BMC Medical Research Methodology

Background: Epidemiological and clinical studies, often including anthropometric measures, have established obesity as a major risk factor for the development of type 2 diabetes. Appropriate cutoff values for anthropometric parameters are necessary for prediction or decision purposes. The cutoff corresponding to the Youden-Index is often applied in epidemiology and biomedical literature for dichotomizing a continuous risk indicator.


Background
Anthropometric parameters such as body mass index (BMI), waist circumference (WC) or waist to height ratio (WHtR) are often applied as indicators of obesity in epidemiological and clinical studies due to their simple application and high correlation with more complex measures [1][2][3]. As a case in point, decisions made from these parameters are necessarily dependent on statistically reliable derived cut-offs. For example, obesity is an established risk factor for the development of clinical type 2 diabetes [1][2][3][4] and also plays a central role in metabolic syndrome according to the National Cholesterol Education Program (NCEP) [5] and the International Diabetes Federation (IDF) [6]. The definitions of metabolic syndrome are based on the same set of risk factors (abdominal obesity, hypertriglyceridemia, low HDL, hypertension, elevated fasting glucose) in the NCEP and by the IDF, but differ in terms of what constitutes the best cut-offs for WC and how to weigh risk factors. Of relevance to our paper, the cut-offs for WC for the IDF classification (94 for male and 88 for female) of metabolic syndrome are lower than those of the NCEP (>102 for male and >88 for female) and have been a point of contention in recent years [7][8][9]. This has resulted in the unanswered question of how to best determine cut-offs in situations where the indicator or risk factor is a continuous variable (in this case WC) and the endpoint is dichotomous (in this article type 2 diabetes).
The determination of such cut-offs is often based on the Receiver Operating Characteristic (ROC) plot [10,11] in epidemiological and applied biomedical literature. The cut-off corresponding with the maximum of the sum of sensitivity (= probability of truly diseased people being diagnosed as such) and specificity (= probability of truly non-diseased people being diagnosed as such) is considered optimally related to correct and incorrect classification rates [12]. Furthermore, the cut-off represents the maximum risk difference between the probability of disease outcome (in our case type 2 diabetes) for levels of exposure (here: the anthropometric parameter) below and above the cut-off [13].
In this paper we present a novel statistical approach for estimating the cut-offs for anthropometric parameters in diabetes epidemiology, based on a representative large multistage longitudinal epidemiological study. The resulting estimator yields excellent finite sample properties, when compared with established approaches from the ROC plot. This suggests that when a continuous indicator has to be dichotomized for prediction or decision purposes, this should be the method used in medical research. We will exemplify our method with using different anthropometric measures to predict incidence and prevalence of type 2 diabetes.

Study population
The estimation of cut-offs for selected anthropometric parameters in relation to their association to risk of type 2 diabetes was performed with use of data from the DETECT study. DETECT (Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment) is a large nationally representative epidemiologic crosssectional and prospective longitudinal study in German primary care settings [14,15]. On a target day in September 2003, a nationwide sample of primary care physicians documented, with help of an extensive patient and physician questionnaire, the health state of over 55,000 patients. In addition, a sub-sample of 7,519 patients passed a more intensive standardized laboratory assessment and was followed up after one year in 2004, and after 5 years in 2007/8. All analyses are based on data from this sub-sample. The study was designed to examine the prevalence and comorbidity of diabetes mellitus, hypertension, dyslipidemia, coronary heart disease and associated medical conditions, as well as to determine the frequency of behavioural and clinical risk factors like abdominal obesity, smoking or physical activity and their influence on onset and progression of the considered disease. The study was approved by ethical commission of TU Dresden (AZ: EK149092003; date: 16.9.2003) and all patients gave informed consent.
The cross-sectional analysis of the DETECT sub sample included 6,965 patients (4,120 females, 2,845 males). 554 patients were excluded from the analysis as no data was available for waist circumference, hip circumference, body height or weight. We included 6,355 patients in the assessment of the longitudinal association between several anthropometric parameters and type 2 diabetes (females/males), with both a follow-up assessment in 2004 or in 2007/8, and information about anthropometric measures at baseline.

Anthropometric parameter
Waist and hip circumference, body height and weight were measured on the target day by the treating physician, according to standardized written instructions and documented in the physician questionnaire. Waist circumference was measured in centimetres, with a tape between the lowest rib and the iliac crest, while hip circumference was measured in centimetres at the widest circumference around the pelvis. Body mass index was calculated as weight (in kg) divided by squared height (in m 2 ). Waistto-hip ratio was defined as waist divided by hip circumference and waist-to-height ratio, as waist circumference divided by body height.

