Do CT Scans help prevent cancer-related deaths?

This paper uses a region-level estimation approach associated with medical procedures to identify the effectiveness of X-ray Computed Axial Tomography (CT) scans as a diagnostic tool in preventing cancer-related deaths. In order to measure the effects of the CT scan on cancer-related deaths, I use data from both the National Health Interview Survey and the Vital Statistics of the United States. For all four regions, we observe an increase in CT scan use after 1979 or, as illustrated specifically in the figure, from 1975 to 1980. All four regions exhibit marked increases in lung cancer-related deaths, very little fluctuation in the number of colon, liver, and stomach cancer-related deaths, and leukemia related deaths remain constant over the observed period; however, the base levels differ from region to region. The key identifying assumption for this study is that no other medical innovations or cancer-reducing policies that were established in a similar time period followed the same pattern as the expansion in use of the CT scan. In order to estimate the effect of the CT scan on select cancer-related death rates, I employ a linear OLS model, with the CT scan as the independent, right-hand side variable and the cancer-related death rate as the dependent, left-hand side variable. In addition, I control for observable characteristics, including a time trend, region fixed effects, and a control for region by year effects. I find statistically significant but suggestive evidence that increased CT scan use can lead to the decrease of lung cancer-related deaths. In addition, I find suggestive evidence that any increase in CT scan use will have no effect on leukemia related deaths. As described above, this finding is expected and confirms my methodology, as CT scans are not typically used to diagnose leukemia. On the other hand, my findings on the effect of CT scan use on colon, liver, and stomach cancer-related deaths is ambiguous. While imprecise, my estimates suggest that the CT scan is indeed an effective diagnostic tool in detecting some types of cancer, leading to a decrease in the number of deaths related to the given cancer

Augmentation Therapy for Severe Alpha-1 Antitrypsin Deficiency Improves Survival and Is Decoupled from Spirometric Decline—A Multinational Registry Analysis

Rationale: Intravenous plasma-purified alpha-1 antitrypsin (IV-AAT) has been used as therapy for alpha-1 antitrypsin deficiency (AATD) since 1987. Previous trials (RAPID and RAPID-OLE) demonstrated efficacy in preserving computed tomography of lung density but no effect on FEV1. This observational study evaluated 615 people with severe AATD from three countries with socialized health care (Ireland, Switzerland, and Austria), where access to standard medical care was equal but access to IV-AAT was not. Objectives: To assess the real-world longitudinal effects of IV-AAT. Methods: Pulmonary function and mortality data were utilized to perform longitudinal analyses on registry participants with severe AATD. Measurements and Main Results: IV-AAT confers a survival benefit in severe AATD (P < 0.001). We uncovered two distinct AATD phenotypes based on an initial respiratory diagnosis: lung index and non-lung index. Lung indexes demonstrated a more rapid FEV1 decline between the ages of 20 and 50 and subsequently entered a plateau phase of minimal decline from 50 onward. Consequentially, IV-AAT had no effect on FEV1 decline, except in patients with a Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 lung index. Conclusions: This real-world study demonstrates a survival advantage from IV-AAT. This improved survival is largely decoupled from FEV1 decline. The observation that patients with severe AATD fall into two major phenotypes has implications for clinical trial design where FEV1 is a primary endpoint. Recruits into trials are typically older lung indexes entering the plateau phase and, therefore, unlikely to show spirometric benefits. IV-AAT attenuates spirometric decline in lung indexes in GOLD stage 2, a spirometric group commonly outside current IV-AAT commencement recommendations

Reply to Chan: Identification of alpha-1 antitrypsin-deficient subjects with normal spirometry who may benefit from alpha-1 antitrypsin replacement

We thank Dr. Chan for his insightful comments and expert analysis of our paper, which raise a number of important questions.In our cohort of 52 individuals with a bronchodilator response (BDR), 40 individuals had follow-up spirometry. There was a mean (6SD) of 7.9 (69.1) subsequent pulmonary function tests performed per person and a mean of 3.4 (62.7) further BDRs performed per person. We repeated the linear mixed model that was used to estimate yearly FEV1 change and included the BDR at baseline as a covariate. BDR was not significantly associated with yearly FEV1 change (22.7 ml/yr; 95% confidence interval:225.2, 19.8;P= 0.82)  </p

Blood gene expression risk profiles and interstitial lung abnormalities: COPDGene and ECLIPSE cohort studies

