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Title:
DIABETES ANALYSIS SYSTEM, AND METHOD IN RELATION TO THE SYSTEM
Document Type and Number:
WIPO Patent Application WO/2021/123217
Kind Code:
A1
Abstract:
Diabetes analysis system for analysis and interpretation of data related to glucose level (GL) in blood, the system is to be applied to determine a treatment recommendation to a patient. The analysis system comprises an input module (2) configured to receive GL related data (4) from measurements of interstitial fluid in subcutaneous tissue. The system further comprises a hypoglycemia identification module (6) configured to identify hypoglycemic events by performing a computer-implemented automatic search of said received GL related data, wherein all uninterrupted glucose levels less than a predetermined level, e.g. glucose levels < 3.5 mmol/L, in a same time series will be considered as one hypoglycemic event, and a hypoglycemia classification module (8) configured to analyze, for each identified hypoglycemic event, the glucose data during a predetermined first time period, e.g. six hours, preceding the hypoglycemic event, to determine the glucose level during the first time period, wherein the hypoglycemia classification module is configured to determine the type (10) of hypoglycemia event, based upon the glucose level during the first time period, by applying a computer- implemented pattern search procedure on a predetermined hypoglycemic classification scheme including different types of hypoglycemia, in order to identify the underlying cause of hypoglycemia.

Inventors:
CEDERBLAD LARS (SE)
ESPES DANIEL (SE)
CARLSSON PER-OLA (SE)
Application Number:
PCT/EP2020/087093
Publication Date:
June 24, 2021
Filing Date:
December 18, 2020
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
DIGITAL DIABETES ANALYTICS SWEDEN AB (SE)
International Classes:
G16H20/10; G16H20/17
Domestic Patent References:
WO2015025187A12015-02-26
Foreign References:
US20130035871A12013-02-07
US20160354543A12016-12-08
US20150347698A12015-12-03
US10321859B12019-06-18
US10373519B12019-08-06
Other References:
ANONYMOUS: "Outlier", WIKIPEDIA, 18 December 2019 (2019-12-18), XP055698794, Retrieved from the Internet [retrieved on 20200527]
D. M. NATHAN ET AL: "Translating the A1C Assay Into Estimated Average Glucose Values", DIABETES CARE, vol. 31, no. 8, 7 June 2008 (2008-06-07), pages 1473 - 1478, XP055099114, ISSN: 0149-5992, DOI: 10.2337/dc08-0545
Attorney, Agent or Firm:
BJERKÉNS PATENTBYRÅ KB (STOCKHOLM) (SE)
Download PDF:
Claims:
Claims

1. Diabetes analysis system for analysis and interpretation of data related to glucose level (GL) in blood, the system is to be applied to determine a treatment recommendation to a patient, the analysis system comprises:

-an input module (2) configured to receive GL related data (4) from measurements of interstitial fluid in subcutaneous tissue and prepare the data, e.g. by removing numerical outliers, c h a r a c t e r i z e d i n that said system further comprises:

-a hypoglycemia identification module (6) configured to identify hypoglycemic events by performing a computer-implemented automatic search of said received GL related data, wherein all uninterrupted glucose levels less than a predetermined level, e.g. glucose levels < 3.5 mmol/L, in the same time series will be considered as one hypoglycemic event,

-a hypoglycemia classification module (8) configured to analyze, for each identified hypoglycemic event, the glucose data during a predetermined first time period, e.g. six hours, preceding the hypoglycemic event, to determine the glucose level during the first time period, wherein the hypoglycemia classification module is configured to determine the type (10) of hypoglycemia event, based upon the glucose level during the first time period, by applying a computer-implemented pattern search procedure on a predetermined hypoglycemic classification scheme including different types of hypoglycemia, in order to identify the underlying cause of hypoglycemia.

2. The diabetes analysis system according to claim 1, wherein the hypoglycemia identification module (6) is further configured to determine the duration of the hypoglycemic event, based upon time series of data of an identified hypoglycemic event, and the severity of the event which is based upon the lowest recorded glucose value,

3. The diabetes analysis system according to claim 1 or 2, comprising a hypoglycemia recoil classification module (12) configured to analyze, for each identified hypoglycemic event, the glucose data during a predetermined second time period, e.g. two hours, following the hypoglycemic event, to determine the glucose level during the second time period, wherein the hypoglycemia recoil classification module is configured determine the type (14) of hypoglycemia recoil, based upon the glucose level during the second time period, by applying a computer-implemented pattern search procedure on a predetermined hypoglycemic recoil classification scheme including different types of hypoglycemia recoil.

4. The diabetes analysis system according to any of claims 1-3, comprising a cluster identification module (16) configured to receive GL values and arranged them as the numbers of GL samples in a time series that exist in specific GL intervals, denoted bins, to determine a GL histogram profile (18) of a patient during a predetermined time period, e.g. one week, and configured to determine a rate of change of glucose level (dGL) histogram profile (20) of a patient during said predetermined time period, e.g. one week,

5. The diabetes analysis system according to claim 4, wherein said cluster identification module (16) is configured to apply a computer-implemented procedure to compare said GL and dGL histogram profiles (18, 20) to sets of a predetermined number, e.g. 8, different GL type profiles (A-H) and dGL type profiles (a-h), respectively, to determine which GL type profile and dGL type profile that essentially corresponds to the determined GL histogram profile and dGL histogram profile, respectively, and to combine said thus determined GL and dGL type profiles to a classification (A-H, a-h) and insert the classification in a classification space, wherein each position in said classification has designated treatment schemes.

6. The diabetes support system according to any of claims 1-5, comprising a prandial event module (22) comprising a prandial event filter configured to detect meals for patient without knowledge on bolus insulin and carbohydrate registrations, wherein the prandial event filter is adapted determine a prandial event by identifying predefined curve shapes of said GL related data, and to classify said identified prandial events by applying a prandial classification based on pattern recognition, and wherein a basal insulin pressure is identified based upon said classified prandial event (24).

