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Scientific Decision Making, Policy Decisions, and the Obesity Pandemic

      Abstract

      Rising and epidemic rates of obesity in many parts of the world are leading to increased suffering and economic stress from diverting health care resources to treating a variety of serious, but preventable, chronic diseases etiologically linked to obesity, particularly type 2 diabetes mellitus and cardiovascular diseases. Despite decades of research into the causes of the obesity pandemic, we seem to be no nearer to a solution now than when the rise in body weights was first chronicled decades ago. The case is made that impediments to a clear understanding of the nature of the problem occur at many levels. These obstacles begin with defining obesity and include lax application of scientific standards of review, tenuous assumption making, flawed measurement and other methods, constrained discourse limiting examination of alternative explanations of cause, and policies that determine funding priorities. These issues constrain creativity and stifle expansive thinking that could otherwise advance the field in preventing and treating obesity and its complications. Suggestions are made to create a climate of open exchange of ideas and redirection of policies that can remove the barriers that prevent us from making material progress in solving a pressing major public health problem of the early 21st century.

      Abbreviations and Acronyms:

      BF (body fat), BMI (body mass index), CHD (coronary heart disease), CVD (cardiovascular disease), EB (energy balance), EE (energy expenditure), EI (energy intake), FLT (first law of thermodynamics), PA (physical activity), RCT (randomized controlled trial)
      Obesity represents a complex set of medical, public health, social, and economic problems that have been refractory to study and effective problem solving. Herein we outline a variety of issues that lie at the heart of our inability to understand the fundamental nature of the problem and that impede inquiry aimed at developing effective solutions.

      Issues and Concerns

      Obesity Is a Pandemic

      Many developed countries and more affluent sectors of emerging economic powers are experiencing a marked increase in the prevalence of overweight and obesity.
      World Health Organization
      Mortality and Burden of Disease Estimates for WHO Member States in 2004.
      World Health Organization
      World Health Statistics 2010.
      The implications of this epidemic for human health, productivity, and health care costs are ominous.
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      • Ebrahim S.
      • Reddy S.
      • Voute J.
      • Leeder S.
      Chronic Disease Action Group
      Prevention of chronic diseases: a call to action.
      • Beaglehole R.
      • Bonita R.
      • Horton R.
      • et al.
      Priority actions for the non-communicable disease crisis.
      In response to the unfolding crisis, funding of obesity research has increased. For example, the US National Institutes of Health annual funding of obesity research is now nearly $1 billion,
      National Institutes of Health
      Strategic Plan for NIH Obesity Research: A Report of the NIH Obesity Research Task Force.
      and the combination of nutrition and obesity research has grown to more than $2 billion per year. Despite this outpouring of resources, the listing of 233 categories of research funding does not include a category for physical activity (PA) or exercise.
      Although this research investment has led to some advances in understanding the genetic, physiologic, and behavioral correlates of obesity, our ability to treat obesity has increased only modestly outside of surgical interventions and potentially a few newly approved pharmacologic agents, and our ability to prevent obesity at the population level has yet to be demonstrated.
      • Andreyeva T.
      • Long M.W.
      • Henderson K.E.
      • Grode G.M.
      Trying to lose weight: diet strategies among Americans with overweight or obesity in 1996 and 2003.
      Prevalence in the general population remains very high, and the recent flattening of rates in the United States is not, by generally accepted scientific standards, attributable to any public health initiatives.
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      Clinical review: behavioral interventions to prevent childhood obesity: a systematic review and metaanalyses of randomized trials.
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      Interventions for the prevention of overweight and obesity in preschool children: a systematic review of randomized controlled trials.
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      Long-term weight control: the National Heart, Lung, and Blood Institute funded multimodal intervention study.
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      Pathophysiology of obesity: why surgery remains the most effective treatment.
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      Losing weight: an ill-fated New Year's resolution.
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      Interventions for preventing obesity in children.
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      • VanWormer J.J.
      • Crain A.L.
      • et al.
      Weight-loss outcomes: a systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up.
      We propose that greater success in this domain may be achieved by overcoming 3 overarching and, to some extent, intersecting shortcomings, each with policy implications: (1) a lack of conceptual clarity in defining obesity, (2) a range of methodologic issues that encourage generating data that perpetuate misconceptions about obesity’s causes, and (3) scholarly dialogues, including peer review processes, that uncritically accept a priori assumptions about cause derived from inaccurate models of obesity and inadequate evidential foundations (Tables 1 and 2). Each of these overarching flaws is associated with a set of policy directives and ad hoc decisions that have contributed to dampening interest in plausible alternatives to conventional explanations as to the causes of and solutions to the obesity epidemic.
      Table 1The Obesity Pandemic: Major Issues in Scientific and Policy Decision Making
      Lack of conceptual clarity
      • The conflation of the definition of obesity and classification of the obese phenotype
      • Definitions of obesity that vary by discipline
        • Epidemiologic and medical: BMI or waist circumference
        • Physiologic: body fat mass or relative body fat percentage
      Imprecise measurement
      • The use of BMI at the population level, although imprecise, is above all practical and acceptable. However, its use at the individual level in obesity interventions is inherently misleading owing to the conflation of body mass with fat mass
      • The storage of energy occurs at the tissue level, yet the measurement and analyses of changes in body mass, fat mass, and adiposity in people examine changes that sum the effect of tissue-level changes across the entire organism and, therefore, cannot distinguish these specific effects
      Obesity paradox
      • Confirmation biases plague research in which the a priori assumption is that obesity is on the causal pathway to many health outcomes (eg, CVD, diabetes)
      • This has led to paradoxes in which, for example, individuals with higher BMIs have better prognoses (eg, cancer, CVD)
      Inferring causality
      • The FLT posits that imbalances between energy intake and energy expenditure invariably lead to alterations in energy storage. Nevertheless, the imprecision of many current measurement protocols renders energy balance a conceptual trap rather than a practical model for understanding obesity and pathologic abnormalities in energy storage
      • Simplistic notions derived from the FLT have led to numerous naive speculations regarding the obesity pandemic and interventions that ignore physiologic and behavioral compensation (eg, physical education or removal of vending machines will decrease obesity)
      Responsibilities of the scientific community
      • The peer review process has failed to curtail the publication of speculations that are conceptually tenuous or devoid of empirical support. For example, if increased food availability was a sufficient cause of obesity, entire populations in developed nations would be obese
      • Lack of due diligence by the research community has facilitated the publication of studies in which vague and imprecise methods have led to results that are suggestive of multiple and divergent explanations
      BMI = body mass index; CVD = cardiovascular disease; FLT = first law of thermodynamics.
      Table 2Propagation of Unproven or Even Disproven Propositions as Though They Are Facts
      NA = not applicable; RCT = randomized controlled trial.
      Data from N Engl J Med.19 References are given only for ideas we classified as myths or presumptions that were not covered by Casazza et al.19
      Factor facilitating propagation of presumptions and mythsExample of presumptions erroneously accepted as fact that seem to be facilitated by the factor in column 1Example of myths erroneously accepted as fact that seem to be facilitated by the factor in column 1
      Failure to conduct the probative studies (typically RCTs with weight or body fat as outcomes and sufficient durations to test postulated effects on body composition) needed to prove or disprove hypothesized effectsRegularly eating (vs skipping) breakfast is protective against obesityNA; things typically can become myths only after probative studies are done
      A resistance to abandoning cherished ideas even when refuting data exist (ie, cognitive dissonance)Early childhood is the period during which we learn exercise and eating habits that influence our weight throughout lifeBreastfeeding is protective against obesity for the breastfed offspring
      Excessive repetitive presentation of the idea (often on the basis of gratuitous association studies long after they are needed) to the point at which the idea comes to be believed merely by the excessive repetition (ie, the mere exposure effect)Eating more fruits and vegetables will result in weight loss or less weight gain, regardless of whether one intentionally makes any other behavioral or environmental changesLarge, rapid weight loss is associated with poorer long-term weight outcomes than is slow, gradual weight loss
      Failure to ask for supporting data from some ideas that seem intuitively obviousPreventing obesity is easier than treating obesity
      • Gill T.
      • King L.
      • Caterson I.
      Obesity prevention: necessary and possible: a structured approach for effective planning.
      Assessing the stage of change or diet readiness is important in helping patients who seek weight-loss treatment AND Setting realistic goals in obesity treatment is important because otherwise patients will become frustrated and lose less weight
      Failure to take into account the passive compensation in energy expenditure that occurs merely as a function of changes in body size that occur with initial alterations in energy intake or expenditureNA; the passive compensation is an established fact, so any calculations that do not accommodate it are effectively myths, not presumptionsSmall, sustained changes in energy intake or expenditure will produce large, long-term weight changes that accumulate indefinitely, which fails to take into account compensatory mechanisms
      Failure to take into account the active compensation in components of energy balance that may occur when another component of energy balance is manipulatedSnacking contributes to weight gain and obesityPhysical education classes in their current format play an important role in preventing or reducing childhood obesity
      Failure to take into account that the active compensation (or lack thereof) in components of energy expenditure that occurs when another component of energy balance is manipulated over a short period (eg, 1 d) may not be maintained if the manipulation is maintained over a longer period; ie, there may be learned compensationReducing portion size in some sources of food will reduce body weight or lead to less weight gain in the long-term

