Interpreting blood GLUcose data with R package iglu.

Continuous Glucose Monitoring (CGM) data play an increasing role in clinical practice as they provide detailed quantification of blood glucose levels during the entire 24-hour period. The R package iglu implements a wide range of CGM-derived metrics for measuring glucose control and glucose variability. The package also allows one to visualize CGM data using time-series and lasagna plots. A distinct advantage of iglu is that it comes with a point-and-click graphical user interface (GUI) which makes the package widely accessible to users regardless of their programming experience. Thus, the open-source and easy to use iglu package will help advance CGM research and CGM data analyses. R package iglu is publicly available on CRAN and at https://github.com/irinagain/iglu.

Introduction

Continuous Glucose Monitors (CGMs) are small wearable devices that record measurements of blood glucose levels at frequent time intervals. As CGM data provide a detailed quantification of the variation in blood glucose levels, CGMs play an increasing role in clinical practice [1]. While multiple CGM-derived metrics to assess the quality of glycemic control and glycemic variability have been developed [2], their complexity and variety pose computational challenges for clinicians and researchers. While some metrics (e.g. mean) can be directly calculated from the data, others require additional pre-processing steps, such as projecting glucose measurements on an equidistant time grid (e.g. CONGA, SDbdm) or the imputation of missing data.

We are aware of two existing R packages for CGM data analyses: CGManalyzer [3] and cgmanalysis [4]. These packages are primarily designed to read and organize CGM data, rather than provide an easy-to-use interface for a comprehensive evaluation of available CGM characteristics. While their analytical utility is undeniable, a substantial number of CGM metrics summarized in [2] is not available. Moreover, both packages require the users to have considerable programming experience, which might be a limiting factor for researchers seeking robust and accessible analytical solutions. EasyGV is another free CGM software in the form of a macro-enabled Excel workbook [5], and thus is more accessible compared to CGManalyzer and cgmanalysis. However, it only allows calculation of 10 metrics. Furthermore, unlike R, Excel is not a script-based programming language, which makes it less desirable for those users who want to create reproducible scripts for all data processing and metric calculation steps. Thus, there remains a need for open-source software that (i) computes most of the CGM metrics available from the literature, and (ii) meets the needs of researchers with varying levels of programming experience.

Our R package iglu calculates all CGM metrics summarized in [2] in addition to several others [6, 12, 19], a full list of currently implemented metrics is summarized in Table 1. A comparison of functionality with CGManalyzer [3] and cgmanalysis [4] is in Table 2. Additional improvements include advanced visualization with lasagna plots [21], and provided example CGM datasets that make it easy to get started. Finally, a distinct advantage of iglu over existing open-source CGM software is a point-and-click graphical user interface (GUI) which makes the package accessible to users with little to no R experience.

Table 1

Summary of CGM metrics implemented in iglu.

Metric name	iglu function	Reference	Time-dependent
Active percent	active_percent	Danne et al. (2017) [6]	Yes
ADRR	adrr	Kovatchev et al. (2006) [7]	Yes
AUC	auc	Danne et al. (2017) [6]	Yes
COGI	cogi	Leelarathna et al. (2019) [8]	No
CONGA	conga	McDonnell et al. (2005) [9]	Yes
CV	cv_glu	Rodbard (2009) [2]	No
CV subtypes	cv_measures	Umpierrez & Kovatchev (2018) [10]	Yes
eA1c	ea1c	Nathan et al. (2008) [11]	No
GMI	gmi	Bergenstal et al. (2018) [12]	No
GRADE	grade	Hill et al. (2007) [13]	No
GRADEeu	grade_eugly	Hill et al. (2007) [13]	No
GRADEhyper	grade_hyper	Hill et al. (2007) [13]	No
GRADEhypo	grade_hypo	Hill et al. (2007) [13]	No
GVP	gvp	Peyser et al. (2018) [14]	Yes
HBGI	hbgi	Kovatchev et al. (2006) [7]	No
LBGI	lbgi	Kovatchev et al. (2006) [7]	No
Hyper Index	hyper_index	Rodbard (2009) [2]	No
Hypo Index	hypo_index	Rodbard (2009) [2]	No
IGC	igc	Rodbard (2009) [2]	No
IQR	iqr_glu		No
J-index	j_index	Wojcicki (1995) [15]	No
MAD	mad_glu		No
MAG	mag	Hermanides et al. (2010) [16]	Yes
MAGE	mage	Service & Nelson (1980) [17]	No
Mean	mean_glu		No
Median	median_glu		No
MODD	modd	Service & Nelson (1980) [17]	Yes
M-value	m_value	Schlichtkrull et al. (1965) [18]	No
Percent Above	above_percent		No
Percent Below	below_percent		No
Percent in range	in_range_percent		No
Quantiles	quantile_glu		No
Range	range_glu		No
ROC (Rate Of Change)	roc	Clarke & Kovatchev (2009) [19]	Yes
SD of ROC	sd_roc	Clarke & Kovatchev (2009) [19]	Yes
SD	sd_glu		No
SD subtypes	sd_measures	Rodbard (2009) [20]	Yes

Table 2

Comparison of iglu functionality with existing R packages for CGM data.