Type 2 diabetes mellitus
Diabetes mellitus was defined exclusively by a doctors' clinical diagnosis being rated as 'definite' in the standardized assessment or the prescription of antidiabetic medication [16]. The classification into type I and type II diabetes also resulted from this diagnosis. For the cut-off estimation, only type II diabetes was used as a disease outcome.
Statistical approaches for estimating the cut-off obtained at the Youden Index J The Receiver Operating Characteristic (ROC) plot is a widely used approach for determining the optimal cut-off for a continuous risk indicator X and a dichotomous disease outcome Y, in which the sensitivity is plotted against the 1-specificity. All possible 2 × 2 cross tables can be located on the curve emerging from the dichotomization of the continuous risk indicator X for all possible levels c of X considered as cut-offs. The diagonal line through the points (0,0) and (1,1) displays the random association between X and Y and is called random ROC. The maximum vertical distance between the ROC curve and random ROC is called the Youden Index [17], J = max c {sensitivity(c) + specificity(c) -1}, for all possible cutoff values c. The cut-off  associated with the Youden Index J represents the point with the maximum risk difference between the dichotomized continuous risk indicator X and dichotomous Y [12]. The cut-off  is often referred to as an optimal cut-off for dichotomizing the continuous risk indicator X in epidemiology [12,18,19], applied biomedical literature [20,21], and psychology [22,23], when related to total correct and incorrect classification rates [12].

A novel nonparametric approach for estimating a cut-off
The association between the disease outcome Y and the exposure X can be modelled in a regression framework where the conditional distribution function P [Y = y|X = x] is studied for estimating a cut-off . In contrast, the established estimators for  based on the ROC plot relate the conditional distribution function P [X  c|Y = 1] (sensitivity) to P [X > c|Y = 0] (specificity). The main ideas for the regression related estimator for  are presented here in short; for the exhaustive mathematical theory see Dempfle [24] and Ferger [25]. The Dempfle and Stute (DS) estimator  n of  is calculated from n independent observations (X i , Y i ), i = 1, ..., n of (X, Y). For simplicity of notation, the sample is assumed to be ordered by increasing risk indicator levels X (X 1  X 2  ...  X n ) with the associated Y values denoted by concomitants.
The maximum likelihood estimator  n for the unknown cut-off  is given by The heuristic idea behind r n (t) is comparing the mean of Y for levels of X smaller than t with the mean of Y for levels of X greater then t. The estimator  n converges to  in probability for n   with an optimal convergence rate of n -1 under weak assumptions on the model, as shown by Dempfle [24] and Ferger [25].
In summary, the algorithm is as follows for calculating the estimator  n . The functional r n has to be calculated for all X 1  X 2  ...  X n and the estimator  n is determined as the datum X c associated with the maximum of r n .

Established methods for estimating the cut-off obtained at Youden Index J
The cumulative distribution of X for diseased patients (Y = 1) is given by G: = P [X  c|Y = 1] and the cumulative distribution of X for healthy patients (Y = 0) is given by E: = P [X  c|Y = 0], respectively. Therefore, the sensitivity of a diagnostic test is 1 -G(c) and the specificity is E(c) for any given cut-off c. The Youden Index J can be written as the Kolmogorov-Smirnov statistics, J = max c |E(c) -G(c)|.
Several methods for estimating the cut-off  = argmax c {sensitivity(c) + specificity(c) -1} have been discussed in recent years. These methods tend to assume either normality of the continuous risk indicator, the existence of a transformation function for non-normal distributed risk indicator into a normal distribution, or the estimated cutoff depends on a smoothing parameter by nonparametric methods like kernel smoothing. The work of Fluss and colleagues [26] is a comprehensive overview, which compares several estimation procedures for J and  in detail.
The ideas and methods of the estimation procedures are presented in short in this paper, technical details can be found elsewhere, for example Fluss et al. [26] or Zou and Hall [27].

Normal method (N)
The cut-off  can directly be estimated by if the assumptions for the healthy population for the diseased population (Y = 1) hold.

Transformed Normal (TN) method
The normality of the distribution of the risk indicator X is often questionable in practical applications [26,27]. Zou and Hall [27] have proposed fitting a power transformation of the Box-Cox type [28]. It is assumed that there exists a monotonic transformation function t(,.)such that t(, X) is normally distributed. The parameter  can be determined by maximum likelihood estimation. The cut-off  is estimated by applying the Normal method in the transformed sample following the application of the inverse transformation function.

Empirical conditional distribution function (EMP) method
Substituting the conditional distribution functions G and E by their empirical distribution functions and and identifying J is an intuitive method for estimating .

