Systematic review with meta-analysis of the epidemiological evidence relating FEV1 decline to lung cancer risk

Abstract

Background: Reduced FEV1 is known to predict increased lung cancer risk, but previous reviews are limited. To quantify this relationship more precisely, and study heterogeneity, we derived estimates of β for the relationship RR(diff) = exp(βdiff), where diff is the reduction in FEV1 expressed as a percentage of predicted (FEV1%P) and RR(diff) the associated relative risk. We used results reported directly as β, and as grouped levels of RR in terms of FEV1%P and of associated measures (e.g. FEV1/FVC).

Methods: Papers describing cohort studies involving at least three years follow-up which recorded FEV1 at baseline and presented results relating lung cancer to FEV1 or associated measures were sought from Medline and other sources. Data were recorded on study design and quality and, for each data block identified, on details of the results, including population characteristics, adjustment factors, lung function measure, and analysis type. Regression estimates were converted to β estimates where appropriate. For results reported by grouped levels, we used the NHANES III dataset to estimate mean FEV1%P values for each level, regardless of the measure used, then derived β using regression analysis which accounted for non-independence of the RR estimates. Goodness-of-fit was tested by comparing observed and predicted lung cancer cases for each level. Inverse-variance weighted meta-analysis allowed derivation of overall β estimates and testing for heterogeneity by factors including sex, age, location, timing, duration, study quality, smoking adjustment, measure of FEV1 reported, and inverse-variance weight of β.

Results: Thirty-three publications satisfying the inclusion/exclusion criteria were identified, seven being rejected as not allowing estimation of β. The remaining 26 described 22 distinct studies, from which 32 independent β estimates were derived. Goodness-of-fit was satisfactory, and exp(β), the RR increase per one unit FEV1%P decrease, was estimated as 1.019 (95%CI 1.016-1.021). The estimates were quite consistent (I2 =29.6%). Mean age was the only independent source of heterogeneity, exp(β) being higher for age <50 years (1.024, 1.020-1.028).

Conclusions: Although the source papers present results in various ways, complicating meta-analysis, they are very consistent. A decrease in FEV1%P of 10% is associated with a 20% (95%CI 17%-23%) increase in lung cancer risk.

Figure 1

Flow diagram for literature searching. The diagram gives details of the four stages of the search; the Medline search, the Embase search, the search based on reviews of interest, and the search based on secondary references. The four criteria for rejecting papers during these four stages are described further in the Methods section under the headings “patients”, “not cohort”, “not lung cancer” and “reviews not of interest”. Note that one of the three papers accepted from the search based on secondary references cited a paper that was also examined but provided no lung cancer results. The four stages produced a total of 33 accepted papers (22 Medline, 5 Embase, 3 reviews of interest, 3 secondary references). Subsequently 7 of these were rejected for reasons described in the first paragraph of the Results section.

Figure 2

Forest plot of the 32 estimates of exp(β). Estimates of β and SE(β) are presented in Table 3 for results presented originally as regression coefficients and in Table 4 for results presented by grouped level of FEV1 or associated measures. For each of the 32 estimates Figure 2 shows the associated values of exp(β) with their 95%CIs. These estimates are shown both numerically and also graphically on a logarithmic scale. The studies are sorted in order of block number, and are referenced by study reference (REF). Multiple blocks within the same study are distinguished by the following codes (M = males, F = females, N = never smokers, X = ex smokers, C = current smokers, LO = FEV₁/FVC ≥ 0.70, and HI = FEV₁/FVC < 0.70). In the graphical representation individual RRs are indicated by a solid square, with the area of the square proportional to the weight (inverse- variance of log RR).

Figure 3

Funnel plot. Funnel plot of the 32 estimates of β against their precision (1/SE). The dotted vertical line indicates the meta-analysis estimate. Estimates based on data originally presented as FEV₁%P are distinguished from other estimates by different symbols.