Metric name	CGManalyzer	cgmanalysis	iglu
Active percent	×	✓	✓
ADRR	×	×	✓
AUC	×	✓	✓
COGI	×	×	✓
CONGA	✓	✓	✓
CV subtypes (mean, sd)	×	✓	✓
CV median	×	✓	×
eA1c	×	✓	✓
Excursions count (over/under)	×	✓	×
GMI	×	✓	✓
GRADE	×	×	✓
GVP	×	×	✓
HBGI/LBGI	×	✓	✓
IGC	×	×	✓
J-index	×	✓	✓
MAG	×	×	✓
MAGE	×	✓	✓
MODD	✓	✓	✓
M-value	×	×	✓
Multiscale entropy	✓	×	×
Percent in range	×	✓	✓
Time in range	✓	✓	×
ROC (Rate of Change)	×	×	✓
SD subtypes	×	×	✓
Summary statistics	✓	✓	✓
Day/night metrics (SD, min, max, AUC)	×	✓	×
GUI for calculation	×	×	✓

Features

Example data

The iglu package is designed to work with CGM data provided in the form of a data frame with three columns: id (subject identifier), time (date and time stamp) and gl (corresponding blood glucose measurement in mg/dL). The package comes with two example datasets that follow this structure. example_data_5_subject contains Dexcom G4 CGM measurements from subjects with Type II diabetes.

example_data_5_subject[1:2,]

id           time   gl

1 Subject 1 2015-06-06 16:50:27 153

2 Subject 1 2015-06-06 17:05:27 137

example_data_1_subject is a subset corresponding to one subject. These data are part of a larger study analyzed in [22].

Illustration of metrics use

Table 1 summarizes all the metrics implemented in the package, which can be divided into two categories: time-independent and time-dependent. All the functions assume that the glucose value are given in mg/dL units. Each function has detailed documentation that describes all the input parameters (and their default values) as well as the specific algorithm used for metric calculation. Full documentation can be accessed from the R console after loading the iglu package (e.g. ? active_percent) or from the accompanying website (https://irinagain.github.io/iglu/).

One example of a time-independent metric is Hyperglycemia index [2], the corresponding iglu function returns a single value for each subject in a tibble object [23]. Subject id will always be printed in the id column, and metrics will be printed in the following columns.

hyper_index(example_data_5_subject)

# A tibble: 5 x 2

id    hyper_index

      

1 Subject 1    0.391

2 Subject 2    4.17

3 Subject 3    1.18

4 Subject 4    0.358

5 Subject 5    2.21

In this example, Subject 2 has the largest Hyperglycemia index, indicating the worst hyperglycemia. This is reflected in percent of times Subject 2 spends above fixed glucose targets.

above_percent(example_data_5_subject)

# A tibble: 5 x 4

id    above_140 above_180 above_250

           

1 Subject 1   26.7    8.40   0.446

2 Subject 2   96.8   74.4   26.7

3 Subject 3   51.5   18.9    5.74

4 Subject 4   32.9    4.97   0

5 Subject 5   70.8   38.1   11.6

The default target values of 140, 180 and 250 mg/dL in above_percent can be adjusted by the user.

Examples of time-dependent metrics include measures of glycemic variability such as CONGA [9] and standard deviation of rate of change [19]. In the example data, the standard deviation of rate of change is the highest for Subject 5:

sd_roc(example_data_5_subject)

# A tibble: 5 x 2

id    sd_roc

   

1 Subject 1 0.620

2 Subject 2 0.642

3 Subject 3 0.831

4 Subject 4 0.617

5 Subject 5 1.05

This provides an additional level of CGM data interpretation, since frequent or large glucose fluctuations may contribute to diabetes-related complications independently from chronic hyperglycemia [24]. Other metrics of glycemic variability confirm the high fluctuations in Subject 5, with all but one of the subtypes of standard deviation being the largest for Subject 5 [20]:

sd_measures(example_data_5_subject)

# A tibble: 1 x 7

id     SdW SdHHMM SdWSH SdDM  SdB SdBDM

   

1 Subject 1 26.4  19.6 6.54 16.7 27.9 24.0

2 Subject 2 36.7  22.8 7.62 52.0 48.0 35.9

3 Subject 3 42.9  14.4 9.51 12.4 42.8 42.5

4 Subject 4 24.5  12.9 6.72 16.9 25.5 22.0

5 Subject 5 50.0  29.6 12.8 23.3 50.3 45.9

The calculations of these variability metrics require evenly spaced glucose measurements across time; however, this is not always the case in practice due to missing values and misalignment of CGM measurement times across subjects (e.g. measurement at 17:30 for Subject 1, but at 17:31 for Subject 2). In order to create a uniform evenly spaced grid of glucose measurements, iglu provides the function CGMS2DayByDay. This function is automatically called for metrics requiring the evenly spaced grid across days, however the user can also access the function directly. The function works on a single subject’s data, and has three outputs.

str(CGMS2DayByDay(example_data_1_subject))

List of 3

$ gd2d     : num [1:14, 1:288] NA 112.2 92 90.1 143.1 …

$ actual_dates: Date[1:14], format: “2015-06-06” “2015-06-07” …

$ dt0      : num 5

The first part of the output, gd2d, is the interpolated grid of values. Each row corresponds to one day of measurements, and the columns correspond to an equi-distant time grid covering a 24 hour time span. The grid is chosen to match the frequency of the sensor (5 minutes in this example leading to (24*60)/5 = 288 columns), which is returned as dt0. The linear interpolation is only performed between observed CGM values that are less than inter_gap minutes apart, otherwise missing values are inserted. By default, the function uses inter_gap = 45 minutes, however this value can be adjusted by the user. The returned actual_dates allows one to map the rows in gd2d back to original dates. The achieved alignment of glucose measurement times across the days enables both the calculation of corresponding metrics, and the creation of lasagna plots discussed in the next section.