      Small L, Lane H, Vaughan L, Melnyk B, McBurnet D. A systematic review of the evidence: the effects of portion size manipulation with children and portion education/training interventions on dietary intake with adults [published online June 15, 2012]. Worldviews Evid Based Nurs. http://dx.doi.org/10.1111/j.1741-6787.2012.00257.

      NA
      Distortion of the existing scientific evidence by publication and reporting biases or misleading statementsRegularly eating (vs skipping) breakfast is protective against obesity
      • de la Hunty A.
      • Gibson S.
      • Ashwell M.
      Does regular breakfast cereal consumption help children and adolescents stay slimmer? a systematic review and meta-analysis.
      Breastfeeding is protective against obesity for the breastfed offspring
      • Cope M.B.
      • Allison D.B.
      White hat bias: a threat to the integrity of scientific reporting.
      a NA = not applicable; RCT = randomized controlled trial.
      b Data from N Engl J Med.
      • Casazza K.
      • Fontaine K.R.
      • Astrup A.
      • et al.
      Myths, presumptions, and facts about obesity.
      References are given only for ideas we classified as myths or presumptions that were not covered by Casazza et al.
      • Casazza K.
      • Fontaine K.R.
      • Astrup A.
      • et al.
      Myths, presumptions, and facts about obesity.

      Major Presumptions and Myths About Obesity

      Recently, several articles
      • Casazza K.
      • Fontaine K.R.
      • Astrup A.
      • et al.
      Myths, presumptions, and facts about obesity.
      • Finkelstein E.A.
      • Bilger M.
      Hard truths and a new strategy for addressing childhood obesity.
      • Sparling P.B.
      • Franklin B.A.
      • Hill J.O.
      Energy balance: the key to a unified message on diet and physical activity.
      • Casazza K.
      • Allison D.B.
      Stagnation in the clinical, community and public health domain of obesity: the need for probative research.
      • Hafekost K.
      • Lawrence D.
      • Mitrou F.
      • O'Sullivan T.A.
      • Zubrick S.R.
      Tackling overweight and obesity: does the public health message match the science?.
      have pointed out that there are many unproven beliefs (presumptions) and disproven beliefs (myths) about obesity erroneously circulating as facts not only in the mass media and the general public but also in the scientific community. Furthermore, these articles suggest some of the factors that may lead to the propagation of these erroneous beliefs. Table 2 provides a nonexhaustive list of examples, quoted or adapted largely from the article by Casazza et al.
      • Casazza K.
      • Fontaine K.R.
      • Astrup A.
      • et al.
      Myths, presumptions, and facts about obesity.

