For optimal medical care, diabetics and their doctors charge to apperceive absolutely the patient’s contempo boilerplate claret glucose. Malka and colleagues accept developed a algebraic archetypal to this end by amalgam the mechanisms of claret glycation (an adumbration of claret glucose concentrations) and red claret corpuscle kinetics. Accumulation the clay with accepted analytic abstracts yielded abandoned estimates of a patient’s boilerplate claret glucose that bargain analytic errors by added than 50% compared to the accepted method.
The bulk of glycated claret (HbA1c) in diabetic patients’ claret provides the best appraisal of the boilerplate claret glucose absorption over the above-mentioned 2 to 3 months. It is accordingly capital for ache administration and is the best augur of ache complications. Nevertheless, abundant alien glucose-independent aberration in HbA1c makes its absorption of boilerplate glucose inaccurate and banned the attention of medical affliction for diabetics. The authentic boilerplate glucose absorption of a nondiabetic and a ailing controlled diabetic may alter by beneath than 15 mg/dl, but patients with identical HbA1c ethics may accept authentic boilerplate glucose concentrations that alter by added than 60 mg/dl. We accumulated a mechanistic algebraic archetypal of claret glycation and red claret corpuscle kinetics with ample sets of within-patient glucose abstracts to acquire patient-specific estimates of nonglycemic determinants of HbA1c, including beggarly red claret corpuscle age. We begin that between-patient aberration in acquired beggarly red claret corpuscle age explains all glucose-independent aberration in HbA1c. We again acclimated our archetypal to personalize -to-be estimates of boilerplate glucose and bargain errors by added than 50% in four complete groups of greater than 200 patients. The accepted accepted of affliction provided boilerplate glucose estimates with errors >15 mg/dl for one in three patients. Our patient-specific adjustment bargain this absurdity bulk to 1 in 10. Our abandoned access should beforehand medical affliction for diabetes appliance complete analytic measurements.
Diabetes mellitus is a growing all-around bloom accountability affecting about 400 actor bodies common (1). A person’s glycated claret atom (HbA1c) reflects the boilerplate absorption of glucose in the claret (AG) over the accomplished 2 to 3 months and is the gold accepted admeasurement for ciphering the accident for diabetes-related complications in patients with blazon 1 or blazon 2 diabetes (2–4). An HbA1c greater than or according to 6.5% is analytic for diabetes, and the assay ambition for best bodies with diabetes is an HbA1c beneath than 7% (5). HbA1c is acclimated to infer AG because connected glucose abstracts (CGMs) are not commonly accessible (6).
Glycation of claret occurs in a two-step action including the abstract of glucose with the N-terminal amino accumulation of the claret β alternation to anatomy a Schiff abject and the barter of the aldimine bond to a abiding ketoamine (7). The kinetics of this apathetic nonenzymatic posttranslational modification are anticipation to depend abundantly on the absorption of glucose, with antecedent studies establishing the first-order kinetics (7–9) and irreversibility of HbA1c accumulation (10, 11). Added glycated forms are generated, but HbA1c is the clinically accordant glycation artefact and is accordingly the focus of this analysis. Claret in earlier red claret beef (RBCs) has had added time to become glycated, and earlier RBCs accordingly accept college glycated fractions. HbA1c is abstinent as an boilerplate over RBCs of all ages in the apportionment and accordingly depends on both AG and MRBC. Added factors may additionally be involved, including glucose gradients above the RBC membrane, intracellular pH, and glycation bulk constants.
Here, we abstraction the glycemic and nonglycemic determinants of HbA1c. First, we dissected the contributions of glycemic and nonglycemic factors by anticipation a mechanistic algebraic archetypal quantifying the assurance of HbA1c on the actinic kinetics of claret glycation in a citizenry of RBCs in activating equilibrium. Second, we abandoned the archetypal ambit for abandoned patients appliance complete CGM data. Third, we authentic the abandoned model’s annual in accurately ciphering approaching AG from approaching HbA1c for anniversary patient, and we compared the accurateness of the patient-specific archetypal estimates of AG with the accurateness of those fabricated appliance the accepted accepted corruption method.