Finally, iglu also allows one to assess the reliability of estimated CGM metrics by providing information on the number of days of data collection together with % of time the CGM device was active during those days (% of non-missing measurements). This information is automatically provided as part of the standardized AGP output discussed in the next section, and can also be obtained directly by calling the function active_percent.

active_percent(example_data_5_subject)

# A tibble: 5 x 5

id    active_percent ndays   start_date    end_date

            <dttm>        <dttm>

1 Subject 1     79.8 12.7 days 2015-06-06 16:50:27 2015-06-19 08:59:36

2 Subject 2     58.9 16.7 days 2015-02-24 17:31:29 2015-03-13 09:38:01

3 Subject 3     92.1 5.8 days 2015-03-10 15:36:26 2015-03-16 10:11:05

4 Subject 4     98.7 12.9 days 2015-03-13 12:44:09 2015-03-26 10:01:58

5 Subject 5     95.8 10.6 days 2015-02-28 17:40:06 2015-03-11 08:04:28

According to [25], 10-14 days of CGM measurements are generally sufficient for assessing outcomes in clinical trials, and for determining potential adjustments to diabetes management based on retrospective review. Given these recommendations, the estimates of CGM parameters for Subject 3 are less reliable than the estimates for other subjects in the example dataset.

To investigate the agreement of metrics calculations with existing software, we selected a subset of metrics for cross-comparison of CGManalyzer, cgmanalysis and iglu on the example dataset. We found that the summary statistics (min, max, mean, quantiles, total SD) are in perfect agreement for all 5 subjects across all three packages. Additionally, cgmanalysis and iglu have perfect agreement in the values of GMI, eA1C, CV, % of glucose values in range and J-index. There is a slight (less than 1%) disagreement in % of time CGM is active between iglu and cgmanalysis, which we suspect is due to varying rounding precision. There is also some disagreement in all three packages in CONGA values (using a common parameter of n = 1 hour), which we suspect is due to differences in handling missing values and in grid interpolation schemes. Overall, the results show good agreement between the three packages as the calculated metrics either match perfectly or are close. Table 3 shows explicit values for Mean, SD, % time CGM is active, GMI, J-index and CONGA (n = 1 hour) for all five subjects across all three packages.

Table 3

Comparison of selected metrics across R packages using example dataset.

Metric name	Subject id	CGManalyzer	cgmanalysis	iglu
Mean	Subject 1	123.7	123.7	123.7
	Subject 2	218.5	218.5	218.5
	Subject 3	154.0	154.0	154.0
	Subject 4	129.7	129.7	129.7
	Subject 5	174.6	174.6	174.6
SD	Subject 1	33.3	33.3	33.3
	Subject 2	52.4	52.4	52.4
	Subject 3	44.8	44.8	44.8
	Subject 4	29.1	29.1	29.1
	Subject 5	55.6	55.6	55.6
% Time CGM is Active	Subject 1	×	79.0	79.8
	Subject 2	×	58.0	58.9
	Subject 3	×	92.0	92.1
	Subject 4	×	98.0	98.7
	Subject 5	×	95.0	95.8
GMI	Subject 1	×	6.3	6.3
	Subject 2	×	8.5	8.5
	Subject 3	×	7.0	7.0
	Subject 4	×	6.4	6.4
	Subject 5	×	7.5	7.5
J-index	Subject 1	×	24.6	24.6
	Subject 2	×	73.3	73.3
	Subject 3	×	39.5	39.5
	Subject 4	×	25.2	25.2
	Subject 5	×	54.4	54.4
CONGA (n = 1 hour)	Subject 1	24.7	25.7	25.9
	Subject 2	19.9	25.1	25.7
	Subject 3	38.2	41.0	39.5
	Subject 4	23.2	22.6	23.3
	Subject 5	49.0	50.0	49.3

Visualizations

The iglu package has several visualization capabilities, which are summarized in Table 4. The main function is plot_glu, which by default provides a time series plot for each subject. The glucose values are plotted on a linear scale, however an optional log parameter can be used to display glucose on a semilogarithmic scale [26]. Fig 1 illustrates the default output on example data with the horizontal red lines indicating user-specified target range, the default range is [70, 180] mg/dL [27]. The visual inspection of the plots confirm the previous conclusions from comparison of Hyperglycemia index and metrics of glycemic variability across subjects: the majority of measurements for Subject 2 are above 180 mg/dL, however the variability is larger for Subject 5.

Table 4

Summary of iglu visualization capabilities.