7. The diabetes analysis system according to any of claims 1-6, comprising an estimate hemoglobin (HbAlc) module (26), wherein said input module (2) is configured to receive HbAlc related data (28) and said estimate HbAlc module is configured to determine estimated HbAlc data (30) based upon said HbAlc related data, and to apply said estimated HbAlc data to a diabetes analysis module (32) that is configured to combine said determined estimated HbAlc data to at least one of the determined type (10) of hypoglycemia event, type (14) of hypoglycemia recoil, and determined GL and dGL type profiles.

8. The diabetes analysis system according to any of claims 1-7, wherein said GL related data (4) comprises data from continuous glucose measurements (CGM) and/or flash glucose measurements (FGM).

9. A computer-implemented method for analysis and interpretation of data related to glucose level (GL) in blood, the method is to be applied to determine a treatment recommendation to a patient, and comprises:

-receiving GL related data from measurements of interstitial fluid in subcutaneous tissue and preparing the data, e.g. by removing numerical outliers, c h a r a c t e r i z e d i n that said method further comprises:

-identifying, in a hypoglycemia identification module, hypoglycemic events by performing a computer-implemented automatic search of said received GL related data, wherein all uninterrupted glucose levels less than a predetermined level, e.g. glucose levels < 3.5 mmol/L, in the same time series will be considered as one hypoglycemic event, and

-analyzing, in a hypoglycemia classification module, for each identified hypoglycemic event, the glucose data during a predetermined first time period, e.g. six (6) hours, preceding the hypoglycemic event, to determine the glucose level during the first time period, and determining the type of hypoglycemia event, based upon the glucose level during the first time period, by applying a computer-implemented pattern search procedure on a predetermined hypoglycemic classification scheme including different types of hypoglycemia, in order to identify the underlying cause of hypoglycemia.

10. The computer-implemented method according to claim 7, comprising determining the duration of the hypoglycemic event, based upon time series of data of an identified hypoglycemic event, and the severity of the event which is based upon the lowest recorded glucose value.

11. The computer-implemented method according to claim 9 or 10, comprising: -analyzing, in a hypoglycemia recoil classification module, for each identified hypoglycemic event, the glucose data during a predetermined second time period, e.g. two (2) hours, following the hypoglycemic event, to determine the glucose level during the second time period, and determining the type of hypoglycemia recoil, based upon the glucose level during the second time period, by applying a computer-implemented pattern search procedure on a predetermined hypoglycemic recoil classification scheme including different types of hypoglycemia recoil.

12. The computer-implemented method according to any of claims 9-11, comprising:

-receiving, in a cluster identification module, GL values and arranging them as the numbers of GL samples in a time series that exist in specific GL intervals, denoted bins, determining, based upon said GL values, a GL histogram profile of a patient during a predetermined time period, e.g. one week, and determining a rate of change of glucose level (dGL) histogram profile of a patient during said predetermined time period, e.g. one week.

13. The computer-implemented method according to claim 12, comprising applying a computer-implemented procedure to compare said GL and dGL histogram profiles to sets of a predetermined number, e.g. 8, different GL type profiles (A-H) and dGL type profiles (a-h), respectively, to determine which GL type profile and dGL type profile that essentially corresponds to the determined GL histogram profile and dGL histogram profile, respectively, and to combine said thus determined GL and dGL type profiles to a classification (A-H, a-h) and insert the classification in a classification space, wherein each position in said classification has designated treatment schemes.

14. The computer-implemented method according to any of claims 9-13, comprising: -receiving HbAlc related data by said input module,

-determining estimated HbAlc data, in an estimate hemoglobin (HbAlc) module, and -combining, in a diabetes analysis module (22), said determined estimated HbAlc data to at least one of the determined type (10) of hypoglycemia event, type (14) of hypoglycemia recoil, and determined GL and dGL type profiles.

15. The computer-implemented method according to any of claims 9-14, wherein said GL related data comprises data from continuous glucose measurements (CGM) and/or flash glucose measurements (FGM).

Description:
Diabetes analysis system, and method in relation to the system

Technical field

The present disclosure relates to a diabetes analysis system, and method in relation to the system. In particular, the disclosure relates to automated analysis and interpretation of glucose related data.

Background

Type 1 diabetes (T1D) is the most common chronic disease in children, for which there is no cure and at least 800 children are diagnosed every year in Sweden alone. Although at a lower incidence, T1D can also debut later in life in all age groups. Individuals diagnosed with T1D will for the rest of their lives entirely depend on exogenous insulin. In addition to daily insulin injections, multiple blood glucose testing is required in order to correctly dose insulin. However, exogenous insulin treatment is by no means able to fully mimic the fine-tuned regulation of insulin secretion in healthy individuals, and individuals with T1D are therefore at constant risk of death or brain damage due to dangerously low glucose levels (GL) (hypoglycemia). Studies have shown that 6-10% of all deaths among patients with T1D is caused by hypoglycemia. At the same time, the inevitable mean increase in blood glucose concentrations dramatically increases the risk of long-term complications, which results in a reduction of life-expectancy in T1D by more than 10 years.

