Effectiveness of individual-focused interventions to prevent chronic disease

DOI: 10.1111/eci.12298 REVIEW Effectiveness of individual-focused interventions to prevent chronic disease Sara Saeed*, Mohammad Golfam*, Reed F. Beall*,†, Fredrick D. Ashbury‡,§,¶,**, Lyle J. Palmer‡,††,‡‡,§§ and Julian Little* * Department of Epidemiology and Community Medicine, †Institute of Population Health, University of Ottawa, Ottawa, ON, Canada, ‡Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada, §Illawarra Medical Health Research Institute, University of Wollongong, Wollongong, NSW, Australia, ¶Division of Preventive Oncology, University of Calgary, Calgary, AB, Canada, **Intelligent Improvement Consultants, Inc., Toronto, ON, Canada, ††School of Translational Health Science, University of Adelaide, Adelaide, SA, Australia, ‡‡Samuel Lunenfeld Research Institute, §§Faculty of Public Health, Ontario Institute for Cancer Research, University of Toronto, Toronto, ON, Canada ABSTRACT Background The burden of chronic disease is projected to assume crisis proportions in most parts of the world by the middle of the century, focusing attention on the need for preventive interventions. We identify and review published research on primary prevention individual-level interventions in current practice and describe and discuss the limitations of the current evidence. The report facilitates prioritizing a research agenda for potential interventions that might be investigated within cohort studies. Materials and methods This study is a rapid review. Computerized database searches (PubMed and EMBASE) were performed in October 2012 to identify articles on primary prevention interventions that are directed at the individual level. Potentially, relevant International Agency of Research on Cancer handbooks and monographs were also reviewed. The review includes articles reported in English on the efficacy or effectiveness of a preventive intervention in an adult population. It excludes articles on alcohol or tobacco smoking. Results Many chronic disease interventions directed at individuals report a protective effect in the short term and some evidence for the efficacy of chemoprevention in chronic disease prevention exists. Evidence these effects persist in the longer term is inconsistent. Conclusions There are currently only limited evidence-based preventions for most chronic diseases, for which a summary is available in Table A1 (see Appendix B). Most individual-level intervention research studies have been conducted using case–control designs and some small, randomized studies. There are fewer impediments to lifestyle modifications when compared to prevention using chemoprevention and vaccination or other methods of prevention of persistent infection. Keywords Chronic disease, individual-level intervention, intervention studies, prevention. Eur J Clin Invest 2014; 44 (9): 882–890 Introduction Global estimates suggest that the prevalence of chronic diseases is rising to magnitudes that will make current strategies for their management unsustainable. In 2008, 36 million deaths were ascribed to chronic disease, accounting for 63% of all deaths worldwide [1]. This crisis has focused attention on the need for preventive interventions. Many studies have sought to determine methods to prevent chronic disease. These include lifestyle behavioural changes and interventions using biomedical or chemo-preventive agents. Additionally, there have been efforts to evaluate 882 comprehensively the effects of different lifestyle factors and risk of chronic disease, either considering one disease at a time, or across a number of diseases. Although the aetiology of most chronic diseases is complex, accumulated evidence shows that many chronic diseases share common risk factors and underlying pathologic mechanisms. Societal forces influence many of these common risk factors, and some argue that societal-level interventions might have greater impact than individual-level interventions [2,3]. On the other hand, interventions focused exclusively on the causative environmental agents at a population level may be undermined by individual-level behavioural responses. For example, although it is well established that ª 2014 Stichting European Society for Clinical Investigation Journal Foundation INTERVENTIONS TO PREVENT CHRONIC DISEASE smoking and drugs may cause disease, they also cause addiction [4]. Thus, an approach to prevention based solely on manipulation of the environment at the societal level may not be adequate to reduce the burden of preventable disease [5]. Novel strategies are required to test the feasibility and effectiveness of chronic disease intervention initiatives. Herein, we review prevention