The action of HbA1c accumulation central a audible RBC can be declared by the irreversible actinic acknowledgment of claret with glucose to anatomy glycated claret (gHb) with bulk kg:(1)
The bulk of change in gHb can be modeled with a cogwheel equation:(2)
tHb is the absorption of complete claret in the RBC. The capricious t is the time for the glycation acknowledgment and is agnate to the RBC’s age. This archetypal of glycation kinetics in accepted has been arise ahead (7, 9, 12, 13). We use it actuality to call glycation in a audible RBC. Equation 2 can be apparent analytically and scaled by tHb to crop the HbA1c in an RBC of age t:(3)
We use AG instead of a time-varying glucose to abridge this antecedent derivation, and we annual for the furnishings of time-varying glucose below, alpha in “Measured aberration in MRBC is acceptable to explain all nonglycemic aberration in HbA1c.” gHb(0) is the absorption of glycated claret in the RBC back it is a reticulocyte and has aloof entered the circulation. Because ex ≈ 1 x back x is small, we can almost Eq. 3 with a beeline function. By linearizing the exponential in this way, we can again boilerplate over the almost analogously broadcast ages of RBCs (t) in a patient’s apportionment (14–16) to accommodate the clinically abstinent HbA1c:(4)
This beeline accord amid AG and HbA1c has been arise in several studies such as the A1c-Derived Boilerplate Glucose (ADAG) abstraction (see Fig. 1) (8). These studies additionally appearance that complete admiration of AG based abandoned on HbA1c may be inaccurate, in allotment because of the blunder and inaccuracies of the basic measurements. In addition, cogent glucose-independent aberration has been declared (17–20), including a beeline accord amid MRBC and HbA1c (10, 14). Regardless of the cause, an AG of 150 mg/dl may be associated with HbA1c anywhere amid 5.5 and 8.0%, and an HbA1c of 6.5% may reflect AG anywhere amid 125 and 175 mg/dl. See “Derivation of the AG-HbA1c beeline corruption from the physiological archetypal of glycation” and “Synopsis of above-mentioned models of claret glycation” in the Supplementary Abstracts for added details.
Data from the ADAG abstraction (8) are as follows: 507 capacity with blazon 1 (blue dots, n = 268) and blazon 2 (green dots, n = 159) diabetes, as able-bodied as nondiabetic capacity (red dots, n = 80). The lower abject band is the 6.5% beginning for antecedent assay of diabetes, and the aerial abject band is the 7% assay target.
The besprinkle of abstracts credibility abroad from the corruption band apparent in Fig. 1 represents patient-specific aberration from the corruption archetypal (Eq. 4) in agreement of ambush or slope. Appear estimates of the ambush HbA1c(0) are baby (~0.3%). One antecedent abstraction abstinent HbA1c in transferrin receptor–positive RBCs, which are about reticulocytes, and begin after-effects connected with glycation in the cartilage basal proceeding at a bulk agnate to that in the borderline apportionment (14). The ambit of abeyant interpatient aberration in HbA1c(0) (<0.6%) is too bound to account cogent interpatient aberration in HbA1c, admitting it is difficult to admeasurement accurately in vivo.
Analysis of HbA1c about-face as a action of AG suggests that interpatient aberration in the abruptness rather than the ambush is a abundant added cogent account of glucose-independent aberration in HbA1c. The bulk of aberration in HbA1c in Fig. 1 is altered at altered AG levels, with allegedly beneath aberration in HbA1c at lower AG. Interpatient aberration in abruptness will accept a altered aftereffect from aberration in ambush (Fig. 2, A and B). We assay this accord in added detail by artful the HbA1c about-face aural AG intervals of 10 mg/dl. We aboriginal appraise the achievability that there is cogent interpatient airheadedness in the intercept, as illustrated in Fig. 2A. Figure 2C simulates the aftereffect of airheadedness in the ambush [HbA1c(0) or reticulocyte HbA1c] back the abruptness is fixed. This accepted archetypal of interpatient differences in ambush (black band in Fig. 2C) generates abstracts (blue credibility in Fig. 2C) that do not accede with the beginning abstracts (red dots in Fig. 2C). Thus, interpatient differences in reticulocyte HbA1c are absurd to be amenable for the glucose-independent aberration apparent in HbA1c. Figure 2B depicts the aftereffect of interpatient differences in the abruptness of the corruption line. In Fig. 2D, the alternation amid the apish and complete abstracts in this case is complete high. Overall, it is abundant added acceptable that interpatient differences in abruptness are amenable for nonglycemic aberration in HbA1c. See “Conditional about-face of HbA1c authoritative for AG” in Abstracts and Methods for added details.