Function call	Visualization description	Main parameters
plot_glu	Multiple plot types: time series and lasagna	plottype, lasagnatype
plot_lasagna	Lasagna plot of glucose values for multiple subjects	datatype, lasagnatype
plot_lasagna_1subject	Lasagna plot of glucose values for a single subject	lasagnatype
plot_roc	Time series of glucose values colored by rate of change (ROC)	subjects, timelag
hist_roc	Histogram of rate of change (ROC) values	subjects, timelag
agp	Ambulatory Glucose Profile (AGP)	maxd, daily

Fig 1

Time series plots for five subjects.

Selected target range is [70, 180] mg/dL.

Another visualization type is provided via lasagna plots [21], which use a color grid rather than a number scale to visualize trends in data over time. The lasagna plots in iglu can be single-subject or multi-subject. The single-subject lasagna plot has rows corresponding to each day of measurements with a color grid indicating glucose values (Fig 2A). An optional within-time sorting across days allows one to investigate average glucose patterns as a function of 24 hour time periods (Fig 2B). The multi-subject lasagna plot has rows corresponding to subjects, with a color grid indicating glucose values across the whole time domain, or average glucose values across days. The highest glucose values are displayed in red, whereas the lowest are displayed in blue. Thus, the numerical glucose values are mapped to color using the gradient from blue to red (Fig 2), which corresponds to the default ‘blue-red’ color scheme. An alternative ‘red-orange’ color scheme can be selected by the user by corresponding modification of the ‘color_scheme’ parameter (using the gradient from red to green to yellow to orange, with green corresponding to values in specified glucose range). Fig 2C displays a customized multi-subject lasagna plot for example data that displays average glucose values across days for each subject; this plot is produced by the following call.

Fig 2

Lasagna plots.

(A) unsorted and (B) time-sorted lasagna plot for Subject 1; (C) unsorted customized multi-subject lasagna plot based on average values across days.

plot_lasagna(example_data_5_subject, datatype = “average”,

midpoint = 140, limits = c(60, 400))

The midpoint specifies the glucose value (in mg/dL) at which the color transitions from blue to red (the default is 105 mg/dL), whereas the limits specify the range (the default is [50, 500] mg/dL). From Fig 2 one can for example infer that the glucose values for Subject 1 tend to be the highest in late afternoon (≈ 15:00—20:00). One can also infer that Subject 1 tends to have the lowest glucose values during night time hours (0:00—6:00) compared to the other four subjects.

While lasagna plots are very similar to stacked bar charts introduced in [28], there are two main differences. First, the stacked bar charts split the glucose values into a fixed number of categories (based on specified glucose cutoffs), where the same color is used within each category. In contrast, the lasagna plots use gradient fill, thus the gradient of the color changes continuously with the change in glucose values. We believe this provides more detailed information on the subject’s glucose profile. Secondly, the stacked bar charts in [28] are created for one subject at a time. In contrast, iglu allows one to create lasagna plots for multiple subjects at once. Using datatype = ‘average’ with lasagnatype = ‘subjectsorted’ facilitates direct cross-comparison of glucose distributions across subjects, whereas lasagnatype = ‘timesorted’ facilitates assessment of population-level trends. Fig 3 shows both types of plots. Fig 3A shows that Subject 2 has the highest levels of hyperglycemia, whereas Subjects 1 and 4 have the lowest levels of hyperglycemia. Fig 3B shows that among the 5 subjects, hyperglycemia is most common in the later afternoon, with the times around 4pm (16:00) and 9pm (21:00) showing the highest glucose values.

Fig 3

Multi-subject lasagna plots in ‘red-orange’ color scheme.

(A) sorted within each subject and (B) sorted within each time point across subjects.

In addition to visualizing absolute glucose values, iglu also allows one to visualize local changes in glucose variability as measured by rate of change [19]. There are two types of visualizations associated with rate of change. The first is a time series plot of glucose values where each point is colored by the rate of change at that given time. Points colored in white have a stable rate of change, meaning the glucose is neither significantly increasing nor decreasing at that time point. Points colored red or blue represent times at which the glucose is significantly rising or falling, respectively. Thus colored points represent times of glucose variability, while white points represent glucose stability. Fig 4A shows a side by side comparison of rate of change time-series plots for two subjects. Subject 1 shows significantly less glucose variability than Subject 5. The function call to produce this plot is as follows.

Fig 4

Rate of change visualizations.

(A) time-series and (B) histogram plots of rate of change for two selected subjects from example dataset.

plot_roc(example_data_5_subject, subjects = c(“Subject 1”, “Subject 5”))

Fig 4B shows a side by side comparison of rate of change histogram plots for the same subjects. Once again, the colors show in what direction and how quickly the glucose is changing. The histogram plots allow one to immediately assess the variation in rate of change. Extreme values on either end of the histogram indicate very rapid rises or drops in glucose—a high degree of local variability. In Fig 4, Subject 1 once again shows lower glucose variability by having a narrower histogram with most values falling between -2 mg/dl/min and 2 mg/dl/min. Subject 5 has a shorter, more widely distributed histogram indicating greater glucose variability. The function call to produce this plot is as follows.

hist_roc(example_data_5_subject, subjects = c(“Subject 1”, “Subject 5”))

Finally, iglu allows one to generate an Ambulatory Glucose Profile (AGP) report in accordance with recommendations in [29]. Fig 5 shows an example report for Subject 1, which includes information on data collection period, time spent in standardized glycemic ranges (cutoffs of 54, 70, 180 and 250 mg/dL) displayed as a stacked bar chart [28], glucose variability as measured by %CV, and visualization of quantiles of the glucose profile across days together with daily glucose views.