strategies directed at individuals, implementation in practice, the limitations of current practice and opportunities for innovative research designs that allow embedding of prevention intervention research projects in large-scale cohort research platforms. Considerable investments have been made and are continuing to be sought, in cohort studies in many jurisdictions [6–9]. An emerging trend in many jurisdictions is citizen science [10], and increasing attention is being given to participant engagement in research. Thus, there is an emerging inherent tension between observing the development of traits and diseases in cohorts, and seeking to return information that might be beneficial to participants [11,12]. This raises the question as to whether cohort studies could be a framework for conducting intervention studies [13]. The Ontario Health Study [14], one of the components of the Canadian Partnership for Tomorrow Project [9], was a motivating example for considering this issue because it is a large cohort with internet-based enrolment and data collection; considerable efforts have been made to engage participants. This paper is a companion to two other articles [15,16]. Primary prevention intervention research receives smaller proportions of health research funding than basic science and clinical research. Consequently, most chronic disease intervention studies involve comparatively small sample sizes and brief timeframes to evaluate effectiveness, cost and sustainability. Moreover, given the limitations in prevention intervention research, it is difficult to assess the effectiveness of the work that has been carried out. Therefore, in this article, we outline the primary prevention approaches at individual-level that have been reported, describe and discuss those used in current practice and identify the limitations of the current evidence. We also discuss the potential for the application of individual-level intervention research studies that are embedded within large-scale cohort research platforms to test feasibility and effectiveness. The results of this rapid review will facilitate prioritizing a research agenda for potential interventions that might be investigated within large-scale cohort research projects. Materials and methods We conducted a rapid review, which differs from a traditional systematic review in that it streamlines one or more components of traditional systematic review methods to synthesize evidence within a shortened timeframe [17]. Here, we adopted to limit the search strategy. The questions and methods were developed by a small working group (SS, RB, MG, JL). Four steps were followed to complete this rapid review. First, the research question was developed to direct the focus of literature to be reviewed, assessed and included. We focused on individual-level primary preventive interventions directed at adults. As this focus is in line with the sampling frame used by many cohort studies, we were able to assess and comment on the extent to which largescale cohort research platforms are appropriate ‘environments’ to test individual-level prevention interventions. Due to time constraints, we did not examine intervention studies on smoking or alcohol prevention. Considerable research on the effects of tobacco and alcohol control measures already exists [18–20]. Second, a systematic literature search was developed in consultation with the working group and a professional medical librarian. The search strategy was completed in PubMed and EMBASE during October 2012. Key words used in the search are listed in the Appendix A. Relevant International Agency of Research on Cancer (IARC) handbooks and monographs were included [21,22]. Third, titles and abstracts were screened by the first author (SS). Article inclusion criteria were as follows: (i) the study investigated a primary intervention aimed at one or more chronic diseases; (ii) the study involved interventions delivered directly at the individual level; and (iii) published within the past 10 years; and (iv) English publication. Postinitial screening phase, 58 articles were identified. Full-text screening was then performed by SS, and reasons for exclusion were recorded. A core body of 39 articles was retained and was reviewed by another member of the team (JL). Fourth, a narrative synthesis of all included studies was performed. Results Lifestyle modifications Diet. Fruit and vegetables are important in health maintenance and nutrition security. In several jurisdictions, it is recommended that adults eat at least five servings of fruits and vegetables daily [23,24]. Randomized controlled trials (RCTs), as well as meta-analysis of RCTs, have reported higher levels of consumption of fruits and