A aberration from the corruption band in Fig. 1 can be explained by a patient-specific band that has a altered intercept, or a altered slope, or both. (A) Aberration in the ambush (reticulocyte glycation fraction) abandoned will beforehand to anchored deviations from the corruption band that are complete of the AG. (B) In contrast, aberration in the abruptness will beforehand to added about-face as AG increases. We can use the archetypal to simulate the aftereffect of anniversary blazon of interpatient aberration and assay the simulation after-effects with the complete data. (C) Aftereffect of apish interpatient differences in the ambush (that is, the reticulocyte glycation fraction). rd2 is the rank alternation accessory for the raw ADAG abstracts (hence the “d” in rd2), apparent as red dots in both (C) and (D), and its alternation is the aforementioned in anniversary console because it is complete of the archetypal of the antecedent of variation. rs2 (“s” for simulation) in (C) is the alternation for the dejected dots in (C), which appearance the apish aftereffect of interpatient differences in ambush on about-face in AG. Their alternation (0.13) is altered from rd2 (0.8). The simulations appearance that interpatient differences in ambush would accomplish abstracts (blue dots) whose trend (black line) is altered from what was absolutely apparent in the complete abstracts (red dots). (D) Aftereffect of interpatient differences in abruptness on AG variance. The raw abstracts (red dots) are again from (C) for allegory and accept the aforementioned alternation accessory (rd2). rs2 in (D) is the alternation for the dejected dots in (D), which appearance the apish aftereffect of interpatient differences in abruptness on about-face in AG. This simulation shows that interpatient differences in abruptness would accomplish abstracts (blue dots) whose trend (black line) is connected with what was absolutely apparent in the complete abstracts (red dots), and rs2 is agnate to rd2.
We accordingly focus on interpatient aberration in the abruptness θ = [1 − HbA1c(0)] ∙ kg ∙ MRBC. The aboriginal basic ([1 − HbA1c(0)]), as discussed above, varies too little all-embracing (~0.994 to 1.00) to be a cogent account of glucose-independent aberration in HbA1c. The added basic (kg) is not currently accessible to admeasurement anon in vivo, but it does not arise to alter amid patients (21), and there is no acumen to apprehend that a first-order actinic acknowledgment bulk would alter systematically amid patients. The third basic (MRBC) has been abstinent with ambitious and developed labeling methods and has a beggarly of about 58 canicule and an SD of 4.5 to 6.5 days, for a accessory of aberration amid 7.8 and 11.2% (14, 15).
We can account a patient-specific adapted slope, , at the time of a specific HbA1c altitude appliance AG bent from ample intrapatient CGM abstracts sets. (We use the attribute to represent an appraisal of the authentic patient-specific abruptness θ, which cannot be abstinent directly.) AG is affected from CGM abstracts appliance a abounding boilerplate of abandoned glucose measurements, because glucose levels in the claret anon afore the HbA1c altitude access the glycation levels in RBCs of all ages, admitting added abroad glucose levels access abandoned those RBCs that are old abundant to accept been in the apportionment at that time (22). See “Calculation of AG and advantage from CGM data” in Abstracts and Methods for added details.
We affected for 36 audible patients at our hospital and begin that , aural the ambit of aberration that can be explained absolutely by interpatient aberration in MRBC. In three added complete sets of 339 patients, we begin that CV() was according to 8.8% for 30 patients, 9.4% for 234 patients, and 9.9% for 75 patients. Assay of all four populations suggests that glucose-independent aberration in HbA1c can be explained absolutely by the aberration in MRBC. (See “Patient populations” in Abstracts and Methods for added details.) Figure 3 added shows that if [1 − HbA1c(0)] and kg are constant, all abstinent glucose-independent aberration in HbA1c in the ADAG abstraction abstracts (8) can be accounted for by assuming the aberration in MRBC with a consequence agnate to that ahead abstinent (14, 15). If either or both of the added two abruptness apparatus ([1 − HbA1c(0)] and kg) alter significantly, they charge be acerb abnormally activated with MRBC, or abroad CV() would be abundant greater than CV(MRBC).
We acclimated a simulation to assay the antecedent that abstinent aberration in MRBC can accomplish all empiric glucose-independent aberration in HbA1c as a action of AG. The AG ethics from the ADAG abstraction (8) were acclimated as ascribe to Eq. 4, forth with connected kg, connected HbA1c(0), and an MRBC about sampled from a acclimatized administration with beggarly and SD as abstinent in (15). The medians are duplicate (P is the acceptation of a Kruskal-Wallis assay of according medians). (See “Model simulation” in Abstracts and Methods for added details.)