Over the last few years, the technology for continuous glucose monitoring (CGM) and flash glucose monitoring (FGM) has dramatically improved, and many countries now reimburse patients for the use of CGM/FGM. In flash glucose monitoring, patients have a sensor inserted on their upper arm and a separate touchscreen reader device. When the reader device is swiped close to the sensor, the sensor transmits both an instantaneous glucose level and a trend graph, e.g. an eight-hour trend graph, to the reader. CGM/FGM relies on the measurement of GL in the interstitial fluid in subcutaneous tissue, i.e. it does not measure blood GL, but in most scenarios, the levels have an accuracy > 80%. CGM sample a GL every 5 th minute, whereas an FGM samples GL every 15 th minute but also allows for the user to scan additional GL in between these 15-minute intervals. This results in 288 data points every day from a CGM and minimum of 96 data points from an FGM. The technology has improved the everyday life for many patients with T1D and insulin-treated type 2 diabetes thanks to their convenience of use. However, the vast amount of data generated from CGM/FGM is difficult to handle for the individual patient and even more so for the healthcare system since the amount of accumulated CGM/FGM- data is ever increasing. Given that most patients visit the clinic only once or twice every year this means that the patient will bring between 20,000-100,000 data points of just glucose data to each visit. The composite of this data reflects the individual risk of long term complications since it describes the actual GL over time. In addition, hidden in this vast amount of data lies numerous readings of hypoglycemic events that could as mentioned, potentially be fatal. Despite the widespread use of CGM/FGM technology in routine care the utilization of the data is still low. In part this can be explained by the fact that CGM/FGM-data to a large extent needs to be interpreted manually and even consensus statements rely on interpretations primarily based on simple measurements such as time spent within target GL. Currently, the target levels for glucose control are normally solely based on HbAlc levels (HbAlc is also known as glycosylated, or glycated hemoglobin), a blood sample that roughly represents the average blood GL over the last 8- 12 weeks. However, HbAlc levels do not resemble the fluctuations in blood GL, and in addition, there are a number of individual discrepancies in HbAlc levels. Considering the unmet need from the healthcare system and the costs related to the use of CGM/FGM, methods need to be developed that make better use of the collected data.

Examples of presently applied technology are disclosed in US-10321859 and in US- 10373519. US-10321859 discloses systems and methods for capturing and analyzing hypoglycemic event data in order to provide feedback to a patient. US-10373519 discloses a system and method for determining and providing activity recommendations including to receive glucose level data and activity data. The objective is to provide recommendations to a user to encourage a greater number of times activities are undertaken.

The object of the present invention is to achieve an improved diabetes analysis system and an improved method capable of performing automated analysis and interpretations of a large amount of collected data, e.g. CGM/FGM-data, and also capable of generating a root cause analysis and recommendations for treatment modifications for diabetes patients. In particular, the object is to achieve an improved system and method that will be a valuable tool for health care professionals (HCP) in order to improve diabetes care.

Summary

The above-mentioned objects are achieved by the present invention according to the independent claims.

Preferred embodiments are set forth in the dependent claims.

According to a first aspect the present invention relates to a diabetes analysis system for analysis and interpretation of data related to glucose level (GL) in blood, the system is to be applied to determine a treatment recommendation to a patient. The analysis system comprises:

-an input module (2) configured to receive GL related data (4) from measurements of interstitial fluid in subcutaneous tissue and prepare the data, e.g. by removing numerical outliers. The system further comprises:

-a hypoglycemia identification module (6) configured to identify hypoglycemic events by performing a computer-implemented automatic search of said received GL related data, wherein all uninterrupted glucose levels less than a predetermined level, e.g. glucose levels < 3.5 mmol/L, in the same time series will be considered as one hypoglycemic event,

-a hypoglycemia classification module (8) configured to analyze, for each identified hypoglycemic event, the glucose data during a predetermined first time period, e.g. six hours, preceding the hypoglycemic event, to determine the glucose level during the first time period, wherein the hypoglycemia classification module is configured to determine the type (10) of hypoglycemia event, based upon the glucose level during the first time period, by applying a computer-implemented pattern search procedure on a predetermined hypoglycemic classification scheme including different types of hypoglycemia, in order to identify the underlying cause of hypoglycemia.

According to a second aspect the present invention relates to a computer-implemented method for analysis and interpretation of data related to glucose level (GL) in blood, the method is to be applied to determine a treatment recommendation to a patient. The method comprises:

-receiving GL related data from measurements of interstitial fluid in subcutaneous tissue and preparing the data, e.g. by removing numerical outliers,

-identifying, in a hypoglycemia identification module, hypoglycemic events by performing a computer-implemented automatic search of said received GL related data, wherein all uninterrupted glucose levels less than a predetermined level, e.g. glucose levels < 3.5 mmol/L, in the same time series will be considered as one hypoglycemic event, and

-analyzing, in a hypoglycemia classification module, for each identified hypoglycemic event, the glucose data during a predetermined first time period, e.g. six (6) hours, preceding the hypoglycemic event, to determine the glucose level during the first time period, and determining the type of hypoglycemia event, based upon the glucose level during the first time period, by applying a computer-implemented pattern search procedure on a predetermined hypoglycemic classification scheme including different types of hypoglycemia, in order to identify the underlying cause of hypoglycemia.

The diabetes analysis system, and the method, according to the above aspects, are advantageous as they provide powerful tools for handling and analyzing a large amount of data related to the glucose level in blood obtained during days, weeks, or months.

Brief description of the drawings

Figure l is a block diagram schematically illustrating the present invention.

Figure 2 is a flow diagram illustrating the method according to the present invention. Figure 3 is a block diagram schematically illustrating an embodiment of the present invention.

Figure 4 is histogram showing glucose profiles according to an embodiment of the present invention.

Figure 5 is a 3D histogram illustrating combined GL and dGL histograms according to an embodiment of the present invention.

Figure 6 is a hypoglycaemia score illustrating an exemplary output from a hypoglycaemia score module. Figure 7 is a hyperglycaemia score illustrating an exemplary output from a hyperglycaemia score module.

Figure 8 is an overview flow diagram illustrating implementation of the system and method of the present invention.

Detailed description

The diabetes analysis system, and the computer-based method, will now be described in detail with references to the appended figures. Throughout the figures, the same, or similar, items have the same reference signs. Moreover, the items and the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

With references to the schematic block diagram shown in figure 1 a diabetes analysis system for analysis and interpretation of data related to glucose level (GL) in blood will be described in detail. The system is to be applied to determine a treatment recommendation for a patient. The analysis system comprises an input module 2 configured to receive GL related data from measurements of interstitial fluid in the subcutaneous tissue of a patient.