vegetables have shown to be inversely related to the development of several chronic diseases [25,26]. Interventions to increase consumption of fruits and vegetables over periods of weeks or months have been shown to: (i) decrease lipid oxidation, a source of indirect oxidative damage European Journal of Clinical Investigation Vol 44 883 S. SAEED ET AL. to DNA; (ii) lower systolic and diastolic blood pressure; and (iii) control cholesterol [26,27]. Furthermore, a meta-analysis of RCTs reports reduction in dietary serum cholesterol appears to reduce coronary heart disease [28,29]. Moreover, interventions of higher intensity and longer duration were found to be more beneficial in making a change than brief interventions, but these also demand more resources and are more complex to design and deliver [30,31]. Numerous mechanistic and epidemiological studies have shown many benefits with single nutrients on chronic disease [21]; however, it is suggested that almost all randomized trials on dietary interventions with single nutrients have shown no benefit [32]. Physical activity. All articles identified on the effects of physical activity as a primary intervention approach unanimously stated that physical inactivity increases risk of many chronic diseases. Adding exercise, including moderate physical activity or aerobic exercise training – 2
5 to 5 h a week or 1– 2
5 h a week of vigorous intense exercise – is considered sufficient to reduce the risk of chronic disease [18,21]. One systematic review of RCTs focusing on the individuallevel that promote physical activity has shown that behaviour changes are observed only during the intervention period, merely weeks or months and are not sustained in long-term follow-up, [21,33,34]. All effects of physical activity generally return to baseline. Therefore, it has been recommended that exercise be promoted at a young age, so that the behaviour continues into later life [21]. Chemopreventive agents Vitamin D. There is some evidence that higher levels of vitamin D may be a protective factor for many chronic diseases [35]. There are two established strategies for increasing vitamin D status, namely oral vitamin D3 intake and sun exposure. Two small-scale RCTs testing the effects of vitamin D3 supplements were reviewed, reported no change in the incidence rate of cancer or other types of chronic disease; however, results were inconclusive due to lack of statistical power. WHO has suggested increasing 25-hydroxyvitamin D levels above 30 lg/mL by means of exposure to ultraviolet radiation or taking at least 50 lg per day of supplemental vitamin D3. However, a caution was included that the long-term effects of high-dose vitamin D are unknown [36,37]. Other studies – including the Framingham Heart Study and NHANES III – suggest that risk of chronic disease increases when doses of serum 25-hydroxyvitamin D reach levels above 40 lg/mL [21,37]. One umbrella overview explains that the role of vitamin D has been explored in relation to a large number of outcomes, covering a wide range of diseases, including skeletal, malignant, cardiovascular, autoimmune, infectious and metabolic 884 www.ejci-online.com diseases [37]. The review suggests that cancer, cognitive and infectious disease outcomes were examined only in observational studies of plasma vitamin D, and the review found no meta-analyses of RCTs of vitamin D supplementation. The review also concluded that a clear role of vitamin D with highly significant results does not exist [37]. Other vitamins and multivitamins. In a recent systematic review focusing on RCTs, data on daily supplementation with (i) b-carotene alone of 20–50 mg, (ii) combined vitamin B2 with niacin supplement or (iii) supplementation with folic acid at daily doses of 0
75 or 30 mg, alone or in combination with vitamin B12 and/or vitamin B6, did not show protective effects against any chronic disease [38]. Vitamin E also was considered to have no effect on preventing chronic disease with the exception of prostate cancer and, in heavy smokers, colorectal cancer. The dosage of b-carotene and retinol in supplementalvitamin RCTs was much higher than the highest intakes reported from dietary sources that had been associated with an apparent protective effect in observational studies. Additionally, vitamin E supplementation was associated with an increased incidence of epistaxis, and a meta-analysis of RCTs reported an excess all-cause mortality of 39 per 10 000 (95% CI 3, 74 per 10 000) for vitamin E doses ≥ 400 IU per day [39]. The same meta-analysis estimated an absolute reduction of allcause mortality of 16 per 10 000 for doses < 400 IU. Multivitamin supplements usually contain vitamins A, B1-2, B6, B12, C-E, b-carotene, folic