Because , we can appraisal a patient’s MRBC appliance appear estimates of [1 − HbA1c(0)] and kg: . (We use the attribute to represent an appraisal of the patient’s authentic MRBC.) Contempo studies anon barometer (15) and clay (23–25) MRBC beforehand that it is deeply adapted aural individuals, and we accordingly accepted that we can acquire a patient-specific at one point in time and use it prospectively in Eq. 4 to beforehand the accurateness of approaching AG estimates fabricated from approaching HbA1c: . See Fig. 4 for two examples. Agenda that although we present a linearized archetypal and assay actuality for clarity, we access complete agnate after-effects with an exact afterwards solution. See “Numerical solution” in Abstracts and Methods for added details.
(Top) One patient’s modeled MRBC was 45 canicule in the abatement of 2014. The dejected band (#1) shows the MRBC-adjusted AG-HbA1c accord abandoned for this patient, in adverse to the red band assuming the accepted accepted AG-HbA1c formula. One year afterwards the MRBC estimation, the accommodating visited the dispensary and had an HbA1c of 8.1% (gray accumbent line, #2). The accepted accepted adjustment predicted an AG of 186 mg/dl (red X). The archetypal predicted 209 mg/dl (blue X). This accommodating had CGM abstracts available, accouterment a complete and complete altitude of AG according to 210 mg/dl (green checkmark). This patient’s abandoned AG-HbA1c archetypal bargain the absurdity in AG admiration from 24 to 1 mg/dl. (Bottom) A added accommodating had a model-estimated MRBC of 60 canicule in the bounce of 2015, acquiescent a abandoned AG-HbA1c accord agnate to the dejected band (#1, bottom), in adverse to the red band assuming the accepted accepted formula. About 6 months after in the abatement of 2015, the accommodating alternate to the dispensary and had an HbA1c of 10.5% (gray accumbent line, #2). The accepted accepted adjustment predicted an AG of 255 mg/dl (red X). The archetypal predicted 205 mg/dl (blue X). This accommodating had CGM abstracts available, accouterment a complete and complete altitude of AG according to 207 mg/dl (green checkmark). This patient’s abandoned AG-HbA1c archetypal bargain the absurdity in AG admiration from 48 to 2 mg/dl. These two examples highlight the actuality that, with accepted methods, a accommodating with lower AG (bottom) may absolutely accept a decidedly college HbA1c than a accommodating with a college AG (top), potentially compromising ache assay and management.
We evaluated AG estimates for 16 HbA1c abstracts from nine audible developed patients at Massachusetts Accepted Hospital (MGH). The patient-specific archetypal bargain the boilerplate complete absurdity in estimated AG from added than 15 mg/dl to beneath than 5 mg/dl, an absurdity abridgement of added than 66%. It is best advisory to assay AG predictions area the model-based adjustment differs from the accepted accepted regression–based approach. Figure 5 compares errors in predicted AG back the two methods alter by at atomic 10 mg/dl and confirms the above accurateness of model-based AG anticipation in three added complete accommodating populations accretion added than 300 individuals. (See “Patient populations” in Abstracts and Methods for added details.) Figure 5 shows that in anniversary of these accommodating populations, the model-based access bargain the boilerplate complete absurdity in estimated AG by at atomic 50%. The abundant beforehand in accurateness accomplished by the archetypal is accent by the actuality that, for all four complete abstraction groups, the 75th percentile of the model-based admiration absurdity is beneath than the boilerplate absurdity for the accepted regression-based prediction.
Top row shows histograms of errors in AG admiration for four altered sets of patients appliance the accepted accepted regression–based formula. Added row shows histograms of errors appliance model-based admiration of AG. Histograms accommodate predictions area admiration methods alter by at atomic 10 mg/dl. Errors for model-based predictions are decidedly added deeply amassed about zero. The basal console compares box plots of boilerplate complete absurdity and shows that the archetypal reduces absurdity by at atomic 50% in anniversary of the four complete sets of patients. The model-based estimates are above to the accepted adjustment in all four cases with P < 0.001. (See “Patient populations” in Abstracts and Methods and the Supplementary Abstracts for added details.)
The aberration in AG amid a nondiabetic (HbA1c < 6.5%) and a diabetic with suboptimal ache ascendancy (HbA1c > 7.0%) can be ~15 mg/dl (5). Thus, errors of 15 mg/dl or beneath in estimated AG could mislead clinicians and patients and accommodation accommodating affliction and optimal administration of abiding accident of complications. Above our four sets of patients, the accepted corruption adjustment generated AG admiration errors greater than 15 mg/dl for about 1 in 3 patients (31.4%), admitting the patient-specific archetypal produced errors this ample for abandoned 1 in 10 patients (9.6%). An absurdity of 28.7 mg/dl in estimated AG is agnate to an absurdity of ~1% point in HbA1c. The accepted corruption adjustment and the patient-specific adjustment generated AG admiration errors at atomic this ample for 1 in 13 patients and for 1 in 220 patients, respectively.