Fig 5

Ambulatory Glucose Profile (AGP) for Subject 1 generated by iglu.

Relationship between metrics

To illustrate the relationships between different metrics and their interpretation, we calculated all metrics for example data of 5 subjects. Fig 6 shows the heatmap of resulting metrics (centered and scaled across all subjects to aid visualization) created using R package pheatmap [30]. The hierarchical clustering of glucose metrics results in six meaningful groups with the following interpretation (from top to bottom): (1) in range metrics; (2) hypoglycemia metrics; (3) hyperglycemia metrics; (4) a mixture of variability and hyperglycemia metrics; (5) CVsd (standard deviation of CV, coefficient of variation, across days); (6) glucose variability metrics. Interestingly, while CVsd is a measure of glucose variability, it behaves quite differently from other variability metrics in these 5 subjects. The hierarchical clustering of subjects confirms our previous observations that Subject 2 has the worst hyperglycemia (highest values for metrics in group (2)), whereas Subject 5 has the highest glucose variability (highest values for metrics in group (6)). The relationship between a reduced list of metrics has also been studied in [31, 32] using sparse principal component analysis. While [31, 32] focus on selection of a few key metrics to describe glucose variability, our goal here is exploratory analysis to illustrate differences and similarities between all metrics on a given dataset.

Fig 6

Heatmap of all metrics calculated using iglu for 5 subjects with Type II diabetes.

Hierarchical clustering is performed on centered and scaled metric values using distance correlation and complete linkage. The cluster tree for metrics is cut at 6 groups, which can be interpreted as follows (from top to bottom): (1) in range metrics; (2) hypoglycemia metrics; (3) hyperglycemia metrics; (4) a mixture of variability and hyperglycemia metrics; (5) CVsd (standard deviation of CV, coefficient of variation, across days); (6) glucose variability metrics. The heatmap supports that Subject 2 has the worst hyperglycemia and Subject 5 has the highest glucose variability.

GUI via shiny application

The iglu package comes with a shiny application [33], which provides a point-and-click graphical user interface (GUI) for all metric calculations and visualizations. The interface can be accessed from R console by calling

iglu::iglu_shiny()

or directly at https://irinagain.shinyapps.io/shiny_iglu/. The users can load their CGM data in .csv format, and export metrics output to the user’s clipboard or to .csv, .xlsx, or .pdf files (Fig 7A and 7B). Fig 7C shows an example of shiny interface for creating customized visualization plots based on user-loaded data.

Fig 7

Shiny GUI interface for iglu.

(A) loading CGM data in .csv format; (B) calculating user-specified quantiles for each subject; (C) creating customized lasagna plot for the selected subject.

Conclusion

The iglu package is designed to simplify computations of CGM-derived glucose metrics, and assist in CGM data visualization. The current version includes all of the metrics summarized in [2] as well as many others (see Table 1). New metrics will be incorporated into the future versions as they develop. More details on the package functionality together with the full documentation are provided in the package website at https://irinagain.github.io/iglu/.

Several limitations exist when compared to existing CGM software. First, the R interface assumes that the CGM data is already loaded into R as a data frame, which requires users to have sufficient R knowledge for data processing. The Shiny app currently only allows one to load CGM data in .csv format, and thus it also requires initial pre-processing by the user, albeit not necessarily in R. This is not the case for CGManalyzer or cgmanalysis, which can work directly with specialized data formats from many popular CGMs. Nevertheless, continuous development of new CGM meters coupled with varying data formats across meters present definite challenges for any CGM software. Secondly, while the list of metrics implemented in iglu is more comprehensive compared to other R packages on CGM (Table 3), it still lacks some functionality that may be desired as part of the AGP output [6], specifically the count of hypoglycemia/hyperglycemia excursions, and separation of metrics into sleep/wake time periods. Thirdly, while the agreement of metric values across software packages is encouraging, it does not necessarily signify the agreement with gold standard (see also the discussion in [4]). Furthermore, a comprehensive cross-comparison across packages is quite difficult as it requires a careful adjustment for potential differences in default parameters used in metrics calculations, in handling of missing values, and in underlying algorithms used. However, we believe that the explicit metric values provided in Table 3 coupled with public availability of our example dataset will serve as a useful preliminary step towards this endeavor. We hope to address some of these limitations in future iterations by leveraging complimentary existing open-source CGM software and our own updates to iglu.