acid, niacin, calcium, iron, zinc, magnesium and selenium. These nutrients have many biological effects and are potentially chemo-preventive for some chronic diseases [36]. One RCT suggested that supplementation with combined b-carotene, vitamin E and selenium at doses one to two times the recommended daily allowance for 5 years reduced gastric cancer incidence by 13–21% [40]. There was also a significant reduction in the risk of liver cancer in those who used selenium supplements of 200 mcg/day for 2 years [40]. Another RCT investigating multivitamins noted a 31% reduction over an 8-year period in the overall cancer risk in men; particularly noteworthy, this RCT showed a 12% reduction in prostate cancer risk [41]. Overall, RCTs of multivitamin supplements in the prevention of chronic disease show inconsistent results; no published studies have shown any adverse effects of its use [38]. Nonsteroidal anti-inflammatory drugs. There is substantial epidemiological and experimental evidence that aspirin and other Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit tumour development in various sites. These possible effects have also been tested in RCTs in humans, and evidence compatible with protective effects has been reported [21]. A major property of aspirin lies in its ability to depress prostaglandin ª 2014 Stichting European Society for Clinical Investigation Journal Foundation INTERVENTIONS TO PREVENT CHRONIC DISEASE synthesis by means of inhibiting COX-2, which is often overexpressed in many cancers. There have been case–control and cohort studies on the associations between NSAIDs use and cancer, especially colorectal cancer [21,42]. An average reduction of neoplasms by 35–50%, with evidence of a dose–response relationship, was observed in these studies [41]. Moreover, there is evidence that aspirin can prevent cardiovascular disease and hypertension [30]. However, well-controlled hypertensive patients with diabetes have an increased risk for nonfatal major bleeds, confirmed via RCTs [21,43]. Nevertheless, there is still uncertainty regarding the overall effect of aspirin on chronic disease prevention [21,43–47]. With respect to cancer, one RCT concluded that ‘alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extra-cranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer [48]’. In contrast, with respect to cardiovascular disease, another study concluded, ‘despite important reductions in nonfatal MI, aspirin prophylaxis in people without prior CVD does not lead to reductions in either cardiovascular death or cancer mortality. Because the benefits are further offset by clinically important bleeding events, routine use of aspirin for primary prevention is not warranted and treatment decisions need to be considered on a case-by-case basis’ [43]. Polypills. ‘Polypills’ are a recent chemoprevention approach. Polypills investigated to date differ in composition of the agent, but generally contain at least one antihypertensive and one lipid-lowering medication [49,50]. Allocation of antiplatelet therapy containing a fixed dose of aspirin, a statin and one or two blood pressure-lowering drugs was found to significantly reduce the risk for major cardiovascular disease by 23%, myocardial infarction by 34% and nonfatal stroke by 25%, in a metaanalysis of primary intervention trials [51]. Further, regardless of baseline risks, it was observed, in a meta-analysis of RCTs, that in comparison with aspirin alone, a mixture of aspirin and clopidogrel, and a mixture of aspirin and ticlopidine, further reduced risk for chronic disease by 10% and 12%, respectively [51]. It is suggested that a polypill containing a statin, a diuretic, a beta-blocker, an ACE inhibitor, aspirin and folic acid be taken by all adults aged over 55 years of age and by adults of any age with diabetes or cardiovascular disease, regardless of risk factors [50,52]. Substantial heterogeneity has been observed in the effects of polypills on blood pressure and lipid profiles [49]. No significant differences in side effects have been observed in comparison with assignment to placebo or a single agent; however, compared with placebo, polypills reduced systolic blood pressure by 9
2 mmHg (95% CI: 13
4, 5
0) diastolic blood pressure by 5
0 mmHg (95% CI: 7
4, 2
6), total cholesterol by 1
22 mM (95% CI: 1
60, 0
84) and LDLcholesterol by 1
02 mM (95% CI: 1
37, 0