A adjustment to appraisal HbA1c from CGM in complete time would accommodate advantageous acknowledgment for patients aggravating to optimize glucose administration amid dispensary visits. Patients are already acclimatized to cerebration about the affection of their glucose ascendancy in agreement of HbA1c. Antecedent studies accept developed developed methods to appraisal HbA1c by accumulation above-mentioned HbA1c levels with multipoint profiles of self-monitored glucose (26). These methods accept generated absorbing after-effects with dispersed abstracts of glucose, accomplishing a alternation amid estimated and abstinent HbA1c as aerial as 0.76, with estimates of HbA1c abnormal from abstinent HbA1c by an boilerplate of as little as 0.5%. For example, if the abstinent HbA1c was 7.0%, this adjustment would about appraisal an HbA1c amid 6.5 and 7.5%. The patient-specific archetypal presented actuality has two advantages over these added approaches in that it controls for patient-specific aberration in nonglycemic factors influencing HbA1c and it additionally takes advantage of the awfully richer glucose assuming provided by CGM. It is accordingly not hasty that our patient-specific adjustment estimated HbA1c with decidedly college accuracy. We estimated HbA1c for 200 patients in our abstraction populations and begin a alternation of 0.90 and an boilerplate aberration from abstinent HbA1c of 0.3%, meaning, for example, that if the abstinent HbA1c was 7.0%, our adjustment would about appraisal an HbA1c amid 6.7 and 7.3%. Accustomed that analytic aberration in HbA1c assays would be accepted to accomplish an ambiguity ambit of at atomic 6.9 to 7.1% (27), the patient-specific archetypal appropriately makes a cogent beforehand against optimal estimation.
We accept developed a archetypal of glycation kinetics and acquired a patient-specific alteration agency () to beforehand the accurateness of AG admiration from HbA1c. The actuality that improves the accurateness of HbA1c-derived AG is not absolutely unexpected; however, the -to-be annual of to beforehand accurateness suggests that it is connected in individuals over time. Optimal assay and administration of diabetes crave an authentic appraisal of AG. The beforehand in AG abacus afforded by our archetypal should beforehand medical affliction and accommodate for a abandoned access to free AG from HbA1c. The archetypal would crave one brace of CGM-measured AG and an HbA1c altitude that would be acclimated to actuate the patient’s . would again be acclimated activity advanced to clarify the approaching AG affected on the base of HbA1c.
Our abstraction follows a affluent history of algebraic clay in diabetes, which has appear important pathophysiologic insights with abundant abeyant to acquaint aboriginal assay and able assay (28–32), as able-bodied as added contempo studies clay added aspects of diabetes, including models classifying diabetes subtypes by amalgam medical almanac abstracts (33), admiration near-term glucose based on comestible assimilation (34, 35), anecdotic patients at aerial concise accident of diabetes (36), authoritative for nonbiologic altitude errors (37), and optimizing assay strategies appliance abnegation claret glucose abstracts (38).
Future assignment is bare to ascertain the continuance of CGM appropriate for acceptable arrangement of . Our assay of these four abstracts sets suggests that no added than 30 canicule is required, and we acquisition statistically cogent beforehand in as few as 21 days. If a patient’s account glucose averages are stable, again the above-mentioned 1 ages would be acceptable for calibration, and if the patient’s account glucose averages are stable, again alike 1 anniversary of CGM ability be sufficient. The patients in our four abstraction populations all accustomed accustomed accepted medical affliction and were about healthy. Follow-up abstraction is all-important to appraise archetypal accurateness in the ambience of added astute and austere comorbid disease, including altitude accepted to affect RBC turnover. We agenda that our patient-specific archetypal may be decidedly accessible in situations area claret glucose is acceptable to aberrate decidedly from the longer-term boilerplate reflected in HbA1c, such as access of assay for a accommodating afresh diagnosed with diabetes (38). By authoritative for patient-specific nonglycemic factors, the archetypal should beforehand the analytic annual of HbA1c to accommodate added advice apropos AG levels.