Kernel method (KM)
The Kernel density estimation method can also estimate the conditional distribution functions of G and E. The functions and are determined using the Gaussian kernel function and the bandwidth recommended by Silverman [29] and applied in Fluss et al. [26] according to Zou et al. [30].

The equivalence of the cut-off estimated by the DS estimator and obtained at the Youden Index
The cut-off  corresponding to the maximum of the Kolmogorov-Smirnov statistics is given by Appel [31] demonstrated in Theorem 1 that a regression function m uniformly maximizes the Kolmogorov-Smirnov distance of sensitivity and specificity. The estimation procedure of Dempfle and Stute [24] yields asymptotically the cut-off associated with the maximum of the Kolmogoroff-Smirnov statistic (Youden Index). We refer to the appendix [additional file 1] for a more detailed view to the relation of both estimation strategies.

Confidence Intervals for the DS estimator
Confidence intervals are important for statistical inference and for the quantification of the precision of point estimates. The limit variable for the maximum likelihood estimator  n is a maximizing point of a compound Poisson process [25]. An analytical solution for the limit distribution of  n for directly obtaining the quantiles of the distribution does not exist. Ferger [25] proposes a Monte-Carlo approximation of the distribution of the smallest and largest maximum point of a compound Poisson process in order to determine its quantiles c 1 and c 2 satisfying , where   (0, 1). We refer to Ferger [25] for a detailed illustration of the procedure for estimating confidence intervals for  n .

Adjusting the cut-off for covariates
The cut-off for the continuous risk indicator X can be strongly influenced by covariates. The novel method for estimating a cut-off is based on a nonparametric regression framework. The introduced estimation procedure works only in the bivariate case and it is not possible to directly add an additional covariate to the regression The estimation procedure is based on the comparison of the mean level of the probability of disease for risk indicator levels smaller or equal and greater than a possible cut-off. It is thus not possible to apply this principle to more than one covariate.
Each point on the ROC curve can be quantified as a conditional expectation of a Bernoulli distributed random variable [32]. Therefore, the conditional expectation of the binary random number given a set of covariates could be modelled by an appropriate regression model for binary data, for example using a generalized linear model [33]. The DS estimator could then be applied to the predicted probabilities to get a covariate adjusted estimate for the cut-off of the risk indicator X.

Application to diabetes epidemiology Baseline characteristics of the DETECT laboratory sample
In the sample of N = 7,519, the mean age was 57.7 (SD = 14.4) with 60.1% female. There was a prevalence of 0.5% for type 1 diabetes, 14.2% for type 2 diabetes, 35.5% for hypertension 35.5%, 29.5% for dsylipidemia, and 12.1% for coronary artery disease (table 1). Male patients (18.1%) were more often affected by type 2 diabetes than females (11.5%) [16]. Table 2 shows the results of cut-off estimations with the use of the DS estimator for several anthropometric parameters for the probability of type 2 diabetes. These cut-offs,

Cross-sectional analysis
based on data from the DETECT study, are useful in discriminating primary care patients with and without type 2 diabetes.
Except for BMI, the cut-offs of all other examined anthropometric parameters were higher in male patients. The optimal cut-off was 102 cm (male) and 92 cm (female) for WC, with the maximum difference in probability for type 2 diabetes over all age groups. According to the DS estimator the optimal cut-off point for HC was 106 cm for male und 105 cm for female patients. A BMI of 27.0 kg/ m 2 in male patients and 28.0 kg/m 2 in female patients was the best cut-off in relation to the occurrence of type 2 diabetes. Our cut-off estimations for WHR were 1.00 (male) and 0.86 (female) and for WHtR 0.58 (male) and 0.55 (female) respectively.
The cumulative distribution of anthropometric parameter for patients with type 2 diabetes (G) and the cumulative distribution of anthropometric parameter for patients without type 2 diabetes (E) were investigated by kernel density plots. The distributions are asymptotical normal across all parameter. The DS estimator yields unbiased estimates for normal data as demonstrated in the simulation study (table 3, table 4 and table 5). This fact applies also for smaller values of J (results are not shown).