67) [49]. Nonetheless, those taking a ‘polypill’ were more likely to discontinue study medication [49]. Prevention of chronic infections The review also identified studies on the prevention of chronic infections. Specifically, these studies primarily focus on human papillomaviruses, hepatitis B, and Helicobacter pylori. Human papillomaviruses. Currently, there are two prophylactic human papillomaviruses (HPV) vaccines on the market, the bivalent vaccine and the quadrivalent vaccine [53,54]. These vaccines are designed to prevent HPV infections and HPVrelated diseases, and RCTs show both these vaccines prevent over 90% of cervical intraepithelial neoplasia grade 2 (CIN2) or higher among females between the ages of 15 and 16 years who have not been exposed to infection with HPV [55]. The efficacy estimates vary by type of study, population, duration of follow-up and vaccination type used [53,55]. Protection with either vaccine, in RCTs, has been shown to be protective for 5– 6 years. In some jurisdictions, catch-up HPV vaccination is offered to women younger than 26 years [56] and is offered to similarly aged males [56]. However, overall the long-term protection and impact of HPV vaccination on the prevention of cervical cancer and other HPV-associated tumours are unknown [56,57]. Hepatitis B virus. A large-scale study investigated the efficacy of vaccination against hepatitis B virus (HBV) in preventing chronic carriage of the virus, as well as hepatocellular carcinoma and chronic liver disease, including liver cirrhosis. It showed that only infants who did not receive the full course of vaccination or those who did not respond to the vaccination became chronic carriers [58,59]. Another study found that the efficacy of the vaccine and levels of the HBV surface antibody decrease with age. Nevertheless, the vaccine effects were present even 20–24 years after the course of vaccination. Thus, HBV vaccination early during life can provide long-lasting protection against carriage, despite decreasing antibody levels [59]. Hepatitis C virus. Currently, there is no active or passive vaccination against hepatitis C virus (HCV) because of the complex genetic heterogeneity of this positively stranded RNA virus [60]. Helicobacter pylori. Limited human and animal studies have shown that Helicobacter pylori eradication therapy inhibits development of gastric carcinogenesis [22,61,62]. In addition, most studies on H. pylori are in vitro based. The source of European Journal of Clinical Investigation Vol 44 885 S. SAEED ET AL. H. pylori is unknown; the recommended preventive measures are basic hygiene [63]. Discussion Many different individual-level interventions have been proposed for the primary prevention of chronic diseases, but evidence of the long-term effects of these has not been definitively established. Most research has had follow-up periods of 2– 5 years, whereas the development of chronic diseases can take substantially longer to manifest. Many of the primary studies of putatively preventive behaviours we considered had limitations. For example, articles reviewing diet or physical exercise noted that exposure was self-reported and therefore were subject to misclassification bias. Most RCTs had limited generalizability because of strict inclusion and exclusion criteria and participation were limited. Studies on chemo-preventive agents and on the prevention of chronic infections have had mixed results; some primary studies showed the benefits of the intervention, whereas others show no effect or even adverse effects (e.g., NSAIDs). Overall, RCTs have found some beneficial effects, but these have typically been accompanied by evidence of adverse side effects [21]. For example, while multivitamins appear to have variable benefits in patients of specific subpopulations, other individuals may derive harm from an intervention such as the increase in lung cancer associated with the use of high doses of betacarotene and preformed retinol [21]. A recent update of the systematic review by Huang et al. [38] concluded that there was no evidence of nutritional doses of vitamins on cardiovascular disease, cancer or mortality in healthy individuals without known nutritional deficiencies [64]. A limitation of most studies on the use of chemo-preventive agents is that very little is known about the optimal time to start and stop a chemo-preventive intervention, which is a recent issue identified in folic acid fortification research [21]. Moreover, long-term effects of chemo-preventive agents and vaccination or other interventions to prevent chronic infection are unknown. Further investigation is required to evaluate the risks and benefits of these approaches over the longer term [21,65,66]. Additionally, most chemoprevention and vaccination trials were not designed to test the primary prevention of chronic disease. There is a need for RCTs with this specific objective [36]. There appear to be fewer potential impediments to lifestyle modifications when compared to prevention using chemoprevention, and vaccination or