From the context of CGM data applications, we acknowledge that an extensive list of metrics may have little utility for individual patient care in day to day clinical practice beyond the commonly used % of glucose values in range, Mean, CV, etc. Despite this, the iglu has important strengths that merit discussion. First, given that CGM is likely to be incorporated in clinical studies outside the realm of Type 1 diabetes, having accessibility to methods for summarizing CGM measures that extend the typical panel is of value. Second, CGM measures provide dynamic characterization of glucose trajectories which can be of immense value when considering the potential impact of conditions that are associated with acute temporal changes in pathophysiological mechanisms that can impact glucose homeostasis. For example, sleep apnea is a common condition that affects 9% of women and 25% of men in the general population. It is well known that sleep apnea is associated with nocturnal repetitive increases in sympathetic activity due to cyclical hypoxemia and recurrent arousals from sleep. Thus, to determine whether these acute changes which are known to increase sympathetic nervous system activity can influence glucose homeostasis measures that capture the dynamic nature of glucose trajectories are needed. Even in clinical scenarios where acute pathophysiological changes are not present, metrics that help probe the temporal nature of glucose are of value. For example, obesity is associated with metabolic flexibility. Having detailed CGM measures that help define the various rate of change (increase and decrease in glucose levels) can provide insight into how conditions such as obesity and polycystic ovary syndrome, alter the diurnal nature of glucose profiles. Furthermore, given the detailed nature of CGM data and the increasing use of acquiring such data, we believe that convenient methods for analyzing CGM data are desperately needed to facilitate the use of CGM methodology by investigators in observational studies and randomized clinical trials.

In summary, while there are existing open-source R packages for CGM data analyses [3, 4], these packages focus more on CGM data reading than exhaustive metric implementation, and require programming experience. Instead, iglu focuses on comprehensive implementation of available CGM metrics and ease of use via accompanying GUI application. All data loading, parameter selection, metric calculations and visualizations are available via point-and-click graphical user interface. This makes iglu accessible to a wide range of users, which coupled with the free and open-source nature of iglu will help advance CGM research and CGM data analyses.

20 Nov 2020

PONE-D-20-30578

Interpreting blood GLUcose data with R package iglu

PLOS ONE

Dear Dr. Gaynanova,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.  Please note that Reviewer 2 made a number of suggestions for modification of the software which should be viewed as optional recommendations.

I have a few comments to add to those of the reviewers:

1) Please perform a careful copy edit as there are typos and missing references.

2) In fig 2c, if these are 24 hour averages how can the x-axis unit be hours?

3) The Shiny interface is an extremely useful step, reducing the need for the user to have programming experience.  However, the user still needs to get the data into 3 column format, which is not the format exported by the CGM software.  Therefore, this step may require programming or manual editing of the data, which could introduce error.

Please submit your revised manuscript by Jan 04 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: The authors present the R package “iglu” and accompanying Shiny app for visualization and analysis of continuous glucose monitor (CGM) data. The software calculates CGM metrics and generates figures not available in other packages, and is accessible to users with little programming experience. It is an excellent piece of software that will significantly ease the burden of analysis for many researchers.

Minor revisions for the paper:

1) There are a couple of small typos, so the paper could do with one more round of copy editing

2) In the interest of fairness, it would be worth including in Table 2 metrics calculated by CGManalyzer and cgmanalysis that are not included in iglu.

3) Please add a little bit more detail on how the package handles missing values. Does the CGMS2DayByDay() function automatically fill in missing data using linear interpolation? Or does it fill in with NA values? Also, the caption of Figure 1 claims that metric calculations are not affected by missing glucose values, but this cannot be true for all metrics so clarification is needed.

4) Figure 4 and the section on “relationship between metrics,” while interesting, seem beyond the scope of this manuscript. The hierarchical-clustering tool does not appear to be available in the Shiny app (although adding it could be extremely useful), which makes the inclusion of this clustered heatmap slightly confusing.

5) Please add some brief comparisons to demonstrate how closely this software agrees with other packages. This does not need to be an in-depth statistical analysis, as that would also be beyond the scope of the paper. However, the primary concern for many readers will be the accuracy of the calculations, so brief side-by-side comparisons between packages would be reassuring.

6) Please add some limitations to the conclusion section.

Minor suggestions for the software:

1) Although the graphing artifact (Figure 1, subject 2) is obvious in this example data, smaller artifacts may be less obvious in real-life data. Missing values should be blank space in the plots to avoid confusion.

2) After loading the 5 subject example data in R, writing to .csv, and loading into the Shiny app, the active_percent() function produces Error: unused arguments (180, 200, 250).

3) The visualizations are generally excellent as they are, but one suggestion would be to look into making the plots interactive using the plotly graphing library in R. This is not necessary for publication, but perhaps a recommendation for future updates.

4) Many researchers use packages like this to generate metrics for further analysis, so it might be nice to have the option to download all the metrics at once rather than manually combining results from multiple functions. Again, this is not a necessary change for publication, but simply a recommendation for the future.

Reviewer #2: Comments to the authors:

1. The paper is well written. This work goes beyond previous methods/software for analysis of CGM data. There is a need for such open source software. This software includes several metrics that were not included in previous software. The work is done well technically.

2. The introduction of Lasagna plots is new and novel. That approach is closely related to the use of stacked bar charts as introduced by Rodbard in 2009, and now included in nearly all outputs for CGM data.It remains to be see to what extent the Lasagna plot is superior to use of the stacked bar chart.

3. The authors note that they might add additional metrics in the future.

New metrics continue to be developed. See for instance Leelarathna et al, re COGI, published in 2020 in Diabetes Technology and Therapeutics.

4. The authors do not include an AGP in their outputs. This is perhaps the most popular component of nearly all displays of CGM data at the present time – along with the stacked bar chart. See Mazze et al, Diabetes Care 1987 and also 2008 2009 and multiple other papers, and subsequent papers from Bergenstal et al. See a recent review from Rodbard in press and online at DTT.

