SURVIVAL ANALYSIS OF IN-PATIENT DIABTICS IN FELEGE HIWOT REFERRAL

HOSPITAL, BAHIR DAR, ETHIOPIA: A RETROSPECTIVE COHORT STUDY

Getahun Fiseha1, Asrat Atsedeweyn2, Kidanemariam Alem3

GF: gechfish17@gmail.com

AA: Asrat07@gmail.com

KA: kidanemariam2012@gmail.com
ABSTRACT

Back ground: Diabetes is a serious, chronic disease that occurs either when the pancreas does
not produce enough insulin (a hormone that regulates blood sugar, or glucose), or when the body
cannot effectively use the insulin it produces.

Methodology: The purpose of this study was to identify factors that affect the survival time of
in-patient diabetics in BFHRH. Among 3730 inpatient diabetics who were followed in Bahirdar
Felegehiwot Referral Hospital during 1st September 2011 to August 30 2017, 480 samples (47
children and 433 adults) were selected from 366 children and 3364 adult inpatient diabetic
populations respectively. The samples from the two groups of population were selected using
proportional sample size allocation formula. After selecting proportional samples from the two
groups of populations, systematic random sampling method was employed to select patients that
were participant in the study. To determine factors that affect the survival time of in-patient
diabetics, compare the survival time as well as examine the association between the survival time
with different demographic and clinical variables, the Kaplan Meier estimation method and the
parametric regression model were applied. Result: The result from Kaplan-Meier estimation
revealed that the survival time of IDM patients is significantly related with age, diabetic disease
complication, place of residence, family history of DM, systolic & diastolic blood pressure,
HIV/or TB co-infection, cholesterol level and type of diabetic disease diagnosed. The Log rank
result also indicates that the survival time of diabetic patients is not statistically different in
experiencing the death event among group classified by sex. The result of the Weibull regression
model indicated that complication of DM, family history of DM, systolic blood pressure, HIV /
or TB Co-infection and cholesterol level significantly contributed to shorter survival time of DM
patients. Conclusion: the findings of this study shows that diabetic disease complication, family
history of DM, systolic blood pressure, HIV/or TB co-infections and cholesterol level are major
factors that affect the survival time of in-patient diabetics. The researcher recommended that the
people should be aware on the burden of those risk factors and well informed about the disease.

Key Words: In-patient diabetics, survival time, Weibull survival regression model
Background: Diabetes is a serious, non-communicable diseases (NCDs) that occurs either when
the pancreas does not produce enough insulin (a hormone that regulates blood sugar, or glucose),
or when the body cannot effectively use the insulin it produces. Insulin is a hormone produced in
the pancreas that allows glucose to enter from food to the body’s cells where it is converted into
energy needed by Muscles and tissues to function. A person with diabetes does not absorb
glucose properly, and glucose remains circulating in the blood (a condition known as
hyperglycemia) damaging body tissues over time [1]. This damage can lead to disabling and life
threatening health complications. Diabetes is among the four non communicable diseases that
needs great attention. Chronic diseases, such as diabetes mellitus, cardiovascular diseases
chronic respiratory disease and cancer are increasing worldwide and they are associated with
poor quality of life and increased economic burden; therefore, development of preventive
measures against chronic diseases is imperative [2].

It is clear that in 20 December 2006, the United Nations General Assembly passed Resolution
61/225 declared diabetes as an international public health issue and World Diabetes Day as a
United Nations Day [3]. According to 2016 WHO report on diabetes mellitus, globally, an
estimated 422 million adults were living with diabetes in 2016 and it is expected to rise to 592
million by 2035. This report also showed that in the Middle East and North Africa, more than
35.4 million people were with diabetes in which the number will be increased to 72.1 million by
2040. According to that report on diabetes mellitus, the prevalence of diabetes has increased in
both developed and developing countries during the last four decades due to the abundance of
food, change of feeding habits and lack of exercise [4].

According to the International diabetes Federation, nowadays, one every 11 adults has diabetes
and this number is expected to rise to one in 10 by 2040 and 642 million people will suffer from
diabetes worldwide. According to that report, it is also estimated that, one in 7 births is affected
by gestational diabetes and 542,000 children have type 1 diabetes globally. This report also
showed that one person per 15 seconds dies from diabetes worldwide. UN, 2014 diabetes report
cards showed that each year, more than 200,000 deaths occur due to diabetes mellitus in US [5].
In developing countries, it is known that people in the middle, productive age are particularly
affected by diabetes. In these countries, 75% of all people with diabetes are under 65 years old
and 25% of all people with diabetes are younger than 44 years old. A study done on diabetes in
Sub Saharan Africa 1999-2011 shows that, Type 2 diabetes accounts over 90% of all diabetic
cases and population prevalence proportions ranged from 1% in rural Uganda to 12% in urban
Kenya. This study also shows that the prevalence of type 1 diabetes was low and ranged from 4
per 100,000 in Mozambique to 12 per 100,000 in Zambia. That study also showed that, most
adult diabetic patients were known to be affected by type 2 diabetes, but now, it occurs in
children too. Based on that study, it is understood that, among people with diabetes mellitus in
developing countries, the majority were in the age group of 45 to 64 years while those in
developed countries are above 65 years old [6].

Assessing the prevalence (the percentage of the population with diabetes) and incidence (the
number of new cases) in sub-Saharan Africa is extremely difficult because of the lack of data in
many countries. As in the rest of the world, type 2 diabetes accounts for over 90% of diabetes in
sub-Saharan African. The IDF also estimates that 6,100 new cases of type 1 diabetes are
diagnosed each year in children in sub-Saharan Africa, contributing to a total of 35,700 recorded
cases in the whole region. Data on the condition of people with diabetes in sub-Saharan Africa
and the complications of diabetes that they suffer is very scarce. However, it is estimated that in
Africa, at least 4.51 million have eye complications and 423,500 are blind due to retinopathy,
2.23 million needs dialysis because of kidney damage (nephropathy), 907,500 have
cardiovascular disease, 399,300 have cerebrovascular disease due to neuropathy and 169,400
have lost a foot because of amputation [7].

