The prevalence of childhood overweight and obesity is increasing worldwide, including the Netherlands [1,2]. Hypertension or prehypertension and low high-density lipoprotein cholesterol (HDL-C) values are related adverse cardiometabolic risk factors that are also highly prevalent in children. The prevalence of hypertension is approximately 3.5%, 9%, and 19% among normal weight, overweight, and obese children, respectively [3-5]. Moreover, 6.2% of normal weight children have low HDL-C levels [6]. Overweight, hypertension, and low HDL-C level in childhood generally persist into adulthood, but are usually asymptomatic. Importantly, the presence of these risk factors in childhood can be detrimental, increasing the lifetime risk of developing severe health complications such as coronary heart disease and type 2 diabetes [7-14].

Once an individual becomes overweight, this condition is usually difficult to reverse, even among children, as changing one’s lifestyle is difficult, and people often revert to their old habits resulting in even poorer health due to weight fluctuations [15]. Therefore, the European Society of Cardiology states that primary lifelong prevention of overweight and related poor cardiometabolic outcome deserves high priority beginning at birth [16]. Primary preventive interventions are particularly important in children aged less than 6 years, as changes in body mass index (BMI) below this age are more predictive of later overweight and poor cardiometabolic outcome than BMI changes after this age [17,18]. Moreover, parental lifestyle interventions when the child is young are associated with improved long-term outcome [19]. In addition, the American Academy of Pediatrics found that early intervention can yield better success in children with high cardiometabolic risk [20,21].

The EPODE (Ensemble Prévenons l’Obésité Des Enfants) program in northern France is a universal primary approach designed to prevent overweight in children by involving the family unit and society as a whole, for example, by changing the environment and influencing social norms. The merits of this approach have clearly been demonstrated [22]. Therefore, the program was successfully adopted, converted, and implemented in the Netherlands as the Youth on Healthy Weight (in Dutch: Jongeren op Gezond Gewicht, or JOGG) program [23]. Despite the introduction of this program, however, the prevalence of overweight remains relatively high, particularly among children from a low socioeconomic background [24]. Therefore, in addition to this universal approach, there is increasing interest in targeting primary prevention to children with the highest risk of becoming overweight and developing related poor cardiometabolic outcome. These risks may be estimated using prediction models or so-called “clinical prediction rules,” which use the best possible combination of risk factors to calculate the likelihood of a specific outcome.

Prototypes of such prediction models have been developed in the Netherlands within two Dutch cohort studies - the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study and the Terneuzen cohort study - and in other countries, including India [25]. The two aforementioned Dutch prototypes are based on the presence of several predictors at birth, including paternal and maternal BMI [26], and on the trajectory of BMI standard deviation scores (BMI SDS) from 2 to 6 years of age [27]. Both Dutch prediction models have fair performance, indicating that targeted primary prevention of overweight and related poor cardiometabolic outcome is feasible with the help of evidence-based prediction models [26,27].

Here, we present the design of our study, which aims to develop dynamic prediction models to estimate the risk of young children (up to 6 years of age) developing overweight, hypertension or prehypertension, low HDL-C levels, and/or a high total cholesterol to HDL-C ratio by early adolescence. The resulting prediction models will be converted into easy-to-use tools called Pro COR (PRediction Of Child CardiOmetabolic Risk), which can be applied both in the Dutch preventive Child Health Care (CHC) system and by pediatricians.

Because the Dutch CHC reaches more than 95% of all children of all ethnicities through 16 regular visits from birth until the age of 6 years, this approach will enable targeted primary prevention for children in this age group. The Pro COR tools will provide risk estimations by taking into account the accumulation and changes in exposure to multiple risk factors throughout life, including familial risk factors [28], smoking exposure, physical inactivity, and changes in BMI [29].

Because we cannot exclude the possibility that children may already have an adverse cardiometabolic profile at this young age, thereby indicating the need for treatment, our secondary aim is to develop risk estimation models to assess the need for further diagnostics of poor cardiometabolic outcome at age 5-6 years and at age 10 years, two ages at which regular visits are made to the Dutch CHC centers.

The study design includes (1) data collection; (2) the development, external validation, and, if required, updating of dynamic prediction rules within two large Dutch cohort studies; and (3) an assessment of whether the resulting tools can be implemented in practice. Therefore, the study will also focus on risk communication, as this is an important aspect that can affect the likelihood of successful implementation.

The outcomes of the prediction rules will be assessed in early adolescence, because BMI SDS values measured between 10 and 18 years of age are highly correlated with adult BMI SDS values and body fat mass [17]. Moreover, as discussed above, hypertension/prehypertension, low HDL-C levels, and high total cholesterol levels often persist from childhood into adulthood, particularly from adolescence [10-12]. Our study proposal has been awarded a TOP Prevention Grant from ZonMw (title: “Targeted primary prevention of overweight and cardiometabolic risk using dynamic risk assessments from infancy onward in Child Health Care”; 200500006) , offering the opportunity to innovate in terms of both content and collaboration. See Multimedia Appendices 1, 2 and 3 for the reviewers’ comments on the original version of the research proposal.