other methods of prevention of persistent infection. Societal-level interventions also are difficult to achieve as they must be carried through a political framework with many competing interests and short-term horizons [67]. Our perspective is that individual-level 886 www.ejci-online.com interventions could potentially be complementary to determinants of health approaches. Furthermore, we support the increasing thinking about moving from rather paternalistic approaches to the new public health concepts of shared decision-making between individuals and health and social care professionals, and emergence of citizen science [68]. Consequently, given the challenging reality of preventive intervention research (i.e. the slow progression of chronic illness and the challenge of parsing out the myriad of possible relevant exposures over time), societal-level interventions could potentially be very powerful ways to proceed. Nevertheless, we maintained the focus of this review on individual-based prevention because that is what might fit in the framework of a longitudinal population-based cohort study. Limitations of rapid review This rapid review, like other reviews, had many limitations to its method of study selection and search strategy. As already mentioned, due to time constraints as well as the nature of the study, we may have missed some studies because of the limited search strategy used. Moreover, grey literature was not searched and the search strategy was not iterative. We did not examine intervention studies on smoking or alcohol prevention, as considerable research on the effects of tobacco and alcohol control measures already exists. Lastly, there was only one reviewer involved in including and excluding articles and extracting data from the included articles. These limitations obviously limit the scope of the review, and we acknowledge that a noncomprehensive evidence synthesis is more prone to bias than a comprehensive synthesis. However, we believe that this was a reasonable approach to pursue in prioritizing a research agenda for potential interventions that might be investigated within large-scale cohort research projects. Conclusion There are currently only limited evidence-based preventions for most chronic diseases, for which a summary is available in Table A1 (see Appendix B). Most individual-level intervention research studies have been conducted using case–control designs and some small, randomized studies. There are fewer impediments to lifestyle modifications when compared to prevention using chemoprevention and vaccination or other methods of prevention of persistent infection. More is known in area of lifestyle changes [69]. In general, it has been suggested that successful approaches are likely be multi-modal, including a combination of prevention interventions including vaccination and chemo-preventive agents, a healthy diet, maintaining healthy weight, physical exercise, avoiding smoking and ª 2014 Stichting European Society for Clinical Investigation Journal Foundation INTERVENTIONS TO PREVENT CHRONIC DISEASE avoiding sedentary behaviours [20,70]. There is great potential to investigate individual-based interventions with multiple outcomes and longer follow-up within framework of cohort study to determine the true effects of interventions. Doing so will also contribute to understanding the differences between those who participate in trials vs. those who do not, especially as these considered relative to community (or broader-based) interventions, so-called natural experiments. Acknowledgements This project was funded through the Population Studies Research Network supported by Cancer Care Ontario with funds from the Ministry of Health and Long-Term Care. Contributions Conceived and designed the experiments: SS, MG, RFB, JL. Performed the experiments: SS. Analysed the data: SS. Wrote the first draft of the manuscript: SS. Contributed to the writing of the manuscript: SS, MG, RFB, LP, FA, JL. ICMJE criteria for authorship read and met: SS, MG, RFB, FA, JL. Agree with manuscript results and conclusions: SS, MG, RFB, LP, FA, JL. Address Department of Epidemiology and Community Medicine, University of Ottawa, Room 3231, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5 (S. Saeed, M. Golfam, R. F. Beall, J. Little); Institute of Population Health, University of Ottawa, 1 Stewart Street, Room 300, Ottawa, ON, Canada K1N 6N5 (R. F. Beall); Dalla Lana School of Public Health, University of Toronto, 155 College Street, 6th Floor, Toronto, ON, Canada M5T 3M7 (F. D. Ashbury, L. J. Palmer); K1N 6N5, Illawarra Health and Medical Research Institute, University of Wollongong, Building 32, Wollongong, NSW 2522, Australia (F. D. Ashbury); Division of