      Defining Obesity: Need for Conceptual Clarity

      Obesity is defined differently in various disciplines and, with these variations in definition, individuals, therefore, will be classified differentially. For example, physiologists and researchers working with animal models will classify a subject as obese in terms of absolute or relative (percentage) body fat (BF). Indeed, among individuals in this group, the terms obesity and adiposity are used interchangeably. However, following the lead of public health practitioners, clinicians, some clinical researchers, and epidemiologists, obesity is typically categorized on the basis of a body mass index (BMI [calculated as the weight in kilograms divided by the height in meters squared]) of at least 30.
      • Rahman M.
      • Berenson A.B.
      Accuracy of current body mass index obesity classification for white, black, and Hispanic reproductive-age women.
      Indeed, when obesity statistics are cited, invariably they are based on the convention of defining individuals with a BMI of at least 30 as obese. On the basis of relatively easily obtained measurements of height and weight, BMI has been used for many decades by clinicians, epidemiologists, and actuaries as a simple estimate of relative weight that can predict health-related outcomes.
      • Donegan W.L.
      • Hartz A.J.
      • Rimm A.A.
      The association of body weight with recurrent cancer of the breast.
      • Lubin F.
      • Ruder A.M.
      • Wax Y.
      • Modan B.
      Overweight and changes in weight throughout adult life in breast cancer etiology: a case-control study.
      • McNee R.K.
      • Mason B.H.
      • Neave L.M.
      • Kay R.G.
      Influence of height, weight, and obesity on breast cancer incidence and recurrence in Auckland, New Zealand.
      • Hebert J.R.
      • Augustine A.
      • Barone J.
      • Kabat G.C.
      • Kinne D.W.
      • Wynder E.L.
      Weight, height and body mass index in the prognosis of breast cancer: early results of a prospective study.
      • Boffetta P.
      • McLerran D.
      • Chen Y.
      • et al.
      Body mass index and diabetes in Asia: a cross-sectional pooled analysis of 900,000 individuals in the Asia cohort consortium.
      Although it is assumed that the single universal attribute of obesity, defined as a BMI of 30 or greater, is an excess accumulation of adipose tissue, it is clear that BMI is composed of much more than fat mass.
      • Gnacinska M.
      • Malgorzewicz S.
      • Guzek M.
      • Lysiak-Szydlowska W.
      • Sworczak K.
      Adipose tissue activity in relation to overweight or obesity.
      Over the decades, this has led to debate on the utility of relying on BMI to describe obesity
      • Garn S.M.
      • Leonard W.R.
      • Hawthorne V.M.
      Three limitations of the body mass index.
      • Gray D.S.
      • Fujioka K.
      Use of relative weight and Body Mass Index for the determination of adiposity.
      • Van Itallie T.B.
      When the frame is part of the picture.
      and to enhancements to increase its utility.
      • Steinkamp R.C.
      • Cohen N.L.
      • Gaffey W.R.
      • et al.
      Measures of body fat and related factors in normal adults, II: a simple clinical method to estimate body fat and lean body mass.
      • Amador M.
      • Rodriguez C.
      • Gonzalez M.E.
      • Bacallao J.
      Assessing obesity with body weight and height.
      • Pasco J.A.
      • Rutishauser I.H.
      Body fat estimated from anthropometric and electrical impedance measurements.
      Notwithstanding the problems inherent in equating a BMI of 30 or greater with obesity, and then making an implicit assumption that those categorized as obese have excess adipose tissue, this extreme state of overweight is a heterogeneous array of physiologic and behavioral adaptations to environmental conditions.
      • Skelton J.A.
      • Irby M.B.
      • Grzywacz J.G.
      • Miller G.
      Etiologies of obesity in children: nature and nurture.
      Not all people with high levels of BF are obese by this classification; likewise, some people with very high BMIs may have little fat mass. For example, females tend to have much higher levels of BF than their male counterparts at all levels of BMI
      • Thomas E.L.
      • Parkinson J.R.
      • Frost G.S.
      • et al.
      The missing risk: MRI and MRS phenotyping of abdominal adiposity and ectopic fat.
      ; yet, their obesity rates, as defined by a BMI of at least 30, are not generally much higher than those of males.
      • Hall K.D.
      • Heymsfield S.B.
      • Kemnitz J.W.
      • Klein S.
      • Schoeller D.A.
      • Speakman J.R.
      Energy balance and its components: implications for body weight regulation.
      In contrast, some individuals (eg, certain categories of elite athletes) may have little BF but BMIs that define them as obese.
      • Kraemer W.J.
      • Torine J.C.
      • Silvestre R.
      • et al.
      Body size and composition of National Football League players.
      Even in most instances in which adiposity is its main driver, obesity is not a single pathologic condition but rather a sign of underlying primary pathologic abnormalities.
      • Heshka S.
      • Allison D.B.
      Is obesity a disease?.
      • Atkinson R.l.
      Etiologies of obesity.
      Clearly, obesity arises from the dynamic interplay of the external environment,
      • Klimentidis Y.C.
      • Beasley T.M.
      • Lin H.Y.
      • et al.
      Canaries in the coal mine: a cross-species analysis of the plurality of obesity epidemics.
      • Vimaleswaran K.S.
      • Li S.
      • Zhao J.H.
      • et al.
      Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene.
      • Kilpelainen T.O.
      • Qi L.
      • Brage S.
      • et al.
      Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.
      inclusive of the social milieu, built environment, and food energy availability
      • Pinnick K.E.
      • Karpe F.
      DNA methylation of genes in adipose tissue.
      • Gluckman P.D.
      • Hanson M.A.
      Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective.
      • Gluckman P.D.
      • Hanson M.A.
      • Low F.M.
      The role of developmental plasticity and epigenetics in human health.
      ; behavioral and developmental processes
      • Kimura Y.
      • Nanri A.
      • Matsushita Y.
      • Sasaki S.
      • Mizoue T.
      Eating behavior in relation to prevalence of overweight among Japanese men.
      • Comuzzie A.G.
      • Allison D.B.
      The search for human obesity genes.
      ; and a variety of genes and epigenetic effects that, in turn, control a myriad of metabolic systems and subsystems that regulate body composition, energy intake (EI) and energy expenditure (EE), and nutrient partitioning.
      • Perusse L.
      • Rankinen T.
      • Zuberi A.
      • et al.
      The human obesity gene map: the 2004 update.
      • Blechman J.
      • Amir-Zilberstein L.
      • Gutnick A.
      • Ben-Dor S.
      • Levkowitz G.
      The metabolic regulator PGC-1alpha directly controls the expression of the hypothalamic neuropeptide oxytocin.
      • Paracchini V.
      • Pedotti P.
      • Taioli E.
      Genetics of leptin and obesity: a HuGE review.
      Although intrinsic (eg, individual genetic and metabolic) factors may play a role in determining who may become obese,
      • Reinehr T.
      • Wabitsch M.
      Childhood obesity.
      • Pijl H.
      Obesity: evolution of a symptom of affluence.
      the preponderance of epidemiologic and ecological evidence indicates that social and environmental factors that determine energy balance (EB) are the primary causes of the secular shift toward higher body weights.
      • Hu F.B.
      Globalization of diabetes: the role of diet, lifestyle, and genes.
      • Nguyen D.M.
      • El-Serag H.B.
      The epidemiology of obesity.
      Definitional issues notwithstanding, characterizing obesity as a distinct condition suggesting a simple, straightforward, and unvarying etiology has biased all phases of obesity-related discourse. Consequently, it has generated a futile search for a single explanation, thus promoting excessively optimistic and generally ineffective interventions and other misguided attempts in the vain hope for “magic (eg, pharmacologic) bullets.” Although BMI provides a reasonable, if crude, estimate of adiposity at the population level, it has little value as a dependent measure in studies of obesity prevention and treatment because changes in body weight may be indicative of alterations in muscle mass, organ mass, other lean body mass, fat mass, body water, glycogen stores, or combinations of these. Therefore, studies reporting decreases in body weight also may exhibit increments in adiposity (ie, percentage fat mass) and decrements in lean body mass.
      • Li X.
      • Cope M.B.
      • Johnson M.S.
      • Smith Jr., D.L.
      • Nagy T.R.
      Mild calorie restriction induces fat accumulation in female C57BL/6J mice.
      • Leibel R.L.
      • Rosenbaum M.
      • Hirsch J.
      Changes in energy expenditure resulting from altered body weight.
      Nevertheless, a recent meta-analysis using BMI to determine overweight and obesity status was performed with data from 97 major epidemiologic studies in nearly 2.9 million people with 270,000 deaths during follow-up.
      • Flegal K.M.
      • Kit B.K.
      • Orpana H.
      • Graubard B.I.
      Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.
      Although this study found that the entire population of obese individuals had a significantly higher mortality rate than did those with a normal BMI (Hazard ratio [HR], 1.18 [95% CI, 1.12-1.25] for obesity [all grades combined]), this was not the case with class I obesity (BMI, 30.00-34.99), which did not have higher mortality rates and actually had 5% lower mortality than did the normal BMI group (18.50-24.99), which was not quite significant statistically. However, the lowest mortality rate occurred in the overweight BMI group (25.00-29.99), with 6% lower mortality compared with the normal BMI group. Obese individuals 65 years and older had no higher mortality rates compared with normal-weight persons, and this applied even to those with a BMI of 35.00 or greater. These findings from a large meta-analysis of cohort data call into question what is an optimal BMI in current populations.