The diabetes analysis system further comprises a hypoglycemia identification module 6 configured to identify hypoglycemic events by performing a computer-implemented automatic search of the received GL related data, wherein all uninterrupted glucose levels less than a predetermined level, e.g. glucose levels < 3.5 mmol/L, in the same time series, will be considered as one hypoglycemic event. Glucose data of the identified hypoglycemic events is then applied to a hypoglycemia classification module 8 configured to analyze, for each identified hypoglycemic event, the glucose data during a predetermined first time period, e.g. three hours, preceding the hypoglycemic event, to determine the glucose level during the first time period. The hypoglycemia classification module is then configured to determine the type f0 of hypoglycemia event, based upon the glucose level during the first time period, by applying a computer-implemented pattern search procedure on a predetermined hypoglycemic classification scheme including different types of hypoglycemia, in order to identify the underlying cause of hypoglycemia. The above-described identification and classification of hypoglycemic events are performed on GL related data obtained during days, weeks, or months, e.g. during the whole time period between follow-up meetings with the responsible physician.

According to an embodiment, the hypoglycemia identification module 6 is further configured to determine the duration of the hypoglycemic event, based upon time series of data of an identified hypoglycemic event, and also the severity of the event which is based upon the lowest recorded glucose value.

According to another embodiment, the diabetes analysis system also comprises a hypoglycemia recoil classification module 12 configured to analyze, for each identified hypoglycemic event, the glucose data during a predetermined second time period, e.g. two hours, following the hypoglycemic event, to determine the glucose level during the second time period. The hypoglycemia recoil classification module is configured determine the type 14 of hypoglycemia recoil, based upon the glucose level during the second time period, by applying a computer-implemented pattern search procedure on a predetermined hypoglycemic recoil classification scheme including different types of hypoglycemia recoil.

According to still another embodiment the diabetes analysis system comprises a cluster identification module 16 configured to receive GL values and arranged them as the numbers of GL samples in a time series that exist in specific GL intervals, denoted bins, to determine a GL histogram profile 18 of a patient during a predetermined time period, e.g. one week, and configured to determine a rate of change of glucose level (dGL) histogram profile 20 of a patient during said predetermined time period, e.g. one week.

In particular, the GL histogram profile 18 comprises a horizontal axis showing bins of GL value intervals and a vertical axis e.g. showing duration in hours in each bin, or percentage of time interval for the histogram analysis in each bin, i.e. in each GL value interval, during the predetermined time period. The dGL histogram profile 20 comprises a horizontal axis showing bins of dGL value intervals and a vertical axis showing duration in hours in each bin, i.e. in each dGL value interval, during the predetermined time period. Examples of GL histograms for two patients are illustrated in figure 4.

In one embodiment, the cluster identification module 16 is configured to apply a computer-implemented procedure to compare said GL and dGL histogram profiles 18, 20 to sets of a predetermined number, e.g. 8, different GL type profiles (A-H) and dGL type profiles (a-h), respectively. This is performed in order to determine which GL type profile and dGL type profile that essentially corresponds to the determined GL histogram profile and dGL histogram profile, respectively, and to combine said thus determined GL and dGL type profiles to a classification (A-H, a-h) and insert the classification in a classification space, wherein each position in said classification has designated treatment schemes. An illustrating example of the classification space is shown in figure 5.

According to another embodiment the diabetes support system comprises a prandial event module 22 comprising a prandial event filter configured to detect meals for a patient without knowledge on bolus insulin and carbohydrate registrations. The prandial event filter is adapted determine a prandial event by identifying predefined curve shapes of the GL related data, and to classify the identified prandial events by applying a prandial classification based on pattern recognition, and wherein a basal insulin pressure is identified based upon said classified prandial event 24.

A prandial event is preferably detected by detecting a steep rising response of the GL as a consequence of the intake of carbohydrates. The higher glycemic index the carbohydrates have, the steeper the response will be, and the time for the start of the meal may be detected by applying three conditions:

Conditions that have to be fulfilled to detect a prandial event: Forward4dGL > 0 AND Forward4dGL > 3 Backward4dGL Then tO — tprancUal

This means that the detection of prandial events is based on comparing the rate of change for GL forward and backward from the possible time of the prandial event.

The prandial event detection monitors the rate of change in GL in a window which is e.g.

3 samples forward and 3 samples backward. If a significant and persistent change occurs, this time is considered to be a candidate for a prandial event. Data is then stored in a vector of candidate events. The second step is a classification of the candidate events to be a real prandial event or not. This is done by using e.g. a random forest methodology where a set of events are classified by clinicians. Ideally, real event registrations with insulin injection time, insulin type and carbohydrates ingested are used to train the system. After training, the classification system will filter out real prandial events from the gross list of candidates. The prandial events are used to identify pre- and post-prandial event GL, the prandial delta, as well as analyzing the basal pressure, i.e. the effect of the basal insulin on the metabolic balance when no bolus insulin nor any meals are included.

The pre-prandial GL is defined as the GL(0), i.e. time of the event. The post-prandial GL is defined as the GL(+3hours). Prandial delta is calculated as GL(+3hours)-GL(0).

Based on the prandial events, the basal insulin pressure can be identified. I.e. the rate of change of GL without the impact of bolus insulin given at the meals. The basal insulin pressure is used as an input to the treatment recommendation.

According to still another embodiment, the diabetes analysis system also comprises an estimated hemoglobin (HbAlc) module 26. The input module 2 is configured to receive HbAlc related data 28 and to apply the data to the estimate HbAlc module 26. This module is configured to determine estimated HbAlc data 30 based upon the HbAlc related data, and then to apply the estimated HbAlc data to a diabetes analysis module 32 that is configured to combine the determined estimated HbAlc data to the determined type determined GL and dGL type profiles.

The GL related data 4 preferably comprises data from continuous glucose measurements (CGM) and/or flash glucose measurements (FGM). Also, any other type of measurement device configured to determine glucose levels, e.g. transdermal sensors, may naturally be applied.