Background Interstitial lung abnormalities (ILA) are radiologic findings that may progress to idiopathic pulmonary fibrosis (IPF). Blood gene expression profiles can predict IPF mortality, but whether these same genes associate with ILA and ILA outcomes is unknown. This study evaluated if a previously described blood gene expression profile associated with IPF mortality is associated with ILA and all-cause mortality. Methods In COPDGene and ECLIPSE study participants with visual scoring of ILA and gene expression data, we evaluated the association of a previously described IPF mortality score with ILA and mortality. We also trained a new ILA score, derived using genes from the IPF score, in a subset of COPDGene. We tested the association with ILA and mortality on the remainder of COPDGene and ECLIPSE. Results In 1469 COPDGene (training n = 734; testing n = 735) and 571 ECLIPSE participants, the IPF score was not associated with ILA or mortality. However, an ILA score derived from IPF score genes was associated with ILA (meta-analysis of test datasets OR 1.4 [95% CI: 1.2–1.6]) and mortality (HR 1.25 [95% CI: 1.12–1.41]). Six of the 11 genes in the ILA score had discordant directions of effects compared to the IPF score. The ILA score partially mediated the effects of age on mortality (11.8% proportion mediated). Conclusions An ILA gene expression score, derived from IPF mortality-associated genes, identified genes with concordant and discordant effects on IPF mortality and ILA. These results suggest shared, and unique biologic processes, amongst those with ILA, IPF, aging, and death.Medicine, Faculty ofNon UBCMedicine, Department ofRespiratory Medicine, Division ofReviewedFacultyResearche

Lung tissue shows divergent gene expression between chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis

Abstract Background Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are characterized by shared exposures and clinical features, but distinct genetic and pathologic features exist. These features have not been well-studied using large-scale gene expression datasets. We hypothesized that there are divergent gene, pathway, and cellular signatures between COPD and IPF. Methods We performed RNA-sequencing on lung tissues from individuals with IPF (n = 231) and COPD (n = 377) compared to control (n = 267), defined as individuals with normal spirometry. We grouped the overlapping differential expression gene sets based on direction of expression and examined the resultant sets for genes of interest, pathway enrichment, and cell composition. Using gene set variation analysis, we validated the overlap group gene sets in independent COPD and IPF data sets. Results We found 5010 genes differentially expressed between COPD and control, and 11,454 genes differentially expressed between IPF and control (1% false discovery rate). 3846 genes overlapped between IPF and COPD. Several pathways were enriched for genes upregulated in COPD and downregulated in IPF; however, no pathways were enriched for genes downregulated in COPD and upregulated in IPF. There were many myeloid cell genes with increased expression in COPD but decreased in IPF. We found that the genes upregulated in COPD but downregulated in IPF were associated with lower lung function in the independent validation cohorts. Conclusions We identified a divergent gene expression signature between COPD and IPF, with increased expression in COPD and decreased in IPF. This signature is associated with worse lung function in both COPD and IPF.http://deepblue.lib.umich.edu/bitstream/2027.42/173729/1/12931_2022_Article_2013.pd

Augmentation therapy for severe alpha-1 antitrypsin deficiency improves survival and is decoupled from spirometric decline - a multinational registry analysis.

Rationale: Intravenous plasma-purified alpha-1 antitrypsin (IV-AAT) has been used as therapy for alpha-1 antitrypsin deficiency (AATD) since 1987. Previous trials (RAPID and RAPID-OLE) demonstrated efficacy in preserving computed tomography of lung density but no effect on FEV1. This observational study evaluated 615 people with severe AATD from three countries with socialized health care (Ireland, Switzerland, and Austria), where access to standard medical care was equal but access to IV-AAT was not. Objectives: To assess the real-world longitudinal effects of IV-AAT. Methods: Pulmonary function and mortality data were utilized to perform longitudinal analyses on registry participants with severe AATD. Measurements and Main Results: IV-AAT confers a survival benefit in severe AATD (P Conclusions: This real-world study demonstrates a survival advantage from IV-AAT. This improved survival is largely decoupled from FEV1 decline. The observation that patients with severe AATD fall into two major phenotypes has implications for clinical trial design where FEV1 is a primary endpoint. Recruits into trials are typically older lung indexes entering the plateau phase and, therefore, unlikely to show spirometric benefits. IV-AAT attenuates spirometric decline in lung indexes in GOLD stage 2, a spirometric group commonly outside current IV-AAT commencement recommendations. </p

Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease.

Rationale: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. Objectives: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. Methods: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. Measurements and Main Results: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV1% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV1 was 3.9% lower (95% confidence interval [CI], -6.55% to -1.26%) and emphysema (the percentage of lung attenuation areas &lt;-950 HU) was 4.14% greater (95% CI, 1.44% to 6.84%) in MZ subjects. We found one gene, PGF (placental growth factor), to be differentially expressed in lung tissue from one study between MZ subjects and MM subjects. Conclusions: Carriers of the AAT Z allele (those who were MZ heterozygous) with COPD had lower lung function and more emphysema than MM subjects with COPD. Taken with the subtle differences in gene expression between the two groups, our findings suggest that MZ subjects represent an endotype of COPD