      Obesity Paradox

      To add to the existing confusion and controversy, the obesity paradox has been well described during the past decade.
      • Lavie C.J.
      • De Schutter A.
      • Patel D.A.
      • et al.
      New insights into the “obesity paradox” and cardiovascular outcomes.
      Overweight and obesity, generally described by BMI criteria, are associated with an increased prevalence of almost all cardiovascular disease (CVD) risk factors and of almost all CVDs, including hypertension, coronary heart disease (CHD), heart failure, and atrial fibrillation. Despite this association, considerable evidence now indicates that overweight and obese patients with the same CVD diagnoses have better short- and long-term prognoses than do their leaner counterparts. Although it was theorized that this paradoxical relationship may be explained, in part, by the relatively weak relationship between BMI and BF, recent studies have found the obesity paradox with BMI, BF, and even measures of central obesity.
      • Lavie C.J.
      • De Schutter A.
      • Patel D.A.
      • et al.
      New insights into the “obesity paradox” and cardiovascular outcomes.
      • Lavie C.J.
      • De Schutter A.
      • Patel D.A.
      • Romero-Corral A.
      • Artham S.M.
      • Milani R.V.
      Body composition and survival in stable coronary heart disease: impact of lean mass index and body fat in the “obesity paradox.”.
      • McAuley P.A.
      • Artero E.G.
      • Sui X.
      • et al.
      The obesity paradox, cardiorespiratory fitness, and coronary heart disease.
      • Lavie C.J.
      • De Schutter A.
      • Patel D.
      • Artham S.M.
      • Milani R.V.
      Body composition and coronary heart disease mortality: an obesity or a lean paradox?.
      Adding to the literature reporting the obesity paradox with BMI, we recently found that the highest mortality rates, at least in patients with CHD, are concentrated in those with the lowest levels of lean body mass, suggesting that this may be as much a lean paradox as it is an obesity paradox.
      • Lavie C.J.
      • De Schutter A.
      • Patel D.A.
      • Romero-Corral A.
      • Artham S.M.
      • Milani R.V.
      Body composition and survival in stable coronary heart disease: impact of lean mass index and body fat in the “obesity paradox.”.
      • Lavie C.J.
      • De Schutter A.
      • Patel D.
      • Artham S.M.
      • Milani R.V.
      Body composition and coronary heart disease mortality: an obesity or a lean paradox?.
      Nevertheless, in patients with CHD
      • McAuley P.A.
      • Artero E.G.
      • Sui X.
      • et al.
      The obesity paradox, cardiorespiratory fitness, and coronary heart disease.
      and in those with heart failure,
      • Lavie C.J.
      • Cahalin L.P.
      • Chase P.
      • et al.
      Impact of cardiorespiratory fitness on the obesity paradox in patients with heart failure.
      it seems that physical fitness significantly alters the relationship between adiposity and subsequent prognosis such that only those with low levels of fitness demonstrate this obesity paradox. Patients with high fitness, regardless of their level of adiposity by BMI, BF, and central obesity, have a favorable prognosis.
      • Lavie C.J.
      • De Schutter A.
      • Patel D.A.
      • et al.
      New insights into the “obesity paradox” and cardiovascular outcomes.
      • McAuley P.A.
      • Artero E.G.
      • Sui X.
      • et al.
      The obesity paradox, cardiorespiratory fitness, and coronary heart disease.
      • Lavie C.J.
      • Cahalin L.P.
      • Chase P.
      • et al.
      Impact of cardiorespiratory fitness on the obesity paradox in patients with heart failure.
      Although further research is needed to determine optimal levels of body composition in patients with CVD, the present data indicate that the greatest attention needs to be directed toward increasing fitness, which is generally obtained with increases in PA and EE, rather than reducing adiposity per se. With respect to CVD, the obesity paradox reflects the complexity of these relationships.

      Scientific Standards, Assumptions, Methods, and Discourse Limiting Examination of Alternative Explanations of Cause

      Presumption

      Most scientific theories and models of obesity are based on the first law of thermodynamics (FLT) and proffer that imbalances between EI and EE lead to changes in energy storage (primarily as lipid). The imprecision of current methods for measuring EI
      • Klesges L.M.
      • Baranowski T.
      • Beech B.
      • et al.
      Social desirability bias in self-reported dietary, physical activity and weight concerns measures in 8- to 10-year-old African-American girls: results from the Girls Health Enrichment Multisite Studies (GEMS).
      • Hill R.J.
      • Davies P.S.
      The validity of self-reported energy intake as determined using the doubly labelled water technique.
      • Schoeller D.A.
      Limitations in the assessment of dietary energy intake by self-report.
      • Black A.E.
      • Prentice A.M.
      • Goldberg G.R.
      • et al.
      Measurements of total energy expenditure provide insights into the validity of dietary measurements of energy intake.
      • Hebert J.R.
      • Ebbeling C.B.
      • Matthews C.E.
      • et al.
      Systematic errors in middle-aged women's estimates of energy intake: comparing three self-report measures to total energy expenditure from doubly labeled water.
      and EE
      • Wong M.Y.
      • Day N.E.
      • Wareham N.J.
      Measurement error in epidemiology: the design of validation studies, II: bivariate situation.
      • Wareham N.J.
      • Jakes R.W.
      • Rennie K.L.
      • Mitchell J.
      • Hennings S.
      • Day N.E.
      Validity and repeatability of the EPIC-Norfolk Physical Activity Questionnaire.
      • Westerterp K.R.
      • Plasqui G.
      Physical activity and human energy expenditure.
      on a large (ie, public health) scale precludes accurate quantification of the EB equation and thus preclude definitive statements regarding the cause of the obesity epidemic.

      Description vs Explanation

      The FLT provides a true but inadequately simplistic and inherently tautological description of the energy imbalance that leads to overweight and obesity. The “criteria for judging causality,” developed by Hill
      • Hill A.B.
      Observation and experiment.
      • Hill A.B.
      The environment and disease: association or causation?.
      in the early 1950s to provide a framework for assessing cause in complex systems and popularized in the 1964 Surgeon General’s report Smoking and Health,
      US Department of Health, Education, and Welfare
      Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Services.
      has been a hallmark of scientific reasoning aimed at assessing evidence in relation to complex causes for more than a half century. The logical flaw in using the FLT to explain secular changes in body weight is reflected in nonadherence to these criteria for judging causality. Specifically, invoking the FLT to explain secular trends in weight gain fails criteria 3, specificity, and 4, temporality. In addition, because of its inability to control for confounding or to estimate effect modification, the FLT provides little useful information for assessing other criteria (ie, the strength of the association, consistency across different sources of evidence, dose-response, plausibility, coherence, and analogy). To illustrate its inability to offer a meaningful explanation of cause, one should consider the analogy of fuel consumption and automobile driving. The average distance driven by motorists has steadily increased since 1980 (in parallel with obesity rates). At the same time, fuel consumption has increased. Although these data are simply and obviously correlated, on their own they do nothing to answer the question: Why are people now driving greater distances? Similarly, to understand the obesity epidemic, we need to search for potentially modifiable root factors that can be measured and modeled to see how well they fit the criteria for judging causality. We should not be satisfied with tautological statements based on the FLT. The flawed logic that naturally flows from naive appeals to the FLT and EB conjectures (eg, increased caloric intake must lead to increased obesity) has biased research funding decisions and the choice of study designs, operational definitions of variables, choice of measurement methods, and analytic procedures, which all condition higher-level decisions regarding how, when, and where to intervene.