5. Most endocrinologists and other diabetes specialists use 70 and 180 as the cutoffs for in range. The present authors use 70 and 140. The graphs will look more familiar and appropriate to many readers if you use 70 and 180, or even 54 70 180 and 250. See Battelino et al, 2019, Diabetes Care. (63 and 140 are used or proposed for pregnancy).

6. It is reasonable for the authors to use their own nomenclature for their own variables in their program. However, for clarity, the authors might use the nomenclature as established in the literature for a number of variables, e.g. the subclassification of SD, i.e. SDT SDw SDb SDhh:mm SDdm SDb//dm and some others. e.g., bottom of page 4/9

7. Several of the metrics have ‘parameters’, i.e. TIR, TBR TAR MR CONGAn IGC (with a,b,c,d, LLTR ULTR). Please specify what default parameters you are using, and whether or not the end user can adjust those parameters. Cf top of page 4/9. Also SDwsh – what are the parameters for h? and is this for the entire series with all possible starting points, or for particular starting points?

8. Throughout - this reviewer prefers use of ‘allows one to map’ rather than ‘allow to map’ (several other instances for the word allows)

9. Page 5/9: under visualizations, line 5: reference to Section ___ (the number of the section is not currently specified)

10. The color scheme used by the authors is perfectly acceptable – but most of the commercial software for CGM data analysis uses a different color scheme. Authors might to well to build in flexibility and allow the end user to select their own color scheme.

11. Consider the possible option to include a logarithmic scale for glucose (Rodbard 2009 .. separate article than the ones cited).

12. Page 6/9: Authors discuss “worse glucose control” at at least two locations in the paper. But worse has several dimensions – can be in terms of TIR TBR TAR SD CV etc. So authors should be careful in using the term “worse” – it is “worse” in only 1 dimension.

13. Authors seem unaware of two articles by Fabris C et al (with Breton or Cobelli or Kovatchev) using principal components analysis and the high degree of correlation of many of the metrics. These probably should be cited, vis a vis the hierarchical analysis used by the present authors.

14. What algorithm are the authors using for MAGE (please use MAGE in all caps – all uppercase). Peter Baghurst has an algorithm (DTT) written in R. Are you using that one? That has been ‘validated’ or at least tested – see Sechterberger et al.

15. CVsd is an entirely new metric—what does it mean> What is it correlated with? Any place where the authors believe it might be helpful?

16. In your function CGMS2DaybyDay, what is the nature of your smoothing function? Any particular reason why it was selected or what its advantages might be relative to some alternatives? Any indication that it performs better than others.

17. You do not seem to include MAG (DeVries, Hermanides ?) also also see distance traveled (DT from Marling). A recent study from Moscada (?) and Nick Oliver indicates that MAG has the highest value for Discriminant Ratio, a criterion they propose as a basis to select among alternative metrics for various aspects of CGM.

18. Various consensus papers (Bergenstal, Danne, Maahs, Battelino) have discussed the statistics that the consensus groups believed should be presented together with the AGP (and other analyses of the CGM data). Please be sure that you have computed and provide the ones that are currently or recently in vogue.

19. Several authors have investigated how much data must be available to obtain reliable estimates of the parameters. These include Xing et al, Riddlesworth et al, and Nick Oliver or others from his group (may be in press or online at the present time, in DTT).

20. There are two major sets of applications for CGM data: The first is for the care of the individual patient. For this, one does not need or want all possible parameters… there is now a consensus that TIR TAR TBR Mean or median, %CV, and perhaps a very few other parameters are sufficient – in any event they are usually more than either the physician, health care practitioner, patient or patient’s family can digest. So, there is very little demand for new metrics – most unfamiliar, and most highly redundant or at least highly correlated with the few mentioned here.

21. The other major application of CGM data is in the context of clinical trials. Here one is interested in significance testing for superiority or non-inferiority for one or the other treatment, using randomized parallel studies or crossover studies. These often involve multivariate corrections e.g. for baseline A1C, or baseline mean glucose, and for clinical sites, and other subsets of the data. This is what a pharmaceutical laboratory would need. The present article, and program, despite all of its strengths, does not really fulfil the needs to these two major potential groups of users (in my opinion). The current study and paper is still valuable, and publishable, but this reviewer would suggest that the authors try to address or at least acknowledge these two major use-cases, and either try to address them in the present paper, or address them in future studies and manuscripts. Perhaps the lack of the ability of the present study and code to address these important use-cases should be included as a limitation of the study. However, the present code should be useful to others trying to address those cases.

22. Hill and Oliver et al have recently published (or have online) a new version of their EZ GV method (still in Excel, I believe) that might be helpful.

Some of the references cited in my comments above: Some of these might be helpful to the authors in the context of the present paper; others may be helpful in the future, to enable them to better coordinate with the “clinical diabetes” side of the relevant literature.