Ethiopia is one of the top five countries with the highest number of people affected by DM in
Sub-Saharan Africa. In Ethiopia, DM is the second cause for patients to attend for healthcare
service in hospitals of the country [8]. Even though previous reports showed that the prevalence
of DM in Ethiopia was 2.5% in the year 2000 and was estimated to rise to 3.5% by 2030, IDF
2012 report showed that the prevalence of DM in Ethiopia was 3.32 % which shows that the
prevalence of DM is increasing rapidly in the country [9]. According to 2013 report of the
International Diabetes Federation (IDF), the number of people aged 20–79 years and living with
diabetes in Ethiopia was estimated to be 4.9 million and more than 2.9 million people live with
impaired glucose tolerance (IDF, 2013). According to this report, the national prevalence of
diabetes among adults in Ethiopia was 4.36%, and diabetes related death among 20-79 years of
age was 34,262 in 2013 [10]. Therefore, this study was motivated to identify the major risk
factors associated with the survival of IDM patients.

METHODOLOGY

Study area
The study was conducted at Felege Hiwot Referral Hospital, in Bahir Dar, which is the capital
city of Amhara National Regional State, located 565 km away from Addis Ababa in North West
of Ethiopia. The hospital is a tertiary health care level hospital serving the population of
Bahir Dar town and remote areas of northwest Ethiopia. According to its office report, the total
population served by the hospital is about 12 million. It is the only governmental and regional
referral hospital in the city that serves the population in the region as referral center [11].

Study Design and period

A retrospective cohort study was employed to retrieve relevant information from medical
records. In this study, those patients who are 2 years and above and who started DM treatment
since 1st September 2011, and have at least one follow up until August 30/2017 was included.
The patients’ identification number was used to extract the necessary information from different
DM recording formats. Thus, in this study, secondary data that is obtained from patients’ follow
up charts was used. Based on patients’ record, the variables which were assumed to be relevant
for the study had been included.
Inclusion Criteria
Since only inpatient diabetics whose age were two years and above were treated in the Hospital,
the study included/considered all IPD whose age was 2 years and above and started DM
treatment since 1st September and have at least one follow up until August 30/2017 in BFHRH.

Exclusion Criteria

This study excluded those patients who had incomplete registration cards or charts during the
review, those patients who started DM treatment from other healthcare institutions, those who
are being transferred to other healthcare institutions. Again, this study didn’t include women with
gestational diabetes and those diabetic patients who died due to accident.
Sample size determination

Based on Cochran (1977), sample size determination formula, the required sample size for this
study was obtained as follows [12].
2
Z p (1− p)
2
d
n= 2
1 Z p ( 1− p )
1+ ⌈ −1 ⌉
N d
2

n0
= 1
1+ ⌈ n −1⌉
N 0
Where, n is the required sample size, N is the total number of Population, Z is the upper
α Z ² p (1− p)
points of standard normal distribution with α = 0.05 significance level, n 0 = ,
2 d²
n0
n 0will be taken as a desired sample size if , is negligible, meaning that less than 5%, if not, it
N
n0
is appropriate to use equation. In our case, since = 0.15, which is not less than 5%, we had
N
used equation. So, for this study, the estimated proportion of death due to DM was taken as p =
0.07. Hence, the required sample size, together with the above specifications became n =
( 1.96 )2 0.07 (1−0.07)
(0.0213)2
2 = 480.
1 ( 1.96 ) 0.07 (1−0.07)
1+ ⌈ −1 ⌉
N (0.0213)
2

Sampling procedure
Since the source population was constructed from two groups of population, that is from
inpatient diabetics whose age is 15 years and above (adult) and whose age is 2-14 years (child),
first we determined the proportion of samples among the two strata (groups of populations) that
would be participate in the study. The total number of inpatient diabetics was 3730 which was
constructed from 366 children (children from 2-14 years) and 3364 adults (patients 15 years and
above). So, based on proportion to size allocation formula, the member of study participants
from child and adult population groups became approximately 47 and 433 respectively with 480
total number of sample size. After obtaining the proportional number of sample size for each of
the two strata (groups of population), the next step was selecting participants using systematic
random sampling (SRS) in each stratum based on their identification number.
Data collection procedure
Data was collected using checklist in BFHRH and relevant data was taken from IPD follow up
charts. So as to keep the quality of data which was going to be gathered, training was given for
data collectors concerning the relevance of the study and some definitions of the variable on the
questionnaire.

The response variable

The response or outcome variable of this study was the time to discharge measured (in months)
from the date of starting DM treatment until the patient’s discharge date.
Predictor Variables

Socio-demographic factors: Sex, Age, Place of residence

Clinical factors: Diabetic disease complication, Systolic blood pressure, Diastolic blood
pressure, Cholesterol level, Family history of IPD, Type of disease diagnosed, HIV/TB Co-
infection

Data Analysis

Generally, survival analysis is a collection of statistical procedures for data analysis for which
the outcome variable of interest is time until an event occurs (time-to-event data), which is
always nonnegative and has a positively skewed distribution [13].