The present invention also relates to a computer-implemented method for analysis and interpretation of data related to glucose level (GL) in blood. The method will be described with references to the flow diagram shown in figure 2.

The method is to be applied to determine a treatment recommendation to a patient and is to be implemented by the diabetes analysis system described above. In the following, some parts of the system will be described, but it is also referred to the description above, and also below, of the various parts of the system.

The method comprises:

-receiving GL related data from measurements of interstitial fluid in subcutaneous tissue -identifying, in a hypoglycemia identification module, hypoglycemic events by performing a computer-implemented automatic search of said received GL related data, wherein all uninterrupted glucose levels less than a predetermined level, e.g. glucose levels < 3.5 mmol/L, in a same time series will be considered as one hypoglycemic event, and

-analyzing, in a hypoglycemia classification module, for each identified hypoglycemic event, the glucose data during a predetermined first time period, e.g. three (3) hours, preceding the hypoglycemic event, to determine the glucose level during the first time period, and determining the type of hypoglycemia event, based upon the glucose level during the first time period, by applying a computer-implemented pattern search procedure on a predetermined hypoglycemic classification scheme including different types of hypoglycemia, in order to identify the underlying cause of hypoglycemia.

Preferably, the method also comprises determining the duration of the hypoglycemic event, based upon time series of data of an identified hypoglycemic event, and to determine the severity of the event which is based upon the lowest recorded glucose value. In a further embodiment, the method comprises:

-analyzing, in a hypoglycemia recoil classification module, for each identified hypoglycemic event, the glucose data during a predetermined second time period, e.g. two (2) hours, following the hypoglycemic event, to determine the glucose level during the second time period, and determining the type of hypoglycemia recoil, based upon the glucose level during the second time period, by applying a computer-implemented pattern search procedure on a predetermined hypoglycemic recoil classification scheme including different types of hypoglycemia recoil.

According to another embodiment the computer-implemented method also comprises: -receiving, in a cluster identification module, GL values and arranging them as the numbers of GL samples in a time series that exist in specific GL intervals, denoted bins, determining, based upon said GL values, a GL histogram profile of a patient during a predetermined time period, e.g. one week, and determining a rate of change of glucose level (dGL) histogram profile of a patient during said predetermined time period, e.g. one week. Further information of the GL and dGL histogram profiles are discussed above in relation to the description of the system.

Preferably, the computer-implemented method also comprises applying a computer- implemented procedure to compare the GL and dGL histogram profiles to sets of a predetermined number, e.g. 8, different GL type profiles (A-H) and dGL type profiles (a- h), respectively, in order to determine which GL type profile and dGL type profile that essentially corresponds to the determined GL histogram profile and dGL histogram profile, respectively. The method further comprises to combine said thus determined GL and dGL type profiles to a classification (A-H, a-h) and insert the classification in a classification space, wherein each position in said classification has designated treatment schemes.

In another embodiment, the computer-implemented method comprises:

-receiving HbAlc related data by the input module,

-determining estimated HbAlc data, in an estimate hemoglobin (HbAlc) module, and -combining, in a diabetes analysis module 32, said determined estimated HbAlc data to at least one of the determined type 10 of hypoglycemia event, type 14 of hypoglycemia recoil, and determined GL and dGL type profiles.

The GL related data advantageously comprises data from continuous glucose measurements (CGM) and/or flash glucose measurements (FGM). Also other types of measurement devices may be applied, e.g. transdermal sensors.

In figure 3 is shown a schematic block diagram of a diabetes analysis system according to one variation of the present invention. In the block diagram some blocks are included that have been described above. In addition, further blocks are shown that optionally may be part of the system.

The flow starts with the patient uploading data from FGM/CGM and other devices such as activity trackers etc. In this, the consistency of data is checked to remove possible outlier samples, i.e. samples that are considered to be statistically unlikely. The filter for removing outliers is cautious not to remove low values since these are analyzed by the hypo identification and classification module. As an example, if sampling time is 15 min, this will result in 4x24 = 96 samples per day, which is 672 samples per week.

The blocks in figure 3 will now be described. Some of the blocks/modules described in the following have also been discussed above.

Estimated HbAlc module

Hemoglobin Ale, often abbreviated HbAlc, is a form of hemoglobin (a blood protein that carries oxygen) that is bound to glucose. A blood test for HbAlc level is routinely performed in people with type 1 and type 2 diabetes mellitus. Blood HbAlc levels are reflective of how well diabetes is controlled. To estimate the HbAlc a mean value of the blood glucose is used as an input to a function that maps the mean value onto an HbAlc value where any length of the time window may be selected for the calculation of the mean value, e.g. day, week, or month. Thus, the system comprises an HbAlc determining module configured to determine an estimated HbAlc level and to generate an HbAlc level signal.

Glycemic variability module

Glycemic variability (GV), which refers to swings in blood glucose levels, has a broader meaning because it alludes to blood glucose oscillations that occur throughout the day, including hypoglycemic periods and postprandial increases, as well as blood glucose fluctuations that occur at the same time on different days.

The broad definition of GV considers the intraday glycemic excursions, including episodes of hyperglycemia and hypoglycaemia, and may be determined according to the following expression.

Time in range module

Time-in-Range (TIR) is the percentage of time that a person spends with their blood glucose levels in a target range. The range will vary depending on the person, but general guidelines suggest starting with a range of 4 to 10 mmol/1.

Time-above-Range (TAR) is the percentage of time that a person spends with their blood glucose levels above a target range.

Time-below-Range (TBR) is the percentage of time that a person spends with their blood glucose levels below a target range.