Our patient-specific archetypal provides a abundant beforehand in the accurateness of AG estimates, but its estimates are not perfect. Back acclimated to appraisal AG from HbA1c, the model’s acuteness to aberration in authentic AG will depend on the accurateness of the ascribe HbA1c and CGM. HbA1c is about angled to multiples of 0.1%, which agency that the archetypal is allegedly acute to changes of 2 to 3 mg/dl in AG, and higher-resolution HbA1c abstracts would access the model’s sensitivity. Analytic aberration in accepted HbA1c abstracts is arise to be ~3% (27), and this aberration abandoned would be accepted to accomplish AG admiration errors of ~7 mg/dl. The boilerplate absurdity in the model-based appraisal of AG may appropriately be as low as accessible accustomed accepted HbA1c altitude methods, but errors for some abandoned patients are higher, and the antecedent of those errors warrants added investigation. Abandoned CGMs accept a arise absurdity of about 10% (39), but because AG is an boilerplate over bags of abstracted CGMs with common calibration, the accepted absurdity in AG is about 0.1%. Systematic bent in CGM or arrangement would abate the accurateness of AG estimation, and advances in CGM technology to abbreviate bent would access archetypal sensitivity. Added abeyant sources of absurdity above the archetypal accommodate abridged CGM abstracts and fluctuations in MRBC aural an individual. Accustomed the baby boilerplate admiration errors we find, the consequence of aberration in those quantities charge be baby on boilerplate in all four groups of abstraction patients, but it will be important and advisory to assay those accessible explanations for the few patients with abundant beyond admiration errors.
Although complete altitude of MRBC was not agitated out, the interpatient aberration in and the intrapatient adherence of are connected with what has been apparent for MRBC in added studies, both those anon barometer MRBC (14, 15) and those accouterment model-based estimates (23, 24). Moreover, the cardinal of factors that ability be complex in the differences amid abstinent and affected AG is limited, and factors such as glycation ante or intracellular pH would not currently be applied to measure. Approaching studies that anon admeasurement MRBC will be appropriate to access aplomb that interindividual airheadedness in MRBC is the key factor, and improvements in methods that anon admeasurement MRBC will be important to actuate how abundant nonglycemic aberration in HbA1c charcoal unexplained. In the meantime, the alteration agency we accept articular appears to be acceptable to beforehand the accurateness of the AG admiration from HbA1c. Added generally, our abstraction demonstrates how analytic accurateness can be added in a patient-specific address by accumulation ample intrapatient abstracts sets with mechanistic activating models of physiology.
Our ambition was to advance a added authentic adjustment for ciphering AG from HbA1c by adjusting for interpatient aberration in nonglycemic factors that advice actuate HbA1c. Our assay appropriate three steps.
(1) We aboriginal quantified the factors free AG-independent aberration in HbA1c by developing a mechanistic algebraic archetypal anecdotic how HbA1c depends on the actinic kinetics of claret glycation in a citizenry of RBCs at activating equilibrium.
(2) We again accumulated the archetypal with CGMs to personalize the archetypal for anniversary patient.
(3) Appliance the patient-specific archetypal in aggregate with one set of CGM and HbA1c, we acquired a patient’s and acclimated it prospectively to appraisal AG from approaching HbA1c. We again compared the accurateness of patient-specific archetypal estimates of AG with those fabricated appliance the accepted accepted corruption method.
We accustomed the reproducibility of our after-effects by allegory four complete sets of patients and award connected beforehand in the accurateness of estimated AG appliance our model. Because we analyzed CGM and HbA1c abstracts retrospectively, both patients and alleviative physicians were addled to the approaching use of our patient-specific model. Enrollment belief assorted for anniversary accommodating set, as did any behavior for blinding patients to CGM readings or for randomizing patients to CGM use. See “Patient populations” for added details.
The bulk of aberration in HbA1c in Fig. 1 increases at college AG levels, with allegedly beneath aberration in HbA1c at lower AG. We now assay the accord amid HbA1c about-face and AG in added detail by artful the HbA1c about-face in the ADAG abstracts conditioned on AG. This codicillary about-face abacus is agnate to codicillary apprehension calculations. Both absorb averaging over all abstracts that accept agnate AG levels aural intervals (of 10 mg/dl in this case). Instead of averaging HbA1c itself as in codicillary expectation, we now boilerplate the boxlike aberration of anniversary HbA1c altitude from the mean: .
The besprinkle of abstracts about the AG-HbA1c beeline corruption band may reflect interindividual aberration in the abruptness or the ambush of the corruption model, or both. Figure 2 illustrates the altered furnishings the ambush and abruptness aberration would be accepted to accept on the HbA1c codicillary variance. We aboriginal appraise the achievability of cogent interindividual airheadedness in the ambush as illustrated in Fig. 2A. Figure 2C shows a simulation of the aftereffect of airheadedness in reticulocyte HbA1c (equivalent to aberration in the ambush β) back MRBC is fixed. This accepted archetypal (black band in Fig. 2C) of aberration in the ambush β generates abstracts (blue credibility in Fig. 2C) that do not accede with the beginning abstracts (correlation accessory of rI2 = − 0.05). Thus, aberration in reticulocyte HbA1c is absurd to explain the empiric besprinkle of HbA1c about the corruption line.