      Simplistic Determinism and Reductionism

      Reliance on FLT-based models leads to neglecting a potentially large array of complex, dynamic, nonlinear, homeostatic systems (eg, energy metabolism and feeding behavior) in favor of static, deterministic equivalency, an extreme form of reductionism in which the complexity of physiologic features and behavior are reduced to basic physics. More importantly, the manifest assumption of FLT-based models is that energy imbalances, no matter how trivial, lead to linear extrapolations to changes in body mass. Measurement and conceptual issues aside, the fallacy of this a priori assumption is obvious; during the past 50 years, it has been reported repeatedly that biological organisms adapt physiologically, behaviorally, or both to perturbations in EB.
      • Li X.
      • Cope M.B.
      • Johnson M.S.
      • Smith Jr., D.L.
      • Nagy T.R.
      Mild calorie restriction induces fat accumulation in female C57BL/6J mice.
      • Keys A.
      • Brozek J.
      • Henschel A.
      • Mickelsen O.
      • Taylor H.L.
      The Biology of Human Starvation.
      • Mayer J.
      • Marshall N.B.
      • Vitale J.J.
      • Christensen J.H.
      • Mashayekhi M.B.
      • Stare F.J.
      Exercise, food intake and body weight in normal rats and genetically obese adult mice.
      • Sullivan E.L.
      • Cameron J.L.
      A rapidly occurring compensatory decrease in physical activity counteracts diet-induced weight loss in female monkeys.
      • Hall K.D.
      Predicting metabolic adaptation, body weight change, and energy intake in humans.
      The effects of acute or chronic changes in any component of the EB equation will be damped via compensatory alterations in EI (ie, feeding behavior) or EE through changes in body composition or PA or some combination of these.
      • Hall K.D.
      Predicting metabolic adaptation, body weight change, and energy intake in humans.
      • Hall K.D.
      • Sacks G.
      • Chandramohan D.
      • et al.
      Quantification of the effect of energy imbalance on bodyweight.
      In addition, the wealth of responses available to free-living people may well reduce, eliminate, or even reverse the intended effects of any environmental alteration (ie, an intervention).
      • Edwards R.
      Sugar-sweetened beverage taxes raise demand for substitutes and could even raise caloric intake.
      • Harris K.C.
      • Kuramoto L.K.
      • Schulzer M.
      • Retallack J.E.
      Effect of school-based physical activity interventions on body mass index in children: a meta-analysis.
      • Faith M.S.
      • Fontaine K.R.
      • Baskin M.L.
      • Allison D.B.
      Toward the reduction of population obesity: macrolevel environmental approaches to the problems of food, eating, and obesity.
      • Taber D.R.
      • Chriqui J.F.
      • Powell L.M.
      • Chaloupka F.J.
      Banning all sugar-sweetened beverages in middle schools: reduction of in-school access and purchasing but not overall consumption.
      This reality makes policy
      • Edwards R.
      Sugar-sweetened beverage taxes raise demand for substitutes and could even raise caloric intake.
      • Taber D.R.
      • Chriqui J.F.
      • Powell L.M.
      • Chaloupka F.J.
      Banning all sugar-sweetened beverages in middle schools: reduction of in-school access and purchasing but not overall consumption.
      • Lin B.H.
      • Smith T.A.
      • Lee J.Y.
      • Hall K.D.
      Measuring weight outcomes for obesity intervention strategies: the case of a sugar-sweetened beverage tax.
      and funding
      National Institutes of Health
      Strategic Plan for NIH Obesity Research: A Report of the NIH Obesity Research Task Force.
      decisions based on deterministic equivalencies unproductive in that they incentivize research that fails to account for the array of recalibrations and adjustments that free-living people undergo.

      Measurement and Introspection

      Very little of the literature on which we base inferences is from the strongest of study designs: randomized controlled trials (RCTs).
      • Allison D.B.
      Evidence, discourse and values in obesity-oriented policy: menu labeling as a conversation starter.
      Likewise, measurement methods commonly used to assess EI and EE lack the accuracy, reliability, and precision necessary to evaluate the efficacy of interventions or even to draw conclusions from carefully designed observational studies when RCTs are infeasible.
      • Lavie C.J.
      • De Schutter A.
      • Patel D.
      • Artham S.M.
      • Milani R.V.
      Body composition and coronary heart disease mortality: an obesity or a lean paradox?.
      • Black A.E.
      • Prentice A.M.
      • Goldberg G.R.
      • et al.
      Measurements of total energy expenditure provide insights into the validity of dietary measurements of energy intake.
      • Wong M.Y.
      • Day N.E.
      • Wareham N.J.
      Measurement error in epidemiology: the design of validation studies, II: bivariate situation.
      • Wareham N.J.
      • Jakes R.W.
      • Rennie K.L.
      • Mitchell J.
      • Hennings S.
      • Day N.E.
      Validity and repeatability of the EPIC-Norfolk Physical Activity Questionnaire.
      • Westerterp K.R.
      • Plasqui G.
      Physical activity and human energy expenditure.
      • Hebert J.R.
      • Ma Y.
      • Clemow L.
      • et al.
      Gender differences in social desirability and social approval bias in dietary self report.
      This also was (and is) true of the relationship between tobacco exposure and health outcomes, to which the criteria for judging causality were most famously applied.
      US Department of Health, Education, and Welfare
      Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Services.
      However, those relationships were easier to sort out for 3 reasons: (1) tobacco exposure is easier to measure than diet or PA (or certainly both), (2) tobacco is very strongly associated with the conditions with which it was first associated (eg, lung cancer
      • Wynder E.L.
      • Graham E.A.
      Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma: a study of six hundred and eighty-four proved cases.
      ), and (3) the effect of tobacco is not as heavily confounded by other factors (although effect modification is important for conditions such as esophageal squamous cell cancer
      • Pottern L.M.
      • Morris L.E.
      • Blot W.J.
      • Ziegler R.G.
      • Fraumeni Jr., J.F.
      Esophageal cancer among black men in Washington, D.C., I: alcohol, tobacco, and other risk factors.
      • Yuan J.-M.
      • Knezevich A.D.
      • Wang R.
      • Gao Y.-T.
      • Hecht S.S.
      • Stepanov I.
      Urinary levels of the tobacco-specific carcinogen N'-nitrosonornicotine and its glucuronide are strongly associated with esophageal cancer risk in smokers.
      ).
      For diet and PA, true criterion measures (eg, doubly labeled water in carefully controlled settings) rarely exist for practical application in large- or even medium-scale epidemiologic or clinical studies, and even doubly labeled water measurements do not assess an important component of PA: intensity. Consequently, marginal intermethod reliability (between-method correlations of ρ≈0.60, indicating that 64% of variability is unexplained) is accepted as adequate validity.
      • Hebert J.R.
      • Ebbeling C.B.
      • Matthews C.E.
      • et al.
      Systematic errors in middle-aged women's estimates of energy intake: comparing three self-report measures to total energy expenditure from doubly labeled water.
      • Kaaks R.
      • Ferrari P.
      • Ciampi A.
      • Plummer M.
      • Riboli E.
      Uses and limitations of statistical accounting for random error correlations, in the validation of dietary questionnaire assessments.
      • Neuhouser M.L.
      • Tinker L.
      • Shaw P.A.
      • et al.
      Use of recovery biomarkers to calibrate nutrient consumption self-reports in the Women's Health Initiative.
      For a variety of practical reasons, observational and even intervention studies rely on inexpensive, inaccurate, and imprecise self-report methods.
      • Oza-Frank R.
      • Cheng Y.J.
      • Narayan K.M.
      • Gregg E.W.
      Trends in nutrient intake among adults with diabetes in the United States: 1988-2004.
      • Hebert J.R.
      • Ma Y.
      • Ebbeling C.B.
      • Matthews C.E.
      • Ockene I.S.
      Self-report data.
      Construct validation is nearly completely ignored,
      • Hebert J.R.
      • Ockene I.S.
      • Hurley T.G.
      • Luippold R.
      • Well A.D.
      • Harmatz M.G.
      Dietary Assessment Working Group of the Worcester Area Trial for Counseling in Hyperlipidemia (WATCH)
      Development and testing of a seven-day dietary recall.
      • Ockene I.S.
      • Hebert J.R.
      • Ockene J.K.
      • et al.
      Effect of physician-delivered nutrition counseling training and an office support system on saturated fat intake, weight, and serum lipid measurements in a hyperlipidemic population: the Worcester-Area Trial for Counseling in Hyperlipidemia (WATCH).
      and methods that could triangulate to objective measures of exposure are rarely used.
      • Fowke J.H.
      • Hebert J.R.
      • Fahey J.W.
      Urinary excretion of dithiocarbamates and self-reported Cruciferous vegetable intake: application of the “method of triads” to a food-specific biomarker.
      • Kabagambe E.K.
      • Baylin A.
      • Allan D.A.
      • Siles X.
      • Spiegelman D.
      • Campos H.
      Application of the method of triads to evaluate the performance of food frequency questionnaires and biomarkers as indicators of long-term dietary intake.
      This satisfaction with inadequate measurement has stunted obesity research and the field of nutritional epidemiology more generally.
      • Taubes G.
      What if it's all been a big fat lie?.
      • Taubes G.
      The soft science of dietary fat.
      Although practical, including financial, constraints must be acknowledged, the scientific community should demand that methodological research be undertaken to improve the accuracy of self-report, including identifying sources of error with the aim of developing better techniques for statistical adjustment. For example, doubly labeled water (even with its acknowledged weaknesses) could be used to measure EE in carefully controlled intervention studies and could provide a leverage point for improving self-report instruments, as we have done previously.
      • Hebert J.R.
      • Ebbeling C.B.
      • Matthews C.E.
      • et al.
      Systematic errors in middle-aged women's estimates of energy intake: comparing three self-report measures to total energy expenditure from doubly labeled water.
      There are important precedents, most notably from the genetics field, for investing heavily in improved measurement methods and supporting large studies needed to address the complexity of many of the traits under study in human genetics and gene-environment interactions
      • Li S.
      • Loos R.J.F.
      Progress in the genetics of common obesity: size matters.
      when the potential benefit is perceived to be high in relation to the probable risk from inaction and inattention.