Hypoglycemia identification and classification module

Hypoglycemia (normally defined as GL < 3.5 mmol/1) occurs due to an imbalance of insulin doses in relation to carbohydrate intake and can be augmented by a number of external and physiological factors such as physical activity for instance. A smaller number of patients record all injected insulin doses and carbohydrates ingested, in that case, the hypoglycemic events can easily be explained and diagnosed. However, most patients do not record insulin doses at all or only a minority of the doses and therefore it is difficult to analyze the cause of hypoglycemic events in the clinical setting. In addition, the number of recorded hypoglycemic events even for a single patient from the last 3-6 months can easily exceed 350 events making it impossible to analyze manually at a clinical visit. By an automated search of the complete data set, all GL < 3.5 mmol/1 are identified. All uninterrupted levels < 3.5 mmol/L in the same time series will be considered as one hypoglycemic event. Based on the hypoglycemic time series of data two different analysis are performed:

1. The duration of the hypoglycemic event.

2. The severity of the event which is based upon the lowest recorded glucose value.

In addition, for each hypoglycemic episode the glucose data is analyzed during e.g. the six (6) hours preceding the first identified hypoglycemic GL. Based on the GL from this time series, the underlying cause of hypoglycemia can be identified even without knowledge of insulin doses and carbohydrate intake. This is achieved by employing a training set of hypoglycemic events identified in both patients which have registered insulin doses and those without registered insulin doses.

In setting up the system, a number of hypoglycemic events (without presentation of insulin doses) is then selected by a stratification algorithm and partly overlapping events are presented to clinical experts for classification. The independent classification of each expert is analyzed firstly for conformity in between evaluators and next the same experts are presented with the remaining hypoglycemic events, but in this case with the data on insulin doses and carbohydrate intake. The classifications on the complete data set is then checked for conformity in-between evaluators but also compared with the first classification made by a peer without knowledge on insulin doses and carbohydrate intake.

After this two-step process of classification, the data will be used to train the machine learning algorithm, the algorithm will be programmed to incorporate data on insulin doses and carbohydrate intake if available. A cluster-sample of algorithm derived classification based on GL alone will again be analyzed for conformity by clinical experts with the addition of insulin and carbohydrate data. The interpretations of the algorithm will automatically generate a probability rating and a cut-off value, based on the comparison with clinical experts, will be defined.

If heart rate data is available this will be used in the classification in order to identify exercise-induced hypoglycemic events. A scenario specific for CGM/FGM is the possibility of false hypoglycemic recordings due to mechanical pressure of the sensor which reduce the interstitial fluid flow creating a local hypoglycemic environment which does not reflect the systemic GL, most commonly observed during sleep. Data on concomitant drugs known to increase the risk of hypoglycemia (for instance opioids, benzodiazepines and indirectly sodium-glucose transport protein2 inhibitors) will be collected and if the patient is using any of such medications this will be highlighted as a contributor if there are no other apparent causes. In a small subset of patients with T1D (<5%) GL can be extremely volatile, also known as brittle-diabetes. In that situation the underlying cause for hypoglycemia will most likely not be identified and in that case the event will be assigned the term “unclassified” and highlighted for the HCP to interpret manually in dialog with the patient.

Example of hypoglycemic classifications are e.g.:

• High basal insulin pressure

• Overcompensation of hyperglycemia

• Overestimated bolus insulin at meal

• Exercise resulting in hypoglycemia (combined CGM/FGM data with heart rate and physical activity data)

• False hypoglycemia due to mechanical pressure on the sensor

• Contribution of concomitant drugs

• Unclassified (less than 5% of all hypoglycemic episodes)

The type of hypoglycemic event is identified by a random forest leamer/predictor or any other similar method. After the training, the predictor will process a large set of data and assign conformity and probability to each event. By combining self-scanned GL for all patients who use an FGM it can also be identified whether the patient was aware of the event and provide more detailed data on how he/she handles it. For instance, does the frequency of self-scanned GL increases in the coming hours after a hypoglycemic event when compared to the average number of scanning.

Thus, herein is described how to achieve a classification of hypoglycemia, including providing a classification by combining input from experts with automated recognition procedures. The thus obtained hypoglycemia classification is then applied for classifying data for a patient.

Hypo recoil identification/classification module

The hypo recoil identification module works in the same way as the identification and classification of hypoglycemic events. When the hypoglycemic event has been resolved, i.e. GL have returned to > 3.5 mmol/1 the following window of e.g. two (2) hours is analyzed to identify if there is recoil in GL. The recoil may not exist or can be an effect of over ingestion by the patient in the ambition to get the GL back to normal or due to a counter-regulatory hormonal response (glucagon, cortisol, adrenaline, and noradrenaline release).

Data from the two-hour window after the hypoglycemic event is used to train the random forest leamer/predictor or any other similar method. A set of training events is selected by a stratification algorithm. This set is then classified by clinical expertise in the same fashion as for the hypo identification system described above. For the hypo recoil classification module, data from individuals that register carbohydrate intake will be used for validation of the interpretation. Also for this parameter heart rate data, if available, will be used in the interpretation since a more pronounced increase in heart rate will be associated with a hormonally based recoil due to the release of adrenaline and noradrenaline. Example of such classifications are e.g. :

• No recoil

• Mild recoil

• Recoil due to over ingestion

• Hormonal based recoil (absence of manual readings during hypoglycemic period increase the likelihood of hormonal recoil) • Recoil leading to hyperglycemia

After the training, the predictor will process a large set of data and assign conformity to each event. In addition, if a recoil of GL is identified (regardless of the cause) the combined contribution on daily average GL and estimated HbAlc levels is analyzed by combining the hypoglycemic event (lowering average- and estimated HbAlc) and the recoil phase (may last for hours and increase the average- and estimated HbAlc level).

From this analysis, a hypoglycemic driven increase in mean blood GL can be identified.

Hypo identification, classification and recoil classification.

