Reply to FJB van Duijnhoven et al.

We are pleased to see the interest that van Duijnhoven et al. (1) have taken in our work. We are appreciative of their acknowledgment of the effort and thought that went into creating the Dietary Inflammatory Index (DII®), and gratified that the DII has emerged as an important tool in inflammationrelated nutritional epidemiologic research over the past 5 y. Understanding that substantial modifications that were described in this most recent article (2) and included in the new version of the DII described in our 2014 paper (3) represent materially important improvements, we were careful not to recommend widespread use of the original (generation 1) version of the DII that was published in 2009 (4). As these authors point out, we responded to their 2013 article (5) with our letter to the editor of the American Journal of Clinical Nutrition (6), in which we delineated the advantages of the new (generation 2) version of the DII and offered technical assistance in using this new version. Despite this offer, we were never contacted by these authors to use the new version of the DII or to discuss pitfalls in the use of the older, first-generation, version. It should be clear from our Perspective paper (2) that we do not endorse researchers using the older version of the DII for any purpose. In the second-generation DII, the number of articles scored has more than doubled, significant additions have been made to the list of food parameters included in the DII, and a global comparative database was created for computing DII scores so that they could be compared across populations. While we did acknowledge that van Woudenbergh et al. created and used the “Adapted DII" (ADII) (5) in advance of our publishing the new version of the DII, this acknowledgment should not be construed as approval or endorsement. We questioned its use at the time, offered an alternative, and continue to recommend against its future use. The standardization that they refer to in no way shape or form resembles the methodologically rigorous method that we used to assemble a comparative database of individual databases from 11 countries around the world against which we could z-score individuals’ dietary intakes. Furthermore, our creation of an energy-adjusted comparative database to produce the energy-adjusted DII (E-DII) does not resemble what they have done with respect to controlling energy intake. So to refer to it as “similar” is misleading in that the E-DII represents a major methodologic improvement as opposed to the more conventional means of controlling energy intake in regression analyses of epidemiologic data. Although one of our early articles examining the relationship between diet-related inflammation and female breast cancer in Germany did use a regression approach to adjust for energy (7), the E-DII, which we have used in most of our recent papers, including articles on markers of type 2 diabetes risk in middle-aged black South African women (8) and survival among women diagnosed with colorectal cancer in the Women’s Health Initiative (9), involves energy adjustment using the density approach, wherein the global database that we developed also was adjusted for energy. In creating the DII, we were meticulous in following the evidence connecting any and all available dietary parameters to the 6 inflammatory biomarkers IL-1β , IL-4, IL-6, IL-10, TNF-α, and C-reactive protein (CRP). So, we do include overall fat and energy intake in the original formulation. We have done numerous sensitivity analyses to understand how including or excluding particular parameters effects outcomes. As we described in our perspectives article (2), we put considerable thought and effort into understanding how fat and energy, in particular, affect DII scores and eventual measures of effect. So, each parameter is included based on applying sound biological and statistical principles. For reasons to which we alluded earlier (2), we may use the EDII in place of the DII. However, the decision to use one rather than the other is deliberate and evidence based. As with the DII, we routinely offer the E-DII to all of our collaborators. Regarding the issue of dietary assessment, typically FFQs do not include data on all 45 food parameters that constitute the DII under ideal conditions. Indeed, in the hundreds of articles that we have published based on FFQs from around the world, the number of available parameters averages about 27 across all DII computations. So, there is nothing inherently flawed about their FFQ with respect to the parameter list. We would like to add that in the few instances where we have been able to compare DII scores using a more comprehensive method [e.g., multiple 24 recalls compared with a structured questionnaire, the 7-d dietary recall, in the SEASONS (Seasonal Variation of Blood Cholesterol) study], we found virtually no reduction in ability to predict interval changes in high-sensitivity CRP values (10). However, this is not because those individual parameters are unimportant in terms of their per-unit effect; indeed, they tend to be strongly anti-inflammatory. The reason why unavailability does not much matter is that these parameters are not consumed in sufficient quantities in the population for them to influence the DII scores. The fact that these authors have observed relationships between their ADII scores and a summary score for lowgrade inflammation indicates just how strong and persistent these associations are in the data. This should in no way detract from our determination that the second-generation DII is superior to the first-generation DII. We have spent many years and thousands of hours of effort in creating the new DII. It has inherent improvements over the original,