The variable time, actually records two different things. The survival time for those subjects who
experienced the event (death in our case), and censored time for subjects who were not
experienced the event.
Descriptive Survival
The Survival Function
Let T be non-negative random variable, associated with the actual survival times, t (time of
survival or not getting the event). When the random variable T has a probability distribution with
underlying probability density function f (t) (probability of getting event at time t), then the
cumulative distribution function of T that represents the probability that a subject selected at
random will have a survival time less than some stated value t is then given by [13]:
t
F (t)= P (T<t) =∫ f (u)du, t ≥ 0
0

Having this, the survival function S ( t ) is defined as:

S ( t ) = P (T ≥t) = 1 - F (t)
The survivor function is the probability that an individual survives from the time origin to
sometime t or beyond t. Survival function has the following characteristics [13]:
They are non-increasing, At time t = 0 (There is absolute certainty to ‘survive’ t = 0) this means
S(t) = S(0) = 1; that is, at the start of the study, since no one has experienced the event yet, the
probability of surviving past time 0 is one and, At time t → ∞, S (t) = S (∞) = 0 (There is
absolute certainty to ‘fail’ eventually); that is, theoretically, if the study period increased without
limit, eventually nobody would survive, so the survivor curve must eventually converge to zero.
The Hazard Function
The hazard function is widely used to express the risk or hazard of experiencing the event (death
in our case) at some time t, and is obtained from the probability that an individual experiencing
the event at time t, conditional on he or she has survived (censored) to that time. That is, the
function represents the instantaneous failure rate for an individual surviving to time t.
The hazard function h(t) is defined as: .
f (t ) d
h (t ) = = - { log S (t) }
s (t) dt
The corresponding cumulative hazard function H( t )is defined by:
t

H( t )=∫ h ( u ) du=−log S (t)

0

Hence the survival function can be rewritten as

S ( t ) =exp{−H (t ) }=e-H(t)
The hazard rate is not a probability, it is a probability rate. Therefore, it is possible that a hazard
rate can exceed one in the same fashion as a density function f(t) may exceed one. Survival data
are summarized through estimates of the survival and hazard function. The Kaplan-Meier,
Nelson-Aalen and Life Tables are the three commonly used methods for estimating survival and
hazard functions [13].
Kaplan-Meier Estimator

The Kaplan-Meier estimator is the standard estimator of the survival function and it is used to
estimate the survival time (time of censoring) of a patient and construct survival curves to
compare the survival experience of a patient between different categorical variables. The
Kaplan-Meier estimator of the survival function at time t is given by (David W. Hosmer, 2008).

{ }
r
ni−d i
S ( t i) = ∏
i=1 ni

The simplest way of comparing the survival times of two or more groups graphically is to plot
the Kaplan-Meier curves for these groups on the same graph. The figure in general shows if the
pattern of one survivorship function lies above another, that group which is defined by the upper
curve lived longer, or had a more favorable survival experience, than the group defined by the
lower curve [14]. However, this graph does show whether or not there is a real difference
between the groups. The observed difference may be a true difference, but equally, it could also
be due merely to chance variation. Assessing whether or not there is a real difference between
groups can only be done by using statistical tests. So, among many statistical tests, we have
employed Log-rank test to comparing two or more independent survival curves.
This is the most frequently used test which assumes weights equal to one, i.e. w i=¿ 1. For the
comparison of two groups of survival data the log rank test statistic is given by [14].

[∑ ( ]
r 2

d 1 i−e^ 1i )
i=0
Q LR= r

∑ v^ 1 i
i=0

This test is used to test the hypothesis that

• H0: Two Survival Functions are identical [( s1(t) = s2(t)] or there is no relationship between
survival time & explanatory variables.
• HA: Two Survival Functions are different (( s1(t) ≠ s 2(t)) or there is relationship between
survival time & explanatory variables.
The statistic Q LR follows a chi-square distribution with one degree of freedom.
We will reject Ho and conclude that the two survival functions are not identical if Q LR is
significant and vice-versa.
Parametric models
Parametric model is a model that assumes the survival time follows a known distribution
(Bradburn et al., 2003). Cox-proportional hazard model is not fully parametric, but it is semi-
parametric model that uses partial likelihood estimation method to estimate parameters, because;
even if the parameters of the regression are known, the baseline distribution of survival or failure
time remains unknown. It doesn’t depend on the distributional assumption for the outcomes, but
parametric models have such assumptions and uses maximum likelihood estimation mechanism
to estimate parameters [14]. In this study, advanced models such exponential, Weibull, Log-
normal and Log-logistic parametric models were employed.
Fitting parametric Model
The likelihood function is an expression that yields a quantity similar to the probability of the
observed data under the model [15]. In parametric model, we can estimate the parameters using
the maximum likelihood estimation method (by maximizing the likelihood function) which is
given as [16]:
n
𝐿 (𝛽) = ∏ Li = ∏ ¿¿
i=1

Where h( tᵢ , Xᵢ , β ) = h 0( tᵢ , Xᵢ , β ) is the hazard function for the individual i.