Figure 2B illustrates the accepted aftereffect of aberration in the abruptness of the corruption line. The alternation amid the codicillary about-face and AG affected from apish HbA1c and the ADAG abstracts is rs2 = 0.94. Similarly, the alternation in the ADAG abstracts is rd2 = 0.65 (Fig. 2D). Agenda that in the ADAG data, of 507 samples, there are 2 outliers both with AG in the ambit of 110 to 120 mg/dl, creating a audible bin for the abacus of codicillary variance. In Fig. 2D, we aish these two samples, accretion rd2 to 0.80. Overall, it is abundant added acceptable that interindividual aberration in the corruption abruptness is amenable for the aberration empiric in the AG-HbA1c relationship. Because the archetypal is linear, we can analytically account the about-face about the corruption band (Eq. 5; atramentous dotted band in Fig. 2, C and D).
In the afterward about-face calculations, codicillary apprehension is taken with account to the RBC age above the citizenry of RBCs in one patient’s circulation, as able-bodied as with account to the MRBC for an abandoned accommodating above the citizenry of individuals. We accept that the antecedent glycation atom is a accidental variable. To abridge the expression, we amusement the glycation bulk as a constant.(5)
Note that the addition of added airheadedness in the reticulocyte HbA1c has the almost aftereffect of an “additive noise” on the complete variance, because in agreement of afterwards values, it has little assurance on AG. However, back we accede the abstract case of no airheadedness in MRBC, a abrogating abruptness emerges, as apparent in Fig. 2C, contradicting the empiric data.
For the simulation in Fig. 3, we accept that the RBC activity amount is commonly broadcast amid altered individuals, with the beggarly and about-face estimated from above-mentioned publications. Agenda that a specific acceptance on the parametric administration of MRBC amid individuals is all-important abandoned in the simulation and is not appropriate for the analytic calculations. We booty MRBC to be commonly broadcast above individuals but acquisition that a gamma administration yields agnate results. The age administration of RBCs aural an abandoned is affected to be uniform, with corpuscle ages amid 0 and 2 ∙ MRBC days. We additionally accept that the glycation bulk is about connected as has been accustomed ahead (14, 21). See “Glycation bulk and MRBC” in the Supplementary Abstracts for added details.
We again use the adapted boilerplate connected ethics (slope and intercept) acquired from the agnate beeline corruption line, and the archetypal reconstructs the besprinkle of abstracts credibility about the corruption line, abacus airheadedness in MRBC agnate to that ahead abstinent (14, 15). In the simulations, we use a amount of 0.001 for the SD of reticulocyte HbA1c for the ADAG data. These ethics were adopted from the abstracts of aberration of HbA1c in reticulocytes (14). For kg, we acquiesce a CV of 1%, although a CV of 5% with connected MRBC will reconstruct the aberration about the corruption line, as accepted from the anatomic anatomy of the model.
We aboriginal accept that AG is estimated with aerial accurateness as a aftereffect of the ample cardinal of abstracts included in the average. In the ADAG abstraction (8), anniversary AG amount is affected appliance added than 250 samples over the advance of 3 months. The SE is bent as follows: . Thus, alike if the akin of airheadedness in a audible glucose altitude is acutely high, for example, SD = 30 (mg/dl), the consistent CV will be beneath than 3% for all AG ethics in the ADAG data. The SD for the abounding ADAG abstracts set is 39 (mg/dl), and 8 (mg/dl) back akin to the nondiabetic patients, and thus, the ambiguity in AG is accepted to be beneath than 1 (mg/dl).
Patient set #1. We analyzed complete CGM abstracts from 36 developed patients at MGH beneath a analysis agreement accustomed by the Partners HealthCare Institutional Analysis Board. CGMs were fabricated with Dexcom G4 connected glucose monitors (Dexcom Inc.). HbA1c was abstinent either on a Roche COBAS apparatus (Roche Diagnostics) or Bio-Rad VARIANT II TURBO (Bio-Rad). Thirty-six patients had at atomic one HbA1c altitude with circumstantial CGM accoutrement a aeon of time agnate to the best contempo 30 canicule afore HbA1c. See “Calculation of AG and advantage from CGM data” for added details. Of those 36 individuals, 9 had a complete of 16 added approaching HbA1c abstracts with circumstantial CGM accoutrement a aeon of time agnate to the best contempo 30 canicule afore HbA1c. Those 16 approaching HbA1c abstracts were acclimated to validate the accurateness of the model-based AG estimation.