By identifying all hypoglycemic events, trends and patterns over time and days can be analyzed. Hence, certain “windows in time” with a high presence of hypoglycemic events can be identified. These could, in turn, be explained by certain behaviors or routines in everyday life which will have to be addressed in dialog with the patient. Based on the systematic classification of hypoglycemic events it can be identified the root cause in relation to the current insulin treatment which can be used as a basis for treatment recommendations. For example, if a patient displays frequent hypoglycemic episodes at night due to a too high basal pressure of insulin the recommendation would be to reduce the basal insulin dose. If instead there are frequent hypoglycemic episodes due to corrective insulin boluses administered when the GL was above target range, the first recommendation would be to avoid corrective doses and instead work with the underlying cause of the high GL, which could be due to a low basal insulin pressure. If a patient with frequent hypoglycemic events use a concomitant drug known to increase the risk of hypoglycemia it would be suggested to the HCP to find an alternative treatment without this side-effect. In this analysis it is also interpreted self-scanned GL from patients who use an FGM. These data points give a unique insight into whether the patient is aware of the event and if so how he/she handles it. Similarly, by identifying recoil GL following a hypoglycemic event it can be provided feedback on the amount of carbohydrates consumed to counteract a hypoglycemic episode. In addition, it can be estimated the impact of the hypoglycemic episode and the following recoil and provide feedback on how much the metabolic control could be improved by avoiding hypoglycemic events.

Hypo risk score module

The hypo risk score is calculated by the hypo risk score module as a combination of the actual GL value as well as the rate of change of the glucose level dGL. Each sample of GL will enable a score and these scores are summarized by parts of a day, by day or over an individually specified period of time.

The cut-off values for both GL and dGL need to be tuned but the principles are:

• A low GL that is falling yields a high-risk score

• A normal GL that is falling yields a moderate risk

By calculating a hypoglycemic risk score it can, based on an individual number, be classified the glycemic profile and the overall risk of hypoglycemic events. A high-risk score is often related to high variability in GL, which often is caused by inadequate basal insulin pressure and frequent corrective insulin boluses. On the other hand, in a patient with poor metabolic control (i.e. high estimated HbAlc and average GL) and a low hypo risk score the treatment recommendations can be more aggressive in terms of percentage increase of both basal- and bolus insulin doses. In figure 6 is shown one example of indicating the hypo risk score. The score is based upon assessing both the absolute GL value as well as the rate of change dGL. The risk score is highest in case of a low GL and a dGL that indicates a quick decrease of GL. The cut off values given in the illustrated score are just examples and will be parameters that will be tuned with input from clinical practice.

Hyper risk score module

The hyper risk score is calculated by the hyper risk score module as a combination of the actual GL value as well as the rate of change dGL. Each sample of GL will enable a score and these scores are summarized by parts of a day, by day or over an individually specified period of time.

The cut-off values for both GL and dGL need to be tuned but the principles are: • A very high GL that continues rising yields a very high-risk score

• A very high GL that is fluctuating yields a high-risk score

• A high GL that is rising yields a moderate risk

• A GL in the upper normal range which is increasing yields a mild risk score

The hyper risk score is based on all episodes with a rapid increase in GL and is a valuable tool much like the hypo risk score in order to summarize the overall risk in one value.

High levels of hyper risk score are often related to inadequate insulin boluses at meals which will result in a rapid increase in GL. Another common cause is ingestion of carbohydrate snacks without administering insulin. In figure 7 is shown one example of indicating the hypo risk score. The score is based on assessing both the absolute GL value as well as the rate of change dGL. The risk score is highest in the case of a high GL and a dGL that indicates a quick increase of GL. The illustrated cut off values are just examples and will be parameters that will be tuned with input from clinical practice.

Prandial event module

A prandial event filter in the prandial event module is configured to detect meals without knowledge on bolus insulin and carbohydrate registrations. If such registrations are available this step is not needed but, as stated above, most patients do not consistently register insulin doses and carbohydrate intake. This module has been described in detail above.

A pre- and post-prandial filter is provided that is configured to identify meals without knowledge of insulin administration and carbohydrate intake. In most CGM/FGM, it is possible to register insulin doses and carbohydrates consumed, but most patients do not register all meals and/or insulin doses. For large scale analysis, it is, therefore, crucial to be able to identify these events without this data input. Based on this analysis the algorithm can systematically evaluate the accuracy of insulin bolus doses at each meal based on the GL prior to the meal compared to that two (2) hours after a meal, which ideally should be equal. Based on this analysis the algorithm can directly advise on how to adjust the bolus insulin doses. By excluding all prandial events from the daily curve the algorithm can evaluate the effect of the basal insulin dose which is the main regulator of GL under fasting conditions. By applying this filter the algorithm can hence give recommendations on both bolus- and basal insulin doses.

Cluster analysis

The cluster analysis is based on histograms of both the GL and the dGL. A histogram is a graph that displays the number of samples from a time series that exists in a specific interval, i.e. a bin. In that way, a large number of samples can be summarized in one graph. In this case, the number of samples in each bin has been replaced by time in bin or percentage of time in the specific analysis period. In the case described herein, each sample is Ts (0.1-15 min) and the time in a specific bin is measured in hours.

It is currently identified 8 clusters of GL profiles, but the number of clusters is not constant and may increase as more patient data are entered. The bin size is set to 1 mmol/L and named of the midpoint. E.g. interval 4 to 5 is named 4.5. The GL clusters are named A, B, ... , H with capital letters and in the order of rising mean GL. Both the GL distribution and the dGL distribution may be clustered using a k-nearest neighbour algorithm, or any other applicable algorithm.

The dGL is analyzed in two ways:

1) With the same histogram analysis as the GL.

2) With measures of the statistical distribution.

The latter is the method that is currently used.