S(tᵢ , Xᵢ , β ) = S0 (t i)exp ⁡(β ' X ) is the survival function for the individual i.
t i, is the survival time for i th individual
δ i, is an indicator of censoring for thei thindividual which is given by 0 for censored and
1 for event/death
x iis a vector of covariates for individual i ( x i 1, x i 2 ,.............. x ip)
Model Selection
The most popular and readily available methods for model fit criteria are Akaike information
criteria (AIC), Bayesian information criterion (BIC) and likelihood ratio test.
1. Akaike information criteria Akaikie (1974) proposed an information criterion (AIC)
statistic to compare different nested and non-nested models. For each model, the value is
computed as [15].
AIC=−2 log (L)+ 2(p+ k )
Where, 𝑝 denotes the number of covariates in the model, L is the maximized value of the
likelihood function for the estimated model and k is the number of model-specific distributional
parameters in the model. For example, k =1, for exponential and k =2, for Weibull, log-normal
and log-logistic models. The model with smaller AIC value will be considered as best fitted
model.
2. Bayesian information criteria (BIC)
The BIC was developed by Gideon E. Schwarz, who gave a Bayesian argument for adopting it.
It is closely related to the Akaike information criterion (AIC). The main advantage of the BIC
approximation is that it includes the BIC penalty for the number of covariates being estimated.
For each model the value is computed as [17].
BIC=−2 log (L)+ P x ln (n)
Where, P is the number of covariates in the model, L is the maximized value of the likelihood
function for the estimated model and n is the number of data points. The model with smaller BIC
value will be considered as the best model.
3. Likelihood ratio test
A likelihood ratio test is a statistical test used to compare the fit of two models, one of which,
(the null model) is a special case of (the alternative model) and is given by [17].
LR=−2[L 0 – L]=2[ L – L0 ]
Where, L0 is the log likelihood with intercept model or null model (model without covariates)
and L is the log likelihood with full or alternative model (model with all covariates).
This test is on the likelihood ratio that expresses how many times more likely the data are under
one model than the other. Model with large LR will be selected as appropriate model.
This likelihood ratio, or equivalently its logarithm, can then be used to compute a p-value.
Different models can be compared using this method.
Assessment of Parametric Model Adequacy
The use of diagnostic procedures for model checking is an essential part of the modeling process.
In parametric model the common method that used to assess the adequacy of parametric models
are graphical methods and residual plots [18].
1. Graphical methods: The graphical methods can be used to check if a parametric distribution
fits the observed data.
 If the survival time follows an exponential distribution, then a plot of log[-log S(t)] vs
log ¿ ) should yield a straight line with slope 1 if the model fits the data well [119]. If the
line is parallel, PH assumptions of Exponential holds true.
  If the survival time follows a Weibull distribution, then the plot of log{-log [S(t)]}
versus log t should yield approximately a straight line starting from intercept log λ with a
slope 𝛾, then the model fits the data well [18 & 19]. If it is parallel, PH assumption of
Weibull holds true.
 If the survival time follows the log-logistic distribution, then the log-logistic assumption
1−S(t )
can be graphically evaluated by plotting log versus log ¿ ). If the model fits the
S(t )
data, then the resulting plot will be a straight line starting from log λ with slop = 𝛾.
 If the survival time follows the log-normal distribution, an assumption can be graphically
1−S(t )
evaluated by plotting log [ ] versus log ¿ ). If the model fits the data, then the
ϕ
resulting plot should be a straight line.
2. Residual plots: Residual plots can be used to assess the adequacy of the models. Residuals
are values that can be calculated for each observation and have the feature that enable us to
know whether the model fits that particular variable or not [20].
Different types of residuals are typical for survival analysis due to the fact that censoring has to
be taken into account. Ordinary residuals from linear or generalized linear models are therefore
often not applicable.
1. Cox-Snell Residuals (overall goodness of fit test)
The residual that is widely used in the analysis of survival data is the Cox-Snell residual, so
called because it is a particular example of the general definition of residuals given by Cox and
Snell (1968). The Cox-Snell residual for the i th individual, i=1, 2, ..., n, is given by [20]:
rci =exp ⁡¿) ^ H i(ti) =−log ^Si (t i)
H o (t i) = ^
^ o (ti) is an estimate of the baseline cumulative hazard function of the i th individual at
Where, H
H i(ti) and ^Si (t i), are estimated values of the cumulative hazard and survivor functions of
time t i, ^
the i th individual at t i . If the plot of Nelson-Aalen (–ln[ ^Si (t i)¿) versus Cox-Snell (rci ) provides
approximately a 45 degree straight line through the origin, this indicates that the selected model
fits the observed data well.
2. Checking proportional hazards assumptions

A. Using Scaled Schoenfeid Residual plots

Residuals: are useful to check the proportionality of the covariates over time, that is, to check
the validity of the proportional hazards assumption. To check proportionality assumption for
each covariate, we plot the scaled Schoenfeid residual on the y- axis against log of survival time
on the x axis. If the model fits the data well, then the residuals will randomly distributed without
any systematic pattern around the zero line which is the reference line. The i th Schoenfeld
residuals for X j , the j th explanatory variable in the model, is given by [21 & 22]:
SCH ji = r c i { X ji − a´ji },

Where, X ji is the value of the j th explanatory variable, j = 1, 2, ……,p, for the i th individual.

∑ X ji exp ( β '´X i)
iε R( t )
a´ji = i

and R( t )is the set of all individuals at risk at timet i.

∑ exp ( β '´X i ) i

iε R (t )
i

If the PH assumption is not valid in the data, we will use AFT models.
B. Test proportional-hazards assumption based on Schoenfeid residuals test
This method is used to test whether the PH assumption is violated or not for covariates
individually or globally. This used to examine to identify if there is correlation among residuals
of covariates and survival time. Global or individual significance of Covariates indicates that the
there is no correlation among covariates and survival times, revealing that the PH assumption is
violated and vice-versa [23].
Ethical consideration
Ethical clearance was obtained from the ethical review committee of the Collage of Natural and
Computational sciences, University of Gondar. The names of the subjects were not extracted to
insure privacy of patients and confidentiality was maintained throughout the data collection and
analysis process. To collect the data, permission was obtained from administrative office of
BFHRH.
RESULTS
In this study, 480 IPD who followed diabetic treatment in BFHRH between 1 st September 2011
and 30th August 2017 were considered. Descriptive statistics of baseline covariates is illustrated
in Table 4.1. The medical cards of those patients were reviewed, out of which 210(43.75%) were
females and 270(56.25%) were males. Among these, 23(10.95%) females and 35(12.96 %)
males were died. From the total IPD participated in this study, 58(12.08%) and 422(87.92%)
died and censored respectively. Of the 480 IPD, 47(9.79%), were children aged 2-14, and the rest
104(21.67%), 49(10.21%), 61(12.71%), 94(19.58%) and 125(26.04 %) were adults aged 15-29,
30-44, 45-59, 60-74 and >=75 years respectively. Among all age groups, the highest proportion
of death 29(30.85%) was occurred in patients with age group 60-74 years followed by
22(17.74%) in patients with age group >=75 years, while proportion of death for patients in the
age group 2-14, 15-29, 30-44, and 45-59years were 2(4.26%), 3(2.88%), 1(2.04%) and 1(1.64%)
respectively. There were 227(47.29 %) and 253(52.71%) patients from rural and urban areas
respectively. The death proportion of rural and urban residents were 31(13.66%) and 27(10.67%)
respectively. Similarly, 334(69.58%) patients had no diabetic complications, while 14(2.92%),
334(69.58%), 21(4.38%), 16(3.33 %) and 54(11.25%), had nephropathy, retinopathy,
neuropathy, CVD and other type of diabetic complications. Among these, the death proportion
was higher, 9(56.25%) for patients who had diabetic neuropathy followed by patients with
diabetic retinopathy 11(52.38%), other types of diabetic complications 12(29.27%), diabetic
nephropathy 4(28.57%), CVD 14(25.93%) and patients without diabetic complication 8(2.4%)
respectively. Out of the total sample, 368(76.67%) patients had negative diabetic family history
while 112(23.33%) patients had positive diabetic family history. Among these, the death
proportion of patients who had positive diabetic family history was 31(27.68%) as compared to
patients who had no negative family history 27(7.34%).