Preventive Oncology, University of Calgary, 2500 University Dr. NW, Calgary, AB, Canada T2N 1N4 (F. D. Ashbury); Intelligent Improvement Consultants, Inc., 10 Milner Business Court, 3rd Floor, Toronto, ON, Canada M1B 3C6 (F. D. Ashbury); School of Translational Health Science, Level 1, 115 Grenfell Street, University of Adelaide, Adelaide, SA 5005, Australia (L. J. Palmer); Samuel Lunenfeld Research Institute, University of Toronto, 1001-522 University Avenue, Toronto, ON, Canada M5G 1W7 (L. J. Palmer); Ontario Institute for Cancer Research, Faculty of Public Health, University of Toronto, Toronto, MaRS Centre, 661 University Avenue, Suite 510, ON, Canada M5G OA3 (L. J. Palmer). Correspondence to: Prof Julian Little, Department of Epidemiology & Community Medicine, Room 3231, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. Tel.: +1 613 562 5800, ext. 8159; fax+1 613 562 5465; e-mail: jlittle@uottawa.ca Received 15 April 2014; accepted 8 July 2014 References 1 Alwan A. Global Status Report on Noncommunicable Diseases 2010. Geneva: World Health Organization; 2011. 2 Rose G. Sick individuals and sick populations. Int J Epidemiol 1985;14:32–8. 3 Marmot M, Friel S, Bell R, Houweling TA, Taylor S. Closing the gap in a generation: health equity through action on the social determinants of health. 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Chronic non-communicable diseases. Ann Trop Med Parasitol 2006;100:5–6. Appendix A Keywords for search Chronic disease AND primary intervention AND prevention AND physical activity OR socioeconomic status OR diet OR polypill OR vitamin D OR Helicobacter pylori OR hepatitis B OR hepatitis C OR multivitamin supplements OR nonsteroidal anti-inflammatory drugs. Appendix B Table 1 Summary of type of evidence and results from each mode of intervention reviewed Intervention Type of evidence Outcome Diet RCTs Fruits and vegetables are recommended to reduce risk for chronic disease Do not focus on single nutrients, as they are no strong source of evidence for these trials Physical activity RCTs Behaviour changes are observed only during the intervention period, merely weeks or months and are not sustained in long-term follow-up Observational studies also suggest physical inactivity increases risk for many chronic diseases Vitamin D Observational No strong evidence for effect of vitamin D Cancer, cognitive and infectious disease outcomes were examined only in observational studies of plasma vitamin D, and the review found no meta-analyses of RCTs of vitamin D supplementation European Journal of Clinical Investigation Vol 44 889 S. SAEED ET AL. www.ejci-online.com Appendix B Continued Intervention Type of evidence Other vitamins and multivitamins RCTs + Observational Outcome Mixed results on effects of multivitamins Some RCTs suggest no protective effects against any chronic disease; others showed some RCTs suggest effect on prostate cancer and, in heavy smokers, colorectal cancer Observational studies suggest long-term use of multivitamins may have a protective effect Nonsteroidal antiinflammatory drugs (NSAIDS) RCTs Mixed evidence suggests the short-term reductions in cancer incidence and mortality and the decrease in risk of major extra-cranial bleeds with extended use, and their low casefatality, add to the case for daily aspirin in prevention of cancer However, Because the benefits are further offset by clinically important bleeding events, routine use of aspirin for primary prevention is not warranted and treatment decisions need to be considered on a case-by-case basis Polypills RCTs Strong evidence suggests polypills reduce the risk of chronic disease Substantial heterogeneity has been observed in the effects of polypills on blood pressure and lipid profiles Human Papillomaviruses (HPV) RCTs Strong evidence via RCTs suggest that HVP vaccines prevent over 90% of cervical intraepithelial neoplasia grade 2 (CIN2) or higher among females between ages of 15 and 16 years who have not been exposed to infection with HPV Long-term protection and impact of HPV vaccination on the prevention of cervical cancer and other HPV-associated tumours are unknown Hepatitis B virus (HBV) Observational Vaccine effects were present even 20–24 years after the course of vaccination HBV vaccination early during life can provide long-lasting protection against carriage, despite decreasing antibody levels Hepatitis C Virus (HCV) Helicobacter pylori No active or passive vaccination against HCV In vitro + animal RCTs Limited evidence shown that Helicobacter pylori eradication therapy inhibits development of gastric carcinogenesis Most studies on H. pylori are in vitro based 890 ª 2014 Stichting European Society for Clinical Investigation Journal Foundation