Current Osteoporosis Reports

https://doi.org/10.1007/s11914-018-0445-9

BONE AND DIABETES (A SCHWARTZ AND P VESTERGAARD, SECTION EDITORS)

The New Possibilities from “Big Data” to Overlooked Associations

Between Diabetes, Biochemical Parameters, Glucose
Control, and Osteoporosis
Christian Kruse 1,2,3

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review To review current practices and technologies within the scope of “Big Data” that can further our understand-
ing of diabetes mellitus and osteoporosis from large volumes of data. “Big Data” techniques involving supervised machine
learning, unsupervised machine learning, and deep learning image analysis are presented with examples of current literature.
Recent Findings Supervised machine learning can allow us to better predict diabetes-induced osteoporosis and understand
relative predictor importance of diabetes-affected bone tissue. Unsupervised machine learning can allow us to understand patterns
in data between diabetic pathophysiology and altered bone metabolism. Image analysis using deep learning can allow us to be
less dependent on surrogate predictors and use large volumes of images to classify diabetes-induced osteoporosis and predict
future outcomes directly from images.
Summary “Big Data” techniques herald new possibilities to understand diabetes-induced osteoporosis and ascertain our current
ability to classify, understand, and predict this condition.

Keywords Diabetes . Osteoporosis . Fractures . Glucose . Big data . Machine learning

Introduction will allow us to discover new patterns in different domains

Coined as the herald of a new era in all aspects of healthcare,
the term “Big Data” is commonplace in today’s scientific and
clinical practice. The term is seldom exemplified and therefore
subject to many diverse definitions and apprehensions to-
wards embracing the enormous possibilities of these new tech-
nologies. For all medical fields, “Big Data” holds a promise to
improve prediction of both hard and soft endpoints, to im-
prove and expand current classification systems, and to data-
mine existing datasets, biobanks, and images. All of these uses
This article is part of the Topical Collection on Bone and Diabetes
* Christian Kruse
ckruse@dcm.aau.dk
1
Steno Diabetes Center North Jutland, Sdr. Skovvej 15,
9000 Aalborg, Denmark
2
Department of Clinical Medicine, Aalborg University, Sdr. Skovvej
15, 9000 Aalborg, Denmark
3
Department of Endocrinology, Aalborg University Hospital,
Hobrovej 19, 9100 Aalborg, Denmark
that will ultimately help clinicians and patients manage diabe-
tes better than today. If we embrace critical validation and
secure, reproducible procedures, we minimize the risk weak
generalizability to foreign cohorts and the erroneous interpre-
tations and conclusions than result from this approach.
For the association between type 1 and type 2 diabetes
mellitus (T1D and T2D) and osteoporosis [1–8], “Big Data”
can improve our understanding by re-using current reposito-
ries of collected data.
Classification and Prediction Using “Big Data”
“Big Data” is founded in traditional statistics and serves sev-
eral purposes within this framework. Two of these are the
ability to enhance outcome prediction and to classify patients
using existing labels (e.g., T1D and T2D) [9–11].
A common approach in epidemiological studies is to model
one or several predictors to an outcome or classification, e.g.,
the 10-year risk of major osteoporotic fractures or T1D/T2D,
and describe how one or more predictors increase or lower the
overall risk [12–15]. This is frequently performed using a gen-
eralized linear model, e.g., logistic regression, where the odds