From all patients included in this study, 309(64.38%), 108(22.50%) and 63(13.13%) had normal,
high and uncontrollable baseline systolic blood pressure. Among these, the highest death
proportion was observed in patients with uncontrollable baseline systolic blood pressure
25(39.68 %) followed by patients with high 26(24.07%) and normal 7(2.27%) baseline systolic
blood pressures respectively. Similarly, 282(58.75%), 149(31.04%) and 49(10.21%) of patients
in this study had normal, high and uncontrollable baseline diastolic blood pressure respectively.
Among these, the highest proportion of death was observed among patients with uncontrollable
baseline diastolic blood pressure 16(32.65%) followed by patients with high 21(14.09 %) and
normal 21(7.45%) baseline diastolic blood pressures which respectively.
Among all patients participated in this study, 371(77.29%) patients were without HIV/or TB co-
infections while 51(10.63%), 47(9.79%) and 11(2.29%) were with HIV, TB and both HIV and
TB co-infections respectively. Among these, the highest proportion of death, was occurred on
patients who had both HIV & TB co-infections 8(72.73%) followed by patients with TB
19(40.43%), HIV 19(37.25%) and without HIV/or TB 12(3.23 %) co-infections.
Out of the entire subjects integrated in this study, 325(67.71%) of patients had normal
cholesterol level while 155(32.29%) of the patients had high cholesterol level. Among these, the
highest proportion of death, 40(25.82%) was observed among patients with high cholesterol level
while 18(5.54%) death occurred among patients with normal cholesterol level.
Finally from the perspective of type of diabetes, 375(78.13%) patients were diagnosed with
type 2 DM and 105(21.88%) patients were diagnosed with type 1 DM. The highest
proportion of death 45(42.86%) was occurred in patients with type 1 diabetes as compared to
patients with type2 diabetes 13(22.41%).
Kaplan-Meier Survival Curves
Figure 4.1 presents the estimated survival function and the 95% confidence intervals that provide
an important descriptive measure of the overall pattern of survival time. The survivorship
function estimate in Figure 4.1 describes steadily declining survival probabilities since the
beginning and then sharp decline around 62 months of follow up. The confidence limits shown in
Figure 4.1 are point wise limits, meaning that for each specified survival time, we are 95%
confident that the probability of surviving to that time is within those limits. Note that the
confidence limits only extend to the largest event time.

Comparison of Survivorship Function

The Log rank (Mantel-Cox) test was employed to identify whether there is significance
difference in survival experience among different level of risk factors and to identify
independent variables that should be included in the final fitted model. The relationship between
each covariates and survival time of inpatient diabetic mellitus patients is presented in Table 4.2.
As it can be seen from this Table, survival time of the IPD was significantly related with age,
place of residence, diabetic disease complication, family history, systolic blood pressure,
diastolic blood pressure, co-infection, cholesterol level and types of diabetic disease at 25%
significant level.
In order to observe whether there is difference in survival experience among patients with
different levels of categorical risk factors, graph of Kaplan-Meier estimates for each categorical
variables have been plotted in Figure A, of Appendix2. FigureA1 shows that the survival curves
of sex overlap each other indicating that the survival times may be identical for these groups.
Statistical test was made by using log-rank (Mantel-Cox) test in Table 4.2 and this shows that
there is no significant difference (p=0.6104) in females and males with respect to survival times.
As we see from FigureA1 of Appendix2, patients in the age group 60-74 years had the lowest
survival time followed by patients with >=75 year while patients with 45-59, 30-44, 2-14 and 15-
29 have slightly better survival experience, respectively. As it can be seen from Table 4.2, the
log rank (Mantel-Cox) test shows that there is significant difference (p = 0.0000) in survival
times among patients with different levels of age groups.
Kaplan-Meier survivor estimates for variable residence, has been plotted in FigureA2 of
Appendix2. This figure shows that patients who came from rural area had slightly better survival
time than patients in the urban after around 40 months follow up times. But the difference in
survival times, was not supported by Statistical tests, since log-rank (Mantel-Cox) test in Table
4.2 shows that there is insignificant (p=0.0960) difference between male and female with respect
to survival times at 5% levels of significance.

As we see from FigureA2 of Appendix2, patients without diabetic complications had better
survival experience followed by Patients with other type of diabetic complications, while
patients with retinopathy had the least survival time. In table 4.2, the log-rank (Mantel-Cox) tests
revealed that there is significant difference (p=0.0000<0.05) with respect to survival times
among patients with different levels of diabetic complication groups.

As illustrated in FigureA4 of Appendix2, patients who had no co-infections had better survival
times and patients who had only TB co-infection had the least survival times up to 40 around
months, but later the survival times of patients with both TB & HIV co-infections became the
least. The log rank statistical test from Table 4.2 indicated that there is significant difference
(p=0.0000<0.05) among different groups of patients with different level of co-infection with
respect to survival times. Among different diabetic categories, type 2 DM patients had the lowest
survival time and as the log rank test shows in Table 4.2, it is also statistically significant
(p=0.0000).

