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To estimate the cost-effectiveness of noncardia gastric adenocarcinoma (NCGA) screening strategies based on new biomarker and endoscopic technologies.
Using an intestinal-type NCGA microsimulation model, we evaluated the following one-time screening strategies for US men: 1) serum pepsinogen to detect gastric atrophy (with endoscopic follow-up of positive screen results), 2) endoscopic screening to detect dysplasia and asymptomatic cancer (with endoscopic mucosal resection (EMR) treatment for detected lesions), and 3) Helicobacter pylori screening and treatment. Screening performance, treatment effectiveness, cancer and cost data were based on published literature and databases. Subgroups included current, former and never smokers. Outcomes included lifetime cancer risk and incremental cost-effectiveness ratios (ICERs), expressed as cost per quality-adjusted-life-year (QALY) gained.
Screening the general population at age 50 reduced the lifetime intestinal-type NCGA risk (0.24%) by 26.4% with serum pepsinogen screening, 21.2% with endoscopy and EMR, and 0.2% with H. pylori screening/treatment. Targeting current smokers reduced the lifetime risk (0.35%) by 30.8%, 25.5%, and 0.1%, respectively. For all subgroups, serum pepsinogen screening was more effective and more cost-effective than all other strategies, although its ICER varied from $76,000/QALY (current smokers) to $105,400/QALY (general population). Results were sensitive to H. pylori prevalence, screen age, and serum pepsinogen test sensitivity. Probabilistic sensitivity analysis found that at a $100,000/QALY willingness-to-pay threshold, the probability that serum pepsinogen screening was preferred was 0.97 for current smokers.
Although not warranted for the general population, targeting high-risk smokers for serum pepsinogen screening may be a cost-effective strategy to reduce intestinal-type NCGA mortality.
Gastric cancer is the third leading-cause of cancer-related mortality worldwide. Despite declines in recent decades, 22,000 individuals in the US are diagnosed each year, less than 30% of these individuals survive more than 5 years, and noncardia gastric adenocarcinoma (NCGA) remains the predominant phenotype. Screening efforts have primarily focused on detecting gastric cancer at earlier stages with more favorable prognosis in countries with high gastric cancer incidence.[3–5] Recent advances in biomarker and endoscopic technologies to detect and treat precancerous and cancerous lesions may offer alternative strategies for NCGA control.
In contrast to other histological subtypes, epidemiological studies have well-established the precancerous development process for intestinal-type NCGA and the role of Helicobacter pylori (H. pylori) infection and smoking. Normal gastric mucosa progresses to invasive cancer through a series of precancerous lesions. By initiating the precancerous process, H. pylori increases disease risk by as much as 6-fold and is estimated to be responsible for approximately 75% of noncardia cancers. Elevating the risk of progression of existing precancerous lesions to more advanced lesions, smoking increases NCGA risk by approximately 2-fold.[9–12] Other risk factors include diet and genetic factors.
As serum levels for pepsinogen I and II reflect the functional and morphologic status of the gastric mucosa, biomarker-based serum pepsinogen screening may identify individuals at higher risk for gastric cancer.[13, 14] A stepwise screening strategy, starting with a serum pepsinogen test followed by endoscopic biopsy sampling for positive test results, can help to distinguish low-risk individuals from high-risk individuals who are more likely to benefit from subsequent surveillance. The generalized use of the test has been limited despite clinical studies on its potential usefulness.[16–18] Gastric cancer control efforts may be further enhanced by advances in endoscopic technology, including endoscopic mucosal resection (EMR), to detect and remove dysplastic/precancerous or cancerous lesions without surgery, which may potentially reduce intestinal-type NCGA risk by 90% among individuals with dysplasia. Findings from a randomized clinical trial suggest that H. pylori treatment may only reduce cancer incidence among individuals without existing precancerous lesions (defined as atrophy, intestinal metaplasia or dysplasia) at time of treatment. The estimated benefits associated with population-based H. pylori screening in the US are therefore likely much lower than previously estimated.
Screening for precursors of NCGA may be an effective strategy for preventing invasive cancer, yet long-term benefits associated with new biomarker and endoscopic technologies are uncertain. Model-based analyses provide a framework for estimating potential benefits and risks associated with screening, extrapolating existing randomized clinical trial results, and guiding the design of future clinical studies by highlighting areas where better data are needed. We therefore employed a decision-analytic simulation-based modeling approach to synthesize the best available epidemiologic, clinical and economic data to assess the potential clinical benefits and cost-effectiveness of alternative screening strategies to reduce intestinal-type NCGA incidence and mortality.
Using a mathematical simulation model of intestinal-type NCGA natural history among US men, we estimated the benefits, costs and cost-effectiveness associated with the following screening-based cancer control strategies: 1) serum pepsinogen screening, 2) endoscopic-based screening, and 3) H