ratios (OR) and statistical significance levels serve as metrics
for interpretation. The precision of the final model is in some
studies tested through receiver operating characteristic (ROC;
[16–18]) where probabilities and observed true outcomes are
compared to ascertain sensitivity, specificity, and overall dis-
criminative capability, i.e., the area under the curve (AUC). The
reliability of the individual probabilities is in a few studies
analyzed and calibrated, for instance to ascertain that 50% of
individuals with 50% probability will sustain the outcome [19].
Logistic regression has several strengths, as computing
time is fast, models reproducible, and probabilities often
well-calibrated. Yet there are also several weaknesses.
Increasing the number of included predictors runs the risk of
type-1 and type-2 errors [20–23] and predictive power
weakens with multicollinearity. This is common when com-
bining clinical diabetes mellitus status, bone mineral density
values, anthropometrics, and medication use [24, 25].
Probabilities resulting from logistic regression model can of-
ten form a sigmoid pattern that overestimates the lower end of
the spectrum and underestimates the higher end. This author’s
opinion is that logistic regression is mostly used for historical
reasons as an approachable curriculum of probability theory
and regression modelling in graduate courses and beyond.
Any discussions about alternatives are seldom observed.
A prime concern is the lack of validation and the ways this
affects interpreting models and risk factor estimates. This re-
lates to the improvements that can be brought forward by “Big
Data” and, in particularly, the subfield of “supervised machine
learning” (SML). Whenever a statistical model is built using
100% of data points from one or more cohorts, the model will
perform very well on the modelled data when subjected to
ROC tests. What is less commonly known is that with in-
creased model complexity, i.e., by more predictors, a model
will perform increasingly well on the modelled dataset, but
incrementally worse on new and unseen data points. This is
often due to so-called inappropriately high model variance
[26–28]. Conversely, an inappropriately simple model, i.e.,
the univariate relationship between age and 10-year fracture
risk, would be termed a model of inappropriately high bias
[29, 30]. An optimal prediction or classification model is one
that balances bias and variance optimally. This optimization
can be semi-automated through “Big Data” procedures.
Concretely, datasets are split into one larger portion used for
modelling, termed the “training” dataset, and one smaller por-
tion used for testing the model on new and unseen data points,
termed the “test” dataset [31–34]. The split can be performed
either internally on the same cohort or externally on datasets
collected independently. Using this approach, the first objective
is not to extract ORs followed by precision metrics, but to
establish optimal generalization capability. Only when this
chapter ends do you describe the relative importance of each
predictor. Intuitively, the strength of interpreting any high or
low risk effect size will be vastly different when extracted from
Curr Osteoporos Rep
a model of a low or high model precision, e.g., a model with an
AUC of .67 versus a model with an AUC of .93.
The second concern relates to the opportunity cost involved
when refraining from models outside the scope linear models.
Even since the late 1980s and early 1990s, more advanced
model types in terms of raw predictive power have been avail-
able. These models are continually enhanced and refined
through greater abstraction and flexibility, and with advances
in cloud computing and graphics processing unit (GPU) tech-
nology in recent years, these models are known applicable on
personal computers.
This opens up several new possibilities, as the different
model types can serve different purposes to researchers and
clinicians. Tree-based models (i.e., classification trees [35],
C5.0 [35], and random forest [36]) create a tree-like model
structure based on cut-offs and categories. As these cut-offs
are simple above/below cut-offs that iteratively divide the orig-
inal population, outlier and collinearity issues are minimal and
the interpretability of the final model becomes very intuitive.
A graphical representation can be produced, e.g., that a BMI
> 32 kg/m2, an HbA1c of 78 mmol/mol for males infers a 78%
risk of osteoporotic fractures. Another model type, neural net-
works [37] (i.e., artificial neural network, convolutional neural
networks, and recurrent neural networks) create one or more
sets, or layers, of predictors that are modelled from the orig-
inal set of predictors. When the neural networks model these
layers to the outcome classes, is it able to learn new predictors
that are composites of original data. For instance, a neural
network could include weight and height to create a parameter
similar to BMI, but further nuance this by weighting in sex,
bone mineral density, and other parameters. Through more
and more layers of predictors, incredibly complex information
is fed forward to give probability estimates of the classes.
Further techniques termed ensembling can be used to compile
multiple models to create a bootstrapped “democracy” of
models that “vote” for the most likely outcome. The main
challenge of using these advanced statistical models relates
to computing resources and computing time. For the afore-
mentioned neural network, whether the optimal balance of
variance and bias is found in 1, 5, or 10 hidden layers, with
1, 10, 100, or even 5000 nodes in each layer, is not known a
priori. Only when several different model complexities have
been tested are we able to decide on the optimal parameters.
This is vastly different from logistic regression modelling that
will fit predictors to outcomes in only one way. The opportu-
nities, however, include substantially improved predictive ca-
pability of outcomes, improved classification methods, and a
stern validation method that lends a better argument to
interpreting individual risk factor estimates.
An example of predicting individual diabetes-related