      Misuse of Population-Level Data Sources

      Numerous data sources are tangential to EI (eg, losses from food inventory and food waste) but are often elevated to causal explanation. Numerous journals have published articles suggesting an invalid determinism (ie, economic forces are not just associated with, but determine, obesity). Although food supply forces (eg, availability and price) may affect purchase and perhaps utilization, the mere presence, purchase, or even increased consumption of food does not necessarily cause long-term changes in adiposity.
      • Hall K.D.
      Predicting metabolic adaptation, body weight change, and energy intake in humans.
      • Hall K.D.
      • Sacks G.
      • Chandramohan D.
      • et al.
      Quantification of the effect of energy imbalance on bodyweight.
      • Matsumura Y.
      Nutrition trends in Japan.
      • Sims E.A.
      • Danforth Jr., E.
      • Horton E.S.
      • Bray G.A.
      • Glennon J.A.
      • Salans L.B.
      Endocrine and metabolic effects of experimental obesity in man.
      • Speakman J.R.
      Obesity: the integrated roles of environment and genetics.
      • Speakman J.R.
      • Stubbs R.J.
      • Mercer J.G.
      Does body mass play a role in the regulation of food intake?.
      • Katanoda K.
      • Matsumura Y.
      National Nutrition Survey in Japan: its methodological transition and current findings.

      Lack of Due Diligence in Upholding Rigorous Standards of Scientific Evidence When Seemingly Good Ends Are Pursued

      Despite that obesity may not simply be the result of overeating,
      • Hall K.D.
      Predicting metabolic adaptation, body weight change, and energy intake in humans.
      • Hall K.D.
      • Sacks G.
      • Chandramohan D.
      • et al.
      Quantification of the effect of energy imbalance on bodyweight.
      • Sims E.A.
      • Danforth Jr., E.
      • Horton E.S.
      • Bray G.A.
      • Glennon J.A.
      • Salans L.B.
      Endocrine and metabolic effects of experimental obesity in man.
      numerous journals continue to publish articles suggesting that the superficial economics (eg, mere availability of cheap “junk” food) has caused the obesity epidemic.
      • Poti J.M.
      • Popkin B.M.
      Trends in energy intake among US children by eating location and food source, 1977-2006.
      • Swinburn B.
      • Sacks G.
      • Ravussin E.
      Increased food energy supply is more than sufficient to explain the US epidemic of obesity.
      • Swinburn B.A.
      • Sacks G.
      • Lo S.K.
      • et al.
      Estimating the changes in energy flux that characterize the rise in obesity prevalence.
      • Duffey K.J.
      • Popkin B.M.
      Energy density, portion size, and eating occasions: contributions to increased energy intake in the United States, 1977-2006.
      • Swinburn B.A.
      • Sacks G.
      • Hall K.D.
      • et al.
      The global obesity pandemic: shaped by global drivers and local environments.
      • Swinburn B.
      Nutrition signposting: the “eat more” message is getting through; what about the “eat less” message?.
      • Gortmaker S.L.
      • Swinburn B.A.
      • Levy D.
      • et al.
      Changing the future of obesity: science, policy, and action.
      Adherence to assumptions with no factual foundation does little to advance scientific understanding. Obesity is widely portrayed as an evil enemy,
      • Gluckman P.D.
      • Hanson M.
      • Zimmet P.
      • Forrester T.
      Losing the war against obesity: the need for a developmental perspective.
      • Klein J.D.
      • Dietz W.
      Childhood obesity: the new tobacco.
      and it is commonly accepted that when we are at war and perceive ourselves to be “the good guys,” valid means of collecting and analyzing data are put aside in favor of expedience in doing what it takes to win the war. The resulting bias permeates the larger social/environmental context, influencing peer review of publication, grants, and, perhaps more importantly, upstream decisions to forgo more expensive, intensive research that addresses the nuances of the complexity of the obesity epidemic.