This is an ongoing research project, and the first results are expected in 2016. The study began in December 2013 and is funded by the Health Research and Development Council of the Netherlands (ZonMw Grant no. 200500006).

Our study will provide an individualized approach for primary prevention of overweight and poor cardiometabolic outcome by combining risk estimates with the existing general approach. This individualized, targeted approach will bridge an existing gap in the primary prevention of overweight and related adverse cardiometabolic outcomes. This is likely both important and relevant, given that the effects of secondary prevention of overweight and obesity have been disappointing—even among younger children—particularly over the long run [44]. Moreover, the success of universal primary prevention has been less pronounced in groups from lower socioeconomic backgrounds [22,24]. Importantly, the Pro COR tools will also enable the identification of children who already have high blood pressure and an abnormal lipid profile, thereby offering these children additional diagnostics and treatment options by their pediatrician; this is particularly relevant, as these adverse cardiometabolic outcomes tend to persist into adolescence and even adulthood, and are usually asymptomatic [10-12].

The success of the Pro COR tools when applied in early childhood will be reflected in the possibility to refer children with increased risk to a primary preventive program. Although such primary preventive interventions are relatively scarce, and although the majority of efforts have focused on developing secondary preventive interventions, several studies have demonstrated the potential benefit of applying primary preventive interventions in this extremely young age group [45-47]. In addition, primary preventive interventions aimed at the most susceptible individuals are often more effective than interventions that target the entire population [48]. Therefore, participating JOGG cities in the Netherlands have opted to implement interventions that are similar to Mini-MEND, a program aimed at children and families with increased risk at the age of 2-4 (or 5) years; this program is currently being evaluated in Australia and the United States [49-51]. Mini-MEND is the younger-age equivalent of MEND (Mind, Exercise, Nutrition, Do It!), a family-based intervention that was designed for older children and was found to be cost-effective in a randomized controlled trial [52].

The Pro COR tools can also be linked to Web-based content, including educational materials, advice, and/or referrals to evidence-based intervention programs, thus stimulating a healthy lifestyle and/or health care–seeking behavior. Finally, the risk estimates generated by the Pro COR tools can also be used to study the effectiveness of interventions, as a risk assessment of future overweight and related cardiometabolic outcomes is likely to be more predictive than the currently used definition of overweight using the cutoffs established by the IOTF [53].

Other methods have been developed to identify children who are at high risk for becoming overweight and/or developing adverse cardiometabolic outcome; such methods include the use of a single risk factor, combining risk factors, and developing risk models, risk algorithms, and risk charts. For example, in both Sweden and the United States, risk charts have been developed to predict adult overweight based on a single BMI measurement during childhood [54,55]. Another study performed in the United States reported crude risk estimates of being overweight by the age of 12 years based on one, two, or three BMI values measured between 2 and 4½ years of age [56]. In the United Kingdom, an overweight risk algorithm was developed to identify at-risk children at age 3 years based on predictors that were assessed in the first year of life [57]. To date, however, most risk models have not been dynamic and barely took into account individual BMI development. Moreover, extremely high-performance prediction models are required before acceptable large-scale implementation is possible in practice.

A strength of our study is that we will include additional candidate predictors, thereby helping optimize the performance—and hence the cost-effectiveness—of these models. Moreover, performing repeat risk assessments enables clinicians to both adapt to and individualize the strategies for each child based on new findings. This approach may contribute to the realization of more tailor-made primary prevention programs, with the aim of reversing the high risk of overweight and adverse cardiometabolic outcome in preadolescence.

One potential limitation of our study is that the outcomes of the prediction models were examined in early adolescence; moreover, the cohort data do not currently offer the opportunity to study these outcomes at adulthood. However, the timing of puberty is associated with adult obesity and poor cardiometabolic outcome [58]. On the other hand, the correlation between BMI SDS at age 10 years and BMI SDS at young adulthood is high (>0.7), suggesting that preventing high BMI SDS by the age of 10 years is relevant in terms of health outcome at adulthood [17]. In future studies, we will expand the prediction models with health outcomes at later ages.

By providing longitudinal guidance to children, the Dutch CHC is highly specialized with respect to the growth and development of children, suggesting that performing dynamic risk assessments is a very feasible approach in this setting. Therefore, the Dutch CHC is ideally positioned to help improve resource allocation by identifying high-risk children and excluding children with relatively low risk.

Finally, the tools that emerge from this study will be made available via the Internet, provided that stakeholders—including parents and/or their representatives—voice the need for Web-based access to the tools.

A potential disadvantage associated with applying the Pro COR tools is that it may cause harm due to stigmatization and parental and/or individual concerns. Therefore, we will investigate the effects of risk communication on possible unwanted side effects in the pilot study. At the same time, we must bear in mind that any potential harm due to the application of current cutoff points for overweight and/or obesity are currently unknown; moreover, the effectiveness of interventions that are based on risk assessments can only be studied after the prediction tools have been developed. Therefore, assuming that prediction tools with high sensitivity, specificity, and negative and positive predictive values can be developed, the next logical step would be to perform a randomized controlled trial designed to evaluate the effects of the prediction tools in combination with primary preventive intervention programs.