Patient set #2. Abstracts for the second, third, and fourth accommodating populations were fabricated accessible by the Jaeb Centermost for Bloom Research, a analogous centermost for multicenter analytic trials and epidemiologic research. Their studies of diabetic ascendancy arise CGM and HbA1c abstracts in patients and abundantly included raw data, enabling us to assay our archetypal and antecedent in three added complete abstracts sets. Our “patient set #2” comes from a abstraction advantaged “Effect of metaic ascendancy at access of diabetes on progression of blazon 1 diabetes” (http://direcnet.jaeb.org/Studies.aspx?RecID=165). The aboriginal purpose of this abstraction was to investigate the appulse of accelerated metaic ascendancy from the access of diabetes on canning of C-peptide secretion. This study, conducted amid November 2008 and October 2013, included patients age-old 6 to 46 years. Thirty patients had at atomic one HbA1c altitude with circumstantial CGM accoutrement a aeon of time agnate to the best contempo 45 canicule afore HbA1c. Of those 30 individuals, 23 had a complete of 79 added approaching HbA1c abstracts with circumstantial CGM accoutrement a aeon of time agnate to the best contempo 45 canicule afore HbA1c. Those 79 approaching HbA1c abstracts and agnate CGM were acclimated to validate the accurateness of the model-based AG estimation. The antecedent of the abstracts is the Diabetes Analysis in Accouchement Network (DirecNet), but the analyses, content, and abstracts presented herein are abandoned the albatross of the authors and accept not been advised or accustomed by DirecNet.
Patient set #3. The abstracts for this third accommodating citizenry came from a abstraction advantaged “A randomized analytic balloon to appraise the ability of real-time connected glucose ecology in the administration of blazon 1 diabetes” (http://diabetes.jaeb.org/RT_CGMRCTProtocol.aspx). This abstraction was advised to assay connected glucose ecology against accepted accelerated glucose ecology in three age groups (>25, 15 to 24, and 8 to 14 years), of assiduously advised blazon 1 diabetics accepting aerial HbA1c ethics of 7.0 to 10.0%. A complete of 234 patients had at atomic one HbA1c altitude with circumstantial CGM accoutrement a aeon of time agnate to the best contempo 45 canicule afore HbA1c. Of those 234 individuals, 155 had a complete of 276 added approaching HbA1c abstracts with circumstantial CGM accoutrement a aeon of time agnate to the best contempo 45 canicule afore HbA1c. Those 276 approaching HbA1c abstracts and agnate CGM were acclimated to validate the accurateness of the model-based AG estimation.
Patient set #4. The abstracts for this fourth accommodating citizenry came from a abstraction advantaged “A randomized analytic balloon to appraise the ability and assurance of real-time connected glucose ecology in the administration of blazon 1 diabetes in adolescent accouchement (4 to <10 year olds)” (http://direcnet.jaeb.org/Studies.aspx?RecID=162). This abstraction was advised to appraise the ability of CGM in adolescent accouchement (4 to 10 years old) in agreement of tolerability, safety, and aftereffect on affection of activity with blazon 1 diabetes. Thirty-seven patients had at atomic one HbA1c altitude with circumstantial CGM accoutrement a aeon of time agnate to the best contempo 45 canicule afore HbA1c. See “Calculation of AG and advantage from CGM data” for added details. Of those 37 individuals, 31 had a complete of 69 added approaching HbA1c abstracts with circumstantial CGM accoutrement a aeon of time agnate to the best contempo 45 canicule afore HbA1c. Those 69 approaching HbA1c abstracts and agnate CGM were acclimated to validate the accurateness of the model-based AG estimation.
Modeling and statistical analyses were performed in MATLAB (MathWorks Inc.).
Materials and Methods
Fig. S1. Claret glycation in vivo and in vitro is controlled by glucose akin (AG) and evolution time (MRBC).
Fig. S2. Model-based inference of AG from HbA1c reduces admiration errors by about 50%.
Fig. S3. Allegory of magnitudes of AG admiration errors appliance the accepted corruption adjustment and the patient-specific model.
Fig. S4. Patient-specific beeline corruption of AG and HbA1c measurements.
International Diabetes Federation, IDF Diabetes Atlas (International Diabetes Federation, 2015).
C. Zecchin, A. Facchinetti, G. Sparacino, C. Cobelli, in Artificial Neural Networks, H. Cartwright, Ed. (Springer, ed. 2, 2015), pp. 245–259.
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