      Discussion and Recommendations

      Our inability to materially and durably decrease the population prevalence of obesity or adiposity in targeted individuals is noteworthy.
      • Kamath C.C.
      • Vickers K.S.
      • Ehrlich A.
      • et al.
      Clinical review: behavioral interventions to prevent childhood obesity: a systematic review and metaanalyses of randomized trials.
      • Monasta L.
      • Batty G.D.
      • Macaluso A.
      • et al.
      Interventions for the prevention of overweight and obesity in preschool children: a systematic review of randomized controlled trials.
      • Weintraub M.
      Long-term weight control: the National Heart, Lung, and Blood Institute funded multimodal intervention study.
      • Waseem T.
      • Mogensen K.M.
      • Lautz D.B.
      • Robinson M.K.
      Pathophysiology of obesity: why surgery remains the most effective treatment.
      • Kassirer J.P.
      • Angell M.
      Losing weight: an ill-fated New Year's resolution.
      • Summerbell C.D.
      • Waters E.
      • Edmunds L.D.
      • Kelly S.
      • Brown T.
      • Campbell K.J.
      Interventions for preventing obesity in children.
      • Franz M.J.
      • VanWormer J.J.
      • Crain A.L.
      • et al.
      Weight-loss outcomes: a systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up.
      Interventions aimed at increasing EE (eg, through improved physical education classes, incentivizing the use of health clubs/exercise facilities, and adding walking/cycling paths to decrease automobile use and increase human-powered transportation) or decreasing EI (eg, through weight-loss programs, nutrition education, taxing specific food commodities, and food labeling) seem not to result in long-term weight loss, despite appeals to the FLT.
      • Schoeller D.A.
      The energy balance equation: looking back and looking forward are two very different views.
      • Brown T.
      • Summerbell C.
      Systematic review of school-based interventions that focus on changing dietary intake and physical activity levels to prevent childhood obesity: an update to the obesity guidance produced by the National Institute for Health and Clinical Excellence.
      • Wilks D.C.
      • Besson H.
      • Lindroos A.K.
      • Ekelund U.
      Objectively measured physical activity and obesity prevention in children, adolescents and adults: a systematic review of prospective studies.
      • Pinelli L.
      • Elerdini N.
      • Faith M.S.
      • et al.
      Childhood obesity: results of a multicenter study of obesity treatment in Italy.
      • Corvalan C.
      • Uauy R.
      • Flores R.
      • Kleinbaum D.
      • Martorell R.
      Reductions in the energy content of meals served in the Chilean National Nursery School Council Program did not consistently decrease obesity among beneficiaries.
      • Foster G.D.
      • Sherman S.
      • Borradaile K.E.
      • et al.
      A policy-based school intervention to prevent overweight and obesity.
      Crude models of obesity have constrained research for decades, from study design choices, selection and measurement of variables, operational definitions, development and use of measurement tools, and decisions as to how, when, and where to intervene. The flawed logic, vague concepts, inaccurate and imprecise measurements, and unsubstantiated a priori assumptions regarding causal relationships that have followed from vague and poorly specified models during the past century have engendered policy and funding decisions that have incentivized research that perpetuates and compounds these errors via confirmation bias while constraining research paths incongruent with prevailing assumptions.
      Conjectures emanating from studies based on the current models of obesity coupled with policy and funding decisions that narrowly constrain future inquiry have contributed to a failure of the peer review process to deepen understanding of obesity at all levels of inquiry. To understand the scope of the problem, we need to remain aware of the fact that obesity arises from the dynamic interplay of the external environment
      • Klimentidis Y.C.
      • Beasley T.M.
      • Lin H.Y.
      • et al.
      Canaries in the coal mine: a cross-species analysis of the plurality of obesity epidemics.
      • Vimaleswaran K.S.
      • Li S.
      • Zhao J.H.
      • et al.
      Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene.
      • Kilpelainen T.O.
      • Qi L.
      • Brage S.
      • et al.
      Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.
      with behavioral and developmental processes
      • Kimura Y.
      • Nanri A.
      • Matsushita Y.
      • Sasaki S.
      • Mizoue T.
      Eating behavior in relation to prevalence of overweight among Japanese men.
      • Comuzzie A.G.
      • Allison D.B.
      The search for human obesity genes.
      and genetic and epigenetic factors.
      • Perusse L.
      • Rankinen T.
      • Zuberi A.
      • et al.
      The human obesity gene map: the 2004 update.
      • Blechman J.
      • Amir-Zilberstein L.
      • Gutnick A.
      • Ben-Dor S.
      • Levkowitz G.
      The metabolic regulator PGC-1alpha directly controls the expression of the hypothalamic neuropeptide oxytocin.
      • Paracchini V.
      • Pedotti P.
      • Taioli E.
      Genetics of leptin and obesity: a HuGE review.
      When conceptualized in this manner, it becomes evident that simple, deterministic statements about the etiology of obesity and narrow interpretation about the scope of fundable research are naive and inherently unscientific.
      • Swinburn B.
      • Sacks G.
      • Ravussin E.
      Increased food energy supply is more than sufficient to explain the US epidemic of obesity.
      Future research should accommodate the apparent complexity of the obesity problem. Conceptualizing a problem implies specification of how to measure and quantify those things that are hypothesized to be important in its cause (or remediation). Because of the narrow interpretation of the causes of the obesity problem, measurement technologies have tended to represent a limited set of possibilities. In planning how to move forward, it is important to consider broadening our interpretation of measurement devices to include study design as an important subset.
      • Miettinen O.S.
      Theoretical Epidemiology: Principles of Occurrence Research in Medicine.
      Although RCTs may be a good choice because of the potentially tight control over extraneous factors, it must be realized that often only 1 or 2 factors can be controlled by design. In addition, it is important to appreciate that just because individuals are randomized to a particular study arm in no way guarantees that baseline factors will be entirely equivalent (or exchangeable), that important effect modifiers or confounders will not change differentially over time, that there will be complete adherence, or that there will not be differential dropout.
      • Hebert J.R.
      • Hurley T.G.
      • Harmon B.E.
      • Heiney S.
      • Hebert C.J.
      • Steck S.E.
      A diet, physical activity, and stress reduction intervention in men with rising prostate-specific antigen after treatment for prostate cancer.
      • Lodi G.
      • Sardella A.
      • Bez C.
      • Demarosi F.
      • Carrassi A.
      Systematic review of randomized trials for the treatment of oral leukoplakia.
      Although these factors would plague even simple pharmacologic interventions, it is reasonable to assume that they might be much more severe in situations in which considerable participant commitment is required and blinding is not possible.
      Regardless of the specific design chosen, measurements should include potential adaptive behavioral and physiologic responses to specific changes in EI or EE that may mitigate their expected effects. Usually these adaptive behaviors occur in social contexts that integrate physiologic factors with social cues.
      • Lundberg P.C.
      • Thrakul S.
      Type 2 diabetes: how do Thai Buddhist people with diabetes practise self-management?.
      • Steptoe A.
      • Dockray S.
      • Wardle J.
      Positive affect and psychobiological processes relevant to health.
      Understanding motivational issues regarding food choices
      • Goldberg J.P.
      • Sliwa S.A.
      Communicating actionable nutrition messages: challenges and opportunities.
      • Kuk J.L.
      • Ardern C.I.
      • Church T.S.
      • Hebert J.R.
      • Sui X.
      • Blair S.N.
      Ideal weight and weight satisfaction: association with health practices.
      • Narchi I.
      • Walrand S.
      • Boirie Y.
      • Rousset S.
      Emotions generated by food in elderly French people.