Longitudinal analysis
In a second step, we used the estimated cut-offs of the different anthropometric parameter to determine their predictive values for the five year incidence of type 2 diabetes. Wherein we calculated the positive and negative predictive value as well as the area under the receiver operator curve (AUC). We found a five year type 2 diabetes incidence of 6.7%, in which male patients (8.5%) were more frequently affected than females (5.6%).
The negative predictive value for the incidence of type 2 diabetes while applying the cut-offs ranged between 92.4 for WHR and 95.1 for BMI in male patients, and 96.7 and 97.9 in female patients, respectively. The positive predictive value of the cut-offs for the researched parameters of

Simulation study on different procedures to estimate the best cut-off for diabetes Design of the Monte Carlo simulation study
We compared the DS estimator (24) with the estimation procedures presented by Fluss et al. [26]. The design of our simulation study was similar when compared to that of Fluss et al. [26], except that the outcome variable Y was also modelled as a realization of a Bernoulli distributed random number, which broadened the design of the simulation study. When simulating the following distributions of X: (1) the conditional distribution of P [X  c|Y = 0] followed a -distribution, the conditional distribution of P [X  c|Y = 1] followed a distribution (as an example for symmetric distributions); (2) P [X  c|Y = 0] followed a -distribution and P [X  c|Y = 1] followed a -dis- The algorithms for estimating the cut-offs and the simulation trials were implemented in STATA 10.1 [34] with a double precision number format. The number of Monte-Carlo replications was set to 5000. The performance of several estimation methods were compared by root mean square error (RMSE); this is a relevant measure for studying the performance of biased estimators, as it combines the systematic bias and the random error of an estimator.

Results of the simulation study
The results of the simulation study for unbalanced sample sizes are displayed in   in table 3, table 4 and  table 5.
To summarize the results of the simulation study, the estimator DS performs well in most simulation trials in case of J  0.6. The performance is getting better for larger sample sizes measured by RMSE. It is remarkable that DS also results in acceptable bias for small sample sizes. This suggests that this estimator should provide an alternative

Discussion
The present study addresses the estimation of the cut-off associated with the Youden Index. We have presented an approach for obtaining optimal cut-offs and demonstrated that this approach has excellent statistical properties in a Monte-Carlo study. The DS estimator is easy to implement and should be applied for estimating a cut-off in epidemiological research.
This method of DS also has minimal assumptions on the underlying statistical model, as it is nonparametric. It should also be emphasized that the procedure estimates  without any smoothing technique, such as kernel regression [35,36] or local polynomial regression [37]. Therefore, the ability to detect a possible cut-off in the data does not depend on any smoothing window or bandwidth.
Essentially the correct estimate of the cut-off only depends on the triangular shape of the function r n . In fact, this function is flattened by decreasing the risk difference for the probability of disease for levels of X below and above . The function r n is a straight line in the case of a risk difference of zero. We thus recommend plotting the function r n in a practical application and assessing its triangular form when using this method (figure 1).
The shape of the estimated regression function m was assumed to be a step function with a discontinuity in  and the magnitude of |a -b|. This assumption, as mentioned in the presentation of the Dempfle and Stute [24], appears to be very restrictive, In actuality, this special shape of the regression function is the most challenging issue, because a monotonic increasing regression function m with m  a for X   and m  b for X >  would boost the difference between the estimated conditional expectations for the risk indicator levels. This estimation procedure only assumes monotonic increase or decrease of risk for disease for increasing or decreasing risk indicator levels, a common assumption. The mathematical theory for a general m can be found in Ferger [25].
The aim of this study was to introduce a new approach for estimating optimal cut-offs of several anthropometric parameters for the probability of type 2 diabetes in a German primary care population. However, as people are gaining more weight becoming more obese with age, appropriate cut-offs for anthropometric parameters are important for deciding whether the level of a parameter is associated with an increased risk for type 2 diabetes for the application in everyday life. The estimated WC value for the female group (92 cm) was above the NCEP ATP III (women > 88 cm) (5), while the WC value for men (102 cm) precisely matched the NCEP cut-off. In both groups, the cut-offs were above the International Diabetes Federation (men > 94 cm; woman >80 cm) (6) criteria for the metabolic syndrome. An explanation for higher cut-off values in our estimations could be that the sample of primary care patients from the DETECT study may have had an increased risk for disease compared with the general population, due to the setting of the study. In this example, cut-offs of different anthropometric parameters represent tools for physicians to make decisions about type 2 diabetes risk. This has implications for further examinations and treatment of concerned patients.

Conclusion
The Dempfle and Stute [24] estimator provides a flexible nonparametric approach for estimating a cut-off for a continuous risk indicator based on the argument of maximum risk difference between the dichotomized continuous risk indicator X and dichotomous outcome Y. The estimation procedure avoids artificial parametric assumptions on the data as it is nonparametric. In addition to the results of the simulation study also suggest that the estimator could be considered as an alternative in epidemiology and clinical studies, when a continuous indicator needs to be dichotomized for prediction or decision purposes. Triangular structure of the function r n for the association of waist circumference and type 2 diabetes for males Figure 1 Triangular structure of the function r n for the association of waist circumference and type 2 diabetes for males.