1. Updated Software for Automated Assessment of Glucose Variability and Quality of Glycemic Control in Diabetes.

Moscardó V, Giménez M, Oliver N, Hill NR.Diabetes Technol Ther. 2020 Oct;22(10):701-708. doi: 10.1089/dia.2019.0416. Epub 2020 Apr 22.PMID: 32195607

2. Assessment of Glucose Control Metrics by Discriminant Ratio.

Moscardó V, Herrero P, Reddy M, Hill NR, Georgiou P, Oliver N.Diabetes Technol Ther. 2020 Oct;22(10):719-726. doi: 10.1089/dia.2019.0415.PMID: 32163723

3. Calculating the mean amplitude of glycemic excursion from continuous glucose monitoring data: an automated algorithm.

Baghurst PA.Diabetes Technol Ther. 2011 Mar;13(3):296-302. doi: 10.1089/dia.2010.0090. Epub 2011 Feb 3.PMID: 21291334

4. Ambulatory glucose profile: representation of verified self-monitored blood glucose data

R S Mazze, D Lucido, O Langer, K Hartmann, D Rodbard PMID: 3552508 DOI: 10.2337/diacare.10.1.111

5. Recommendations for standardizing glucose reporting and analysis to optimize clinical decision making in diabetes: the Ambulatory Glucose Profile (AGP).

Bergenstal RM, Ahmann AJ, Bailey T, Beck RW, Bissen J, Buckingham B, Deeb L, Dolin RH, Garg SK, Goland R, Hirsch IB, Klonoff DC, Kruger DF, Matfin G, Mazze RS, Olson BA, Parkin C, Peters A, Powers MA, Rodriguez H, Southerland P, Strock ES, Tamborlane W, Wesley DM.Diabetes Technol Ther. 2013 Mar;15(3):198-211. doi: 10.1089/dia.2013.0051. Epub 2013 Feb 28.PMID: 23448694

6. J Diabetes Sci Technol . 2009 Nov 1;3(6):1395-401.

doi: 10.1177/193229680900300620. A semilogarithmic scale for glucose provides a balanced view of hyperglycemia and hypoglycemia David Rodbard 1 PMID: 20144394 PMCID: PMC2787040 DOI: 10.1177/193229680900300620

7. Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range.

Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, Bosi E, Buckingham BA, Cefalu WT, Close KL, Cobelli C, Dassau E, DeVries JH, Donaghue KC, Dovc K, Doyle FJ 3rd, Garg S, Grunberger G, Heller S, Heinemann L, Hirsch IB, Hovorka R, Jia W, Kordonouri O, Kovatchev B, Kowalski A, Laffel L, Levine B, Mayorov A, Mathieu C, Murphy HR, Nimri R, Nørgaard K, Parkin CG, Renard E, Rodbard D, Saboo B, Schatz D, Stoner K, Urakami T, Weinzimer SA, Phillip M.Diabetes Care. 2019 Aug;42(8):1593-1603. doi: 10.2337/dci19-0028. Epub 2019 Jun 8.PMID: 31177185 Free

8. International Consensus on Use of Continuous Glucose Monitoring. Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, Garg S, Heinemann L, Hirsch I, Amiel SA, Beck R, Bosi E, Buckingham B, Cobelli C, Dassau E, Doyle FJ 3rd, Heller S, Hovorka R, Jia W, Jones T, Kordonouri O, Kovatchev B, Kowalski A, Laffel L, Maahs D, Murphy HR, Nørgaard K, Parkin CG, Renard E, Saboo B, Scharf M, Tamborlane WV, Weinzimer SA, Phillip M.Diabetes Care. 2017 Dec;40(12):1631-1640. doi: 10.2337/dc17-1600.PMID: 29162583 Free PMC article. Review

9. Outcome Measures for Artificial Pancreas Clinical Trials: A Consensus Report. Maahs DM, Buckingham BA, Castle JR, Cinar A, Damiano ER, Dassau E, DeVries JH, Doyle FJ 3rd, Griffen SC, Haidar A, Heinemann L, Hovorka R, Jones TW, Kollman C, Kovatchev B, Levy BL, Nimri R, O'Neal DN, Philip M, Renard E, Russell SJ, Weinzimer SA, Zisser H, Lum JW.Diabetes Care. 2016 Jul;39(7):1175-9. doi: 10.2337/dc15-2716.PMID: 27330126 Free PMC article. Review

10. Evaluating Glucose Control With a Novel Composite Continuous Glucose Monitoring Index. Leelarathna L, Thabit H, Wilinska ME, Bally L, Mader JK, Pieber TR, Benesch C, Arnolds S, Johnson T, Heinemann L, Hermanns N, Evans ML, Hovorka R.J Diabetes Sci Technol. 2020 Mar;14(2):277-283. doi: 10.1177/1932296819838525. Epub 2019 Mar 31.PMID: 30931606 Free PMC article.

11. A Review of Continuous Glucose Monitoring-Based Composite Metrics for Glycemic Control. Nguyen M, Han J, Spanakis EK, Kovatchev BP, Klonoff DC.Diabetes Technol Ther. 2020 Aug;22(8):613-622. doi: 10.1089/dia.2019.0434. Epub 2020 Mar 4.PMID: 32069094

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1 Feb 2021

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2 Mar 2021

Interpreting blood GLUcose data with R package iglu

PONE-D-20-30578R1

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Reviewer #1: All comments have been addressed

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Reviewer #1: Yes

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5 Mar 2021

PONE-D-20-30578R1

Interpreting blood GLUcose data with R package iglu

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