Glycemic outcomes during a 52-week study of the FDA-approved UVA-Padova virtual patient simulator. Percent time in hypoglycaemia is indicated by the blue circular radius.
Extended Data Fig. 9 Outcomes of a human pilot study evaluating KNN-DSS augmented decision support.
Outcomes of a human pilot study evaluating KNN-DSS augmented decision support over 4 weeks where the first recommendation is given at the start of week 2. For panels a-f, boxplot limits indicate the first and third quartiles, centerline indicates the median, and whiskers mark the last non-outlier data-point within 1.5xIQR. For panels a-f, participant data collected during week 1 and the final week were compared using a two-tailed Wilcoxon signed-rank test, with significance level of 5%. a, Frequency of hypoglycaemia was nominally reduced on the final week compared with week 1 of the study (0.86 vs 0.64, P = 0.051, n = 16 independent subjects). b Serious hypoglycaemia was nominally reduced on the final week compared with week 1 of the study (0.34% vs. 0.19%, P = 0.56, n = 16 independent subjects). c Postprandial hypoglycaemia events were nominally reduced on the final week compared with week 1 (0.29 vs 0.14, P = 0.08, n = 16 independent subjects). d Frequency of overnight hypoglycaemia was significantly reduced on the final week compared to week 1 (0.50 to 0.29, P= 0.04, n = 16 independent subjects). e Serious hypoglycaemia overnight was significantly reduced on the final week compared to week 1 (0.48% to 0.11%, P = 0.03, n = 16 independent subjects). f Postprandial hypoglycaemia overnight was nominally reduced on the final week compared to week 1 (0.14 to 0. 07, P = 0.06, n = 16 independent subjects).
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Tyler, N.S., Mosquera-Lopez, C.M., Wilson, L.M. et al. An artificial intelligence decision support system for the management of type 1 diabetes. Nat Metab 2, 612–619 (2020). https://doi.org/10.1038/s42255-020-0212-y
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DOI: https://doi.org/10.1038/s42255-020-0212-y
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