From a clinical perspective it is mainly two characteristics that are useful: How many samples represent a GL that is quickly falling or rising, i.e. the tails of the distribution, and how the center is skewed towards rising or falling. Therefore, in one exemplary implementation, for the dGL distribution the Skewness and Kurtosis are calculated. Skewness is a measure of symmetry, or more precisely, the lack of symmetry. A distribution, or data set, is symmetric if the left and right part of the center point are equal. Kurtosis is a measure of whether the data are heavy-tailed or light-tailed relative to a normal distribution. The “patient-time intervals” (day-weeks-months) are clustered in 8 dGL profiles with increasing kurtosis and varying skewness. The dGL clusters are named a, b, c...h where the h cluster has the highest dGL values, i.e. highest kurtosis. Also other algorithms may be applied, but it is also possible to use the bin-density directly.

The combination of GL and dGL cluster forms a position in the classification space. A patient in e.g. [C,a] has a tight distribution of GL and small variations of dGL. On the other hand, a patient in [H,h] has a very problematic metabolic control with GL over the whole range and very fast swings from low values to high values. In figure 5 one illustrative example of a classification space showing combined GL and dGL clusters.

The clinical conclusion is that a patient cannot improve the GL control without first reducing the dGL thus forming the trajectory towards improved glycemic control. This presents a preferred direction of improvement for patients with poor glycemic control, starting with reducing the variations before the mean values are reduced.

Each combination in the space will also be associated with a set of root causes of why metabolic control is not optimal.

The classification space of GL and dGL may be extended to the third dimension with the same kind of histogram for physical activity.

GL and dGL Cluster Identification

The combination of GL and dGL cluster forms a position in the classification space. A patient in e.g. [C,a] has a tight distribution of GL and small variations of dGL. On the other hand, a patient in [H,h] has a very problematic metabolic control with GL over the whole range and very fast swings from low values to high values. Each position in the classification space is associated with one or several underlying root causes and are presented in general terms to the patient and HCP, and based on all other parameters analyzed, the most important underlying root cause for that individual will be identified. In addition, the classification space provides a trajectory and plan or improvement.

Providing a two-dimensional cluster classification space defined by clusters of GL and dGL, respectively, where each cluster is a histogram including a number of events that fulfills the requirements of that cluster, comprising a predetermined number of clusters each having different GL/dGL profiles, e.g. 8 clusters of different GL/dGL profiles. Treatment planning - diabetes analysis module

Based on the automated analysis the most likely root causes for suboptimal glucose control are identified. Underlying root causes can include too high or low basal insulin pressure, hypoglycemic episodes due to repeated correction insulin doses, too high or low insulin doses at meals, and much more. The underlying root causes will be systematically evaluated based on some or all parameters included in the block diagram shown in figure 3.

By analyzing a large number of patients and weeks and classifying these weeks into clusters like [C,a] and [B,d] we can identify subgroups of patients with different profiles or signatures. The estimated HbAlc is calculated for each patient and the average HbAlc is calculated for each cluster combination, i.e. 8x8= 64 sets of patient weeks. Not all combinations are possible and the movements in the classification space over time follow specific patterns, much like the predefined moves in chess where the moves for different checkers are predefined. Based on these large scale analyses a database of patient recorded GL and matching GL and dGL clusters have been built. By using the database the most suitable trajectory towards an improved metabolic control may be identified based on the movement in the classification space that has been observed for other patients. This is like finding a path in the forest where the straight-line from point X to point Y is usually not the most appropriate path. By using the collected experience from our database on how patients can move in the classification space it can be forecasted the most efficient trajectory which will be presented to the HCP and in turn to the patient.

The treatment recommendations will be a summary of all individual recommendations generated by each parameter of analysis. These will be weighted together in order to give a conform recommendation.

The analysis of most importance for the treatment recommendation is the combination of GL and dGL cluster identification with the estimated HbAlc level. In current clinical practice, HbAlc levels are used as a single measure of treatment goals but it does not take into account the level of glucose excursions and hypoglycemic events. Hence, a patient can currently be classified as optimally treated despite experiencing volatile glucose excursions and frequent hypoglycemic episodes. By combining the estimated HbAlc levels with the cluster identification defined herein the bar will be raised for the treatment goals and be able to quickly identify patients with a high degree of glucose variability even if the estimated HbAlc is within the target range.

Finally, with references to figure 8, an overall workflow will be discussed involving the system and method described above.

The layout of the overall workflow loops each time a patient meets with his/her health care professionals (HCP) with new analysis, understanding the current situation and planning the next steps towards the long term goal.

The flow starts with the patient uploading data from FGM/CGM and other devices such as activity trackers etc. In this, the consistency of data is checked to remove possible outlier samples. In the following step the essential features are calculated to facilitate subsequent machine learning steps. In machine learning, pattern recognition, and in image processing, feature extraction starts from an initial set of measured data and builds derived values (features) intended to be informative and non-redundant, facilitating the subsequent learning and generalization steps that will enable improved interpretations of the data.

In the following step, the features are analyzed together with the treatment target to find root causes behind any deviations from the target. If there is no deviation, the immediate recommendation will be an unaltered treatment recommendation, and the following process steps are omitted.

If there is a deviation between the treatment target and the current situation, the inferred root causes are used to define a short-term target that is realistic to reach within a defined time of follow-up which is a step on the path towards the long-term target, i.e. optimal glucose control with a high degree of flexibility. Based on the short-term target the trajectory for the improvements to address is defined. Finally, the treatment adjustment proposals based on the short-target are derived and presented to the HCP along with the proposed trajectory towards the fulfilment of the long-term target. These adjustments proposed to the HCP will have to be approved based on clinical judgment before presented to the patient. The HCP can also modify the treatment plan if he/she finds this suitable, these modifications will be stored for future augmentation of the algorithm after approval of a scientific board. Thus, in order to fully utilize the potential of CGM/FGM in diabetes care, it has been developed a diabetes analysis system that can generate automated interpretations and, in addition, generate recommendations for treatment modifications. The system will be a much needed and valuable tool for HCP in order to improve diabetes care. The present invention is not limited to the above-described preferred embodiments.

Various alternatives, modifications, and equivalents may be used. Therefore, the above embodiments should not be taken as limiting the scope of the invention, which is defined by the appending claims.