Similarly, Kaplan-Meier survivor estimates for family history, systolic blood pressure, diastolic
blood pressure and cholesterol level were plotted in figure A of Appendix2. As the results depict,
patients with poor health indicators like positive diabetic family history, uncontrollable systolic
and diastolic blood pressure, high cholesterol level, had small survival times and all are
highly significant(p=0.0000).
Checking Proportional Hazard Assumptions

In order to use the parametric models, first we have to check proportional hazard assumptions to
identify whether we should use proportional (PH) parametric models or accelerated failure time
parametric (AFT) models. If the PH assumptions hold true then, we can use both PH and AFT
parametric models alternatively (only for Exponential & Weibull models), otherwise, we will use
AFT parametric models. There are many methods that used to check or verify proportionality
hazards assumptions. In this study, Scaled Schoenfeid residual test, log [-log S(t)] versus log(t)
and Scaled Schoenfeid residual plots have been used to check proportionality assumptions.

Method 1: Using scaled Schoenfeid Residual Plots:

From Figure 4.2, we found that the plot of Schoenfeid residuals against time for all variables
except age, show that observations are randomly distributed without any systematic pattern with
zero slope line. But, even if the slope of the line for variable age is zero, the observations were
distributed non-randomly with systematic patterns. Therefore, we can conclude that the
proportionality hazards assumption is violated.

Method 2: Using the Log [-log S(t)] versus log S(t) plots

As it can be seen from Figure 4.3, the plots for different diastolic blood pressure groups as well
as different age groups are not parallel. This indicates that the hazard for patients with different
diastolic blood pressure as well as different age groups is not proportional. This also implies that
the PH assumption is violated.

Method 3: Using test of proportional-hazards assumption based on Schoenfeid residuals.

As graphical assessment of PH assumption is subjective, formal statistical tests of correlation
(rho = a relation between time and residuals or covariates), has been employed as it is seen in
Table 4.3. From this table, we can see that collectively, the null hypothesis which states that
there is no correlation between time and covariates or residuals ( ρ=0) or the PH assumption is
not violated, is insignificant (0.4987>0.05) and individually, except variable age, all covariates
are insignificant at 5% level of significance. Even though the global test shows that the PH
assumption is not violated, the p-values for variable age grouped as 45-59 (p = 0.0347) & >=75
(p = 0.0314) are significant at 5% significance level. So, we reject the null hypothesis of
proportional hazards assumption for variable age, which states that there is no correlation
between survival times and covariate age, which implies that PH assumption is violated for
variable age. Since we have used parametric models rather than Cox-PH model, there is no need
of stratification for variable age in which the PH assumption is violated.
Univariable analysis
In any kind of statistical analysis, it is commonly advisable to use univariable statistical analysis
before doing multivariable statistical analysis. In survival analysis it is advisable to conduct
univariable Kaplan Meier analysis for each categorical covariate and Cox regression analysis for
each continuous covariate. The variables, which are significant at 20 to 25% significant level,
can be a candidate covariate for the multivariable statistical analysis. Log-rank test was
performed to investigate the significance of the observed difference in the Kaplan-Meier
estimates of the survivor functions among different categories of the factors as it is shown in
table 4.1. In the K-M analysis of each covariates, age, place of residence, diabetic disease
complication, diabetic family history, systolic blood pressure, diastolic blood pressure, HIV/TB
co-infection, cholesterol level and type of diabetic disease diagnosed were significantly
associated with survival of IDM patients while sex was not significant at 25% level of
significance. Therefore, those variables, which were significant at 25% level of significance in
the log rank test, were incorporated to the multivariable analysis. Univariable analysis of the
final Weibull regression model was done as shown in Table 1 appendix 4. This also showed that
except sex, all covariates were significant at 25% level of significance and hence were candidate
for the multivariable analysis.
To make comparison of parametric models that used to analyse the survival of IPD,
multivariable analysis for parametric regression models (Exponential, Weibull, Log normal and
Log logistic) had been fitted to IPD data as shown.
Comparison of parametric models
After fitting parametric models as shown in Table 4.4, the next step is comparing parametric
models and selecting the model that fit the data well. Model comparison was done using AIC,
BIC and LR in Table 4.5 bellow. Based on this table result, Weibull regression model with
smallest AIC and BIC values and largest LR value, was selected to analyse IPD data.
Model adequacy
1. Cox-Snell Residuals
After the model has been selected and fitted to an observed set of survival data the next step was
assessing the adequacy of the fitted Weibull regression model. As it is designed in methodology
part, the adequacy of Exponential, Weibull, log-normal and Log-logistic survival regression
model was checked using Cox-Snell residuals (Figure 4.4). If the selected model is the correct
one, the points shall follow a 45 degree line at the origin. Thus, in our case, plot of the Cox-Snell
residuals for Weibull regression model provided reassembly a straight line through the origin as
compared to other parametric survival regression models and this also indicates that the Weibull
regression model fitted the data well. Similarly, as shown in Appendix 3 Figure C, the plot of
hazard functions in the Weibull model seems straight that passes through the origin as compared
to the other parametric models that indicates the Weibull model fitted the IPD data than the rest
parametric models.
Multivariable analysis of Weibull Regression Model
After selecting and checking the adequacy of the final fitted Weibull survival regression model
that used to analyse the IPD data, multivariable analysis was done using the final fitted Weibull
AFT regression model as shown in Table 4.6. Those variables, whose p-value was significant at
25% level of significance in the univariable analysis of the Weibull regression model and the
log-rank test presented in Table 1 in appendix 3 and Table 4.2, respectively, were included in the
multivariable analysis. In the multivariable analysis of the final Weibull regression AFT model,
variables that have p-value less than or equal to 0.05 were considered as significant variables and
hence were used for interpretation. Results presented in Table 4.6 show that the estimated
coefficients ( β aft ) of the covariates in the final Weibull regression model along with their
associated standard error, Z-score, significance level, time ratio (TR) and 95% confidence
interval for the time ratio (TR). As it can be seen from this table, the covariates diabetic disease
complication, diabetic family history, systolic blood pressure, co-infection and cholesterol level
were found to be statistically significant effect at 5% level of significance. The remaining
variables which were significant at 25% level of significance in the univariable analysis and the
Log rank test (such as, Age, place of residence, diastolic blood pressure and type of diabetic
disease) were found to be insignificant at 5% of significance level in the multivariable analysis
of the final Weibull regression model.
The Weibull hazard regression model that predicts the survival time of in-patient diabetics in
BFHRH can be modeled as:
h(t , X , β)=0.0000053681 t 1.9154034466 exp ( X β). Having this, the survival time can be also
modeled as S(t , X , β )= exp ⁡[−0.0000018413t 2.9154034466 exp ( X β ) ]