events, i.e., hypoglycemic episodes in DMT, has recently been
shown through machine learning procedures in a work by
Sudharsan et al. [38]. In this work, it is exemplified how
Curr Osteoporos Rep
sensitivity and specificity are presented transparently,
allowing conclusions about risk factors to be seen in this light.
Similarly, work from Kuwait by Farran et al. [39] showed how
multiple outcomes can be modelled at the same time using the
same predictors to utilize data for multiple, simultaneous pur-
poses. And using machine learning to move from cohorts to
individuals in terms of predicting weight loss, Baum et al. [40]
extracted relative importance of specific predictors to isolate
individuals who were more likely than others to benefit from
weight loss intervention in a retrospective dataset.
Clustering Techniques to Discover New “Big Data”
Patterns
The aforementioned SML procedure requires prior knowledge
of labels and classes for each data point. This will often be a
human conclusion, e.g., if a patient is classified as T1D or
T2D. However, one of the greatest possibilities of “Big
Data” in the medical field arises when labels are omitted and
we allow machines to learn for themselves.
This learning procedure thus becomes “unsupervised ma-
chine learning” (USML), describing a setting where labels are
omitted and human supervision therefore removed. Here, sta-
tistical methods are implemented to group data points by math-
ematical similarity or dissimilarity to discover new patterns
within data [41]. The approach can be used to construct a set
of so-called clusters where the data points of each cluster are
deemed to be more structurally coherent in said cluster com-
pared to other clusters [42]. The number of clusters is selected
manually and can theoretically range from 2 to equal the num-
ber of data points. Certain metrics are used to validate the
coherence of each cluster, ranging from perfect separation to
clusters that could result from random chance [43, 44]. The
included variables can be used as-is to locate each point in X-
dimensional space and calculate each between-data point dis-
tance [42], or preceded by reducing the number of studied
variables using so-called dimensionality reduction techniques.
The possibilities of this approach are best exemplified by
highlighting the differences from a similar SML approach. In
current clinical practice, knowledge of age, BMI, C-peptide,
and hemoglobin A1c could be used to classify a patient as
T1D, T2D, or a subtype of diabetes mellitus. If the label of
“diabetes type” is omitted, a USML procedure would instead
establish clusters of similarity or dissimilarity using the same
information. One resulting cluster could intuitively consist of
younger patients with low C-peptide and low BMI, while
another could consist of patients of older age, higher BMI,
and normal to increased levels of C-peptide. However, in-
creasing the number of examined clusters could isolate further
patient groups, e.g., a further phenotype segmentation of T2D
by extra factors such as BMI, high insulin sensitivity, and
comorbidity burden. Outside the scope of pure clinical infor-
mation, organizational information could be included to assist
treatment centers with planning and program development,
e.g., appointment absenteeism and visit durations.
Several studies have implemented clustering algorithms in
DMT, albeit to our knowledge without including osteoporosis
as a part of the included information domains. Nagarajan et al.
used K-means clustering to isolate type-1 DMT, type-2 DMT,
and gestational DMT and reached good accuracy metrics with
this automatic approach [45]. Karasneh et al. clustered DMT
patients using diabetes parameters and depressive symptoms to
discover new patterns and hypotheses [46]. Sanakal et al. [47]
used a combination of clustering and classification to described
DMT patients as healthy or not healthy. The use of novel var-
iables such as ethnicity was used by Okosun et al. [48] to find
patterns of diabetes status within ethnic groups. Pre-diabetes
was also data-mined using clustering by Kim el. [49•] in an
attempt to find risk phenotypes. The possibilities of using dis-
tributed computing are exemplified by Sharmila et al. [50] to
improve computing type and almost use data in real time to
classify DMT patients. Combining clinical features with orga-
nizational traits is also shown by Kagawa et al. [51] in a frame-
work of expert-driven data analysis of DMT.
Image Analysis Using “Big Data”
Using both SML and USML in “Big Data,” we are already
able to use image data directly, especially to improve our
understanding of diabetes-induced osteoporosis (DIO). In cur-
rent osteoporosis practice, imaging techniques such as dual-
energy X-ray absorptiometry (DXA) are used to establish nu-
merical bone mineral density (BMD) values that are then used
for classification (i.e., WHO-defined osteoporosis/osteopenia/
normal bone [52]) and prediction (i.e., FRAX® based 10-year
fracture risk [53]) purposes. Yet certain pitfalls in this ap-
proach are well-known, for example, that greater BMD trans-
lates to higher fracture risk in DIO [1], higher BMD in the
lumbar spine due to vertebral fractures or in the hip due to
osteoarthritis [54], and the seldom discussed fact that a sub-
stantial proportion of fractures occur in patients above the T-
score − 2.5 threshold of the WHO [55].
Using images directly, whether acquired by DXA, comput-
ed tomography (CT), or other modalities, SML and USML
can skip this step to learn a direct link between raw images and
classifications, predictions, and cluster segmentation. In prac-
tice, each pixel of each image is converted to either grayscale
tone (0–255) or red, green, and blue (RGB) signal (0–255 for
each) and used similar to age, C-peptide, and BMI to classify,
predict, and establish clusters. Advanced models such as
convolutional neural networks can discover specific portions
in groups of images that relate to specific outcomes. We can
automate what the human eye can see, e.g., previous vertebral
fractures, osteoarthritis, and malignancy, but also identify spe-
cific conditions that are hard or even impossible to identify by
humans, namely DIO, primary hyperparathyroidism, or 10-

year fracture risk in itself. In contrast to the current WHO
spectrum of bone disease classification, the total dimensional
structure of data could be used to establish specific clusters
directly that could translate to new phenotypes.
The main challenge of this approach relates to computing
power of both model complexity and image resolution. As even
portable phones currently produce images with resolutions of
3072 by 2304 pixels, an image of color would translate to
21,233,664 variables of information. Converging such dimen-
sionality for thousands of images requires substantial, distrib-
uted computing power, and even with dimensionality reduction
techniques, representing data in a reduced way still requires
substantial predictors and infers a loss of predictive or classifi-
cation power. With advances in new processing techniques, i.e.,
GPU-based computing [56], higher bandwidth with distributed
architecture holds great promise to decrease modelling time.
Few examples exist in later years of applying such so-called
deep learning image analysis to classify and predict diabetes-
related outcome. A substantial work by Gulshan et al. [57] used
retinal fundus images to classify diabetic retinopathy using ma-
chine learning and presented very high sensitivity and specific-
ity. Within the past 10 years, similar work has been presented
primarily in diabetic retinopathy as well [58•]. To our knowl-
edge, using image analysis specifically for DIO clustering and
hip fracture prediction has not been performed.
Conclusions
Taken together, the “Big Data” techniques of SML and USML
represent enormous potential to improve prediction and clas-
sification tasks in clinical practice and epidemiological re-
search, and to discover new patterns in data that help research
understand phenotypes in unbiased, data-driven ways. It is
particularly noticeable that the techniques are readily avail-
able, available under open-source licenses and for datasets in
the common scope of 500–100,000 data points, possible to
implement on personal computers for research purposes.
Current challenges exist in terms of computing power, data
quality, and apprehension due to security and privacy con-
cerns, which need to be discussed openly if “Big Data” is to
move from research use to full clinical implementation in our
intended way of improving research quality and certainty of
decisions. Several major retrospective cohorts, e.g., the MrOS
[59] and SOF [60] studies already have data available that
could further our understanding of the association between
DMT and osteoporosis, and how image analysis can improve
our understanding of this field.
Compliance with Ethical Standards
Conflict of Interest Christian Kruse declares no conflict of interest.
Curr Osteoporos Rep
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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