      and the willingness and ability to engage in a sufficient PA dose (ie, intensity, frequency, and duration) over time
      • Kuk J.L.
      • Ardern C.I.
      • Church T.S.
      • Hebert J.R.
      • Sui X.
      • Blair S.N.
      Ideal weight and weight satisfaction: association with health practices.
      • Yap T.L.
      • Davis L.S.
      Physical activity: the science of health promotion through tailored messages.
      also represents an important part of successfully designing studies that will materially improve obesity-related outcomes.
      Recognizing that such adaptive behaviors cannot be controlled by design,
      • Friedenreich C.M.
      • Thune I.
      • Brinton L.A.
      • Albanes D.
      Epidemiologic issues related to the association between physical activity and breast cancer.
      • Prentice R.L.
      • Kakar F.
      • Hursting S.
      • Sheppard L.
      • Klein R.
      • Kushi L.H.
      Aspects of the rationale for the Women's Health Trial.
      existing methods for collecting this kind of information can be used across a variety of experimental and observational study designs for broad applicability in advancing and deepening our understanding of the causes and treatments of obesity.
      • Monasta L.
      • Batty G.D.
      • Macaluso A.
      • et al.
      Interventions for the prevention of overweight and obesity in preschool children: a systematic review of randomized controlled trials.
      • Casazza K.
      • Fontaine K.R.
      • Astrup A.
      • et al.
      Myths, presumptions, and facts about obesity.
      • Sparling P.B.
      • Franklin B.A.
      • Hill J.O.
      Energy balance: the key to a unified message on diet and physical activity.
      • Casazza K.
      • Allison D.B.
      Stagnation in the clinical, community and public health domain of obesity: the need for probative research.
      • Flegal K.M.
      • Kit B.K.
      • Orpana H.
      • Graubard B.I.
      Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.
      Such statistical methods are well described and commonly used in epidemiologic research, in which effect modification and potential confounding are ubiquitous concerns in the analysis of real-world data, whether collected in the context of an RCT or observationally.
      • Heroux M.
      • Janssen I.
      • Lam M.
      • et al.
      Dietary patterns and the risk of mortality: impact of cardiorespiratory fitness.
      • Ali M.M.
      • Fang H.
      • Rizzo J.A.
      Body weight, self-perception and mental health outcomes among adolescents.
      • Fraser G.E.
      A search for truth in dietary epidemiology.
      It also is important to choose appropriately from the continuum of efficacy and effectiveness study designs.
      • Stevens J.
      • Taber D.R.
      • Murray D.M.
      • Ward D.S.
      Advances and controversies in the design of obesity prevention trials.
      The use of experimental designs may, indeed, be more appropriate for the study of the causes of obesity, and we would tend to recommend such designs in general.
      • Mattes R.D.
      • Shikany J.M.
      • Kaiser K.A.
      • Allison D.B.
      Nutritively sweetened beverage consumption and body weight: a systematic review and meta-analysis of randomized experiments.
      • Elobeid M.A.
      • Allison D.B.
      Putative environmental-endocrine disruptors and obesity: a review.
      However, note that the actual differences in EI vs EE necessary to cause measurable changes in energy stores tend to be relatively small (ie, just a few extra kilocalories per day can lead to a couple of kilograms of weight gain per year).
      • Blundell J.E.
      • Stubbs R.J.
      • Hughes D.A.
      • Whybrow S.
      • King N.A.
      Cross talk between physical activity and appetite control: does physical activity stimulate appetite?.
      • Moore M.S.
      Interactions between physical activity and diet in the regulation of body weight.
      The fact that even morbidly obese people are in relatively good balance over extended periods of time underlines people’s adaptive ability.
      • Pijl H.
      Obesity: evolution of a symptom of affluence.
      • Hall K.D.
      Predicting metabolic adaptation, body weight change, and energy intake in humans.
      • Rogers P.J.
      Eating habits and appetite control: a psychobiological perspective.
      Therefore, compensatory factors that cannot be incorporated as design features of any proposed study must be controlled analytically. This requires anticipating possible mechanisms and either using existing methods or developing new ones to measure these factors and analyze data that are collected using appropriate assessment methods.
      To address the public health dimension of the problem, at least some of these studies must be conducted in the context of how people actually lead their lives. Unlike studies of many pharmaceutical agents, behavioral interventions cannot be blinded from the perspective of the participants.
      • Hebert J.R.
      • Hurley T.G.
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      • et al.
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      Also, there may be ethical issues that either inhibit randomization or cause individuals (eg, the morbidly obese) to refuse to be randomized.
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      Regarding assessment of the primary exposures, it seems necessary to improve measurement techniques and curtail the use of inaccurate self-reports of diet and PA without identifying methods of adjustment to improve accuracy. We must increase investments in measuring EI and EE more accurately in large-scale surveys and epidemiologic studies. Developing more practical objective measurement methods should be a high priority because widely used self-reports are often subject to large sources of measurement bias.
      • Freudenheim J.L.
      • Marshall J.R.
      The problem of profound mismeasurement and the power of epidemiological studies of diet and cancer.
      Although developing entirely new methods may be desirable, identifying sources of error and then using these data to develop analytic methods to reduce their influence on drawing erroneous inferences might be a desirable interim goal. Rapid progress in developing objective measures of PA that are feasible for use in large-scale studies of free-living individuals is encouraging.
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      • Bowles H.R.
      • Troiano R.
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      Assessment of physical activity using wearable monitors: recommendations for monitor calibration and use in the field.
      Likewise, work that has been conducted on defining sources of measurement error in relation to an “objective” criterion measure (eg, doubly labeled water)
      • Hebert J.R.
      • Ebbeling C.B.
      • Matthews C.E.
      • et al.
      Systematic errors in middle-aged women's estimates of energy intake: comparing three self-report measures to total energy expenditure from doubly labeled water.
      • Adams S.A.
      • Matthews C.E.
      • Ebbeling C.B.
      • et al.
      The effect of social desirability and social approval on self-reports of physical activity.
      and then using this information to improve estimation of construct validators (eg, body weight, body composition, and serum lipid levels)
      • Hebert J.R.
      • Ebbeling C.B.
      • Ockene I.S.
      • et al.
      A dietitian-delivered group nutrition program leads to reductions in dietary fat, serum cholesterol, and body weight: findings from the Worcester Area Trial for Counseling in Hyperlipidemia (WATCH).
      • Hebert J.R.
      • Ebbeling C.B.
      • Olendzki B.C.
      • et al.
      Change in women's diet and body mass following intensive intervention in early-stage breast cancer.
      holds promise for advancing this field of obesity research.

      Conclusion

      Current rates of obesity and related conditions continue to place unrelenting strain on health care resources and to reduce productivity. If our response is to be commensurate with the seriousness of the problem, the scientific community must demand higher standards in efforts to understand obesity’s causes and potential solutions.

      Supplemental Online Material

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      • Correction
        Mayo Clinic ProceedingsVol. 88Issue 8
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          In the article “Scientific Decision Making, Policy Decisions, and the Obesity Pandemic,” published in the June 2013 issue of Mayo Clinic Proceedings (2013;88(6):593-604), the citation to reference 21 lists the wrong journal. It should be J Cardiopulm Rehabil Prev, not J Mol Signal. It is now listed correctly here:
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