Interpretation and Presentation of the Final Weibull Model using time ratio

DDC: Looking at diabetic disease complication, keeping other covariates constant, the survival
of patients who had neuropathy diabetic complication was 38% (TR= 0.62, 95% CI=0.46 0. 83)
less than the survival times of patients without diabetic complications while the survival times of
patients with CVD was 32% (TR=0.68, 95% CI= 0.54, 0.86) times less than the survival times of
those patients without any diabetic complications. Similarly, the survival times of those patients
who had diabetic nephropathy and retinopathy were 28% less than the survival times of patients
without any diabetic complications with different confidence intervals ((TR=072, 95% CI= 0.53,
0.98 and TR= 0.72, 95% CI = 0.57, 0.92) respectively.

FH: The survival of patients who had positive diabetic family history was 0.84 times the survival
times of patients with negative diabetic family history [TR= 0.84, 95% CI= 0.74, 0.96]. This
means that the survival times of patients with positive family history was decreased by 16% as
compared to the survival times of patients who had negative diabetic family history.

SBP: Looking at systolic blood pressure, after adjusting other covariates constant, survival of
patients who had uncontrollable baseline systolic blood pressure was 0.65 times the survival of
patients with normal baseline systolic blood pressure (TR= 0.65, 95%CI= 0.51, 0.84). This
shows that the survival times of patients who had uncontrollable baseline systolic blood pressure
was decreased by 35% than patients who had normal baseline systolic blood pressure. Similarly,
the survival times of patients who had high baseline systolic blood pressure was 0.71 times the
survival times of patients with normal baseline systolic blood pressure (TR= 0.71, 95%CI= 0.55,
0.91) indicating that the survival times of patients with high baseline systolic blood pressure was
29% less than the survival times of patients with normal baseline systolic blood pressure.

COI: On the other hand, the survival times of patients who had only TB co-infections was 39%
less than the survival times of patients who had no both HIV & TB co-infections (TR= 0.61,
95%CI= 0.50, 0.75). Similarly, the survival times of patients who had both HIV& TB co-
infections was decreased by 34% than patients without HIV & TB co-infections (TR= 0.66,
95%CI=0.49, 0.88) while the survival times of patients who had only HIV co-infection was 27%
less than the survival times of patients without HIV/ or TB co-infections (TR=0 .73, 95%CI=
0.59, 0.90).

CHOL: Finally, cholesterol level of IDM was another predictor variable related with the
survival of IPD. Adjusting other variables constant, the survival times of in-patient diabetics who
had high cholesterol level was 21% less than the survival times of patients who had normal
cholesterol level [TR= 0.79, 95% CI= 0.66, 0.94].

Interpretation and Presentation of the Final Weibull Model using hazard ratio.

Since STATA 14 software can’t calculate the hazard ratio of AFT models, I had calculated the hazard
ratio by hand as follow.

DDC: Looking at diabetic disease complication, keeping other covariates constant, the hazard of
−(−0.48)
patients with neuropathy diabetic complication was e 0.23 = 8.06 as compared with the hard of
−(−0.39)
patients without diabetic complications while the hazard of patients with CVD was e 0.23 =
=5.45 times the hazard of patients without diabetic complication. Similarly, the hazard of
−(−0.33) −(−0.32)
patients with diabetic nephropathy and retinopathy respectively, were e 0.23 = 4.20 and e 0.23

= 4.02 times as compared with hazard of patients without DM complication.

FH: keeping other factors constant, the hazard of patients who had positive diabetic family
−(−0.17)
history was e 0.23 = 2.10 times the hazard of those patients who had negative diabetic family
history.

SBP: Looking at systolic blood pressure, after adjusting other covariates constant, the hazard of
−(−0.43)
patients who had uncontrollable baseline systolic blood pressure was e 0.23 = 4.49 times the
hazard of patients who had normal baseline systolic blood pressure. Similarly, the hazard of
−(−0.34)
patients with high baseline systolic blood pressure was e 0.23 = 4.39 time the hazard of patients
who had normal baseline systolic blood pressure.
−(−0.49)
COI: On the other hand, the hazard of patients who had only TB co-infection was e 0.23 = 8.42
times the hazard of patients who had no TB/HIV co-infections while patients who had both TB
−(−0.42)
& HIV co-infections were e 0.23 = 6.21 times to die than patients who had no both TB & HIV
co-infections. Similarly, the hazard of patients who had only HIV co-infection was 4.02 times
the hazard of patients without TB/HIV co-infections.
 −(−0.48)
CHOL: Finally, the hazard of patients who had high cholesterol level was e 0.23 = 2.84 times
the hazard of patients who had normal cholesterol level.

DISCUSSION

To predict and model the survival times of in-patient diabetics, various parametric regression
models were applied. The parametric survival models were fitted using STATA 14 statistical
software and results are presented in table 4.4. From this table, four covariates namely, diabetic
disease complication, systolic blood pressure, co-infection and cholesterol level in Exponential
AFT model, three covariates namely, diabetic disease complication, co-infection and
cholesterol level in both Lognormal and Log-logistic survival regression models and five
covariates namely, diabetic disease complication, family history, systolic blood pressure, co-
infection and cholesterol level in Weibull AFT survival regression model were statistically
associated with the survival times of IDM patients. Among these parametric survival regression
models as shown in table 4.5, the Weibull AFT survival regression model which had the lowest
AIC and BIC values and highest LR value as compared to the other three survival parametric
models selected in this study to predict the survival times of IPD in BFHRH.

As it is expressed in the above, in the final fitted Weibull AFT regression model, we found that
five variables that jointly serve as predictive factors on the survival of IPD. These variables are
diabetic disease complication, family history, baseline systolic blood pressure, co-infection and
baseline cholesterol level of IPD.

Diabetic disease complication is a prognostic factor that significantly predicts the survival times
of in-patient diabetics. This study revealed that the survival times of patients with neuropathy,
CVD, diabetic nephropathy and retinopathy were decreased by 38%, 32%, 28% and 28% than
the survival times of patients who had no diabetic complications. In terms of hazard, the study
revealed that the hazard of patients with diabetic neuropathy, CVD, nephropathy and retinopathy
were 8.06, 5.45, 4.20 and 4.02 times the hazard of those patients without DM complication
respectively. The result is comparable with earlier study, by Derbachew Asfaw Teni [22] in
Addis Ababa yekatit XII referral Hospital using Weibull AFT regression model, showing that the
hazard of patients with nephropathy, neuropathy, retinopathy and CVD diabetic complications
were, 10.34, 8.39, 6.84 and 4.13 times the hazard of patients who had no any diabetic
complications respectively. The result of this study is also analogous with the previous study
which was done at Addis Ababa Tikur Anbesa Hospital by Tigabu Hailu Kassa [23] using
Weibull AFT model, revealed that, the hazard of patients with nephropathy, CVD, neuropathy &
retinopathy diabetic complications were 4.935, 4.531, 4.158 and 3.865 times the hazard of those
patients who had no any diabetic complications respectively.

In this study, family history of diabetic disease was found to be prognostic factor that has
significant impact on the survival times of IPD. The result depicts that the survival times of in-
patient diabetics who had positive diabetic family history was decreased by 16% as compared to
the survival times of in-patient diabetics who had no positive diabetic family history. In terms of
hazard, the hazard of patients who had positive diabetic family history was 2.10 times the hazard
of patients who had no positive diabetic family history. The result is analogous with earlier
study, by Derbachew Asfaw Teni [22] in Addis Ababa yekatit XII hospital, showed that the
hazard rate of diabetic patients who had positive diabetic family history was 2.130 times the
hazard of patients who had no positive diabetic family history. Again the result of this study is
also related with previous study by Tigabu Hailu Kassa [23], which showed that the hazard of
patients who had positive diabetic family history was 6.694 times the hazard of those patients
with negative diabetic family history.

Cholesterol level is also a prognostic factor that significantly predicts the survival time of
diabetic patients. The result of this study indicates that the survival times of patients who had
high cholesterol level was decreased by 21% as compared to the survival times of patients who
had normal cholesterol level. In other word, the hazard of patients with high cholesterol level
was 2.84 times the hazard of patients with normal cholesterol level. The result is similar with the
previous study by Derbachew Asfaw Teni [22], which found that the hazard of patients who had
high cholesterol was 2.65 times the hazard of those having a normal cholesterol level. The
finding is also confirmed by previous study which was done in Tikur Anbesa referral Hospital by
Tigabu Hailu Kassa [22 & 23], which showed that the hazard of patients who had high
cholesterol level was 3.747 times the hazard of those patients who had normal cholesterol level.

Conclusions
Parametric survival model with baseline hazard Weibull distribution was found appropriate this
dataset. The study identified that diabetic disease complication, diabetic family history, baseline
systolic blood pressure, HIV|TB co-infections and cholesterol level were significant factors
associated with survival times of IDM patients.

Abbreviations

DM: Diabetes mellitus, IPD: In-patient diabetics, IDM: Inpatient Diabetes Mellitus, WHO:
World Health Organization, IDF: International Diabetes Federation, BFHRH: Bahir Dar Felege
Hiwot Referral Hospital, T1DM: Type one diabetes mellitus, T2 DM: Type two diabetes
mellitus, UAER: Urinary Albumin Excretion Rate, CVD: Cardio Vascular Disease, BIC:
Bayesian Information Criteria, AIC: Akaike Information Criteria, PH: Proportional Hazard,
AFT: Accelerated Failure Time Model, TR: Time Ratio, CI: Confidence Interval, FH: Family
History, DDC: Diabetic Disease Complication, SBP: Systolic Blood Pressure, DBP: Diastolic
Blood Pressure, CHOL: Cholesterol Level, PLR: Place of Residence, COI: Co-infection, HIV:
Human Immune Virus, K-M: Kaplan-Meier, TB: Tuberculosis, CEO: Chief Executive Officer,
SSA: Sub-Saharan Africa, NCDs: None Communicable Disease, SRS: Simple random sampling

ACKNOWLEDGEMENTS

I would like to greatly appreciate all the co-investigators for their contribution in this work. I
would like to extend my sincere gratitude to Dr. Asrat Atsedeweyn and Mr. Kidanemariam Alem
(MSc), for their unreserved and constructive guidance and comments from the stage of the
research proposal up to thesis write up.

Authors’ contribution
AA: Contributed by providing valuable comments to the whole document from the beginning up
to the end of this work, drafting and revision of the manuscript for important intellectual content.
KM: Contributed to design, interpretation of data, and revision of the manuscript for important
intellectual content.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its
supplementary information files].
Ethics approval and consent to participate
Ethical clearance was obtained from Natural and Computational Science Ethical review
committee.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Statistics Department, College of Natural and Computational Science, Dire Dawa, Ethiopia
2
Biostatistics and Epidemiology Department, College of Medicine and Health Science, Gondar,
Ethiopia
3
Statistics Department, College of Natural and Computational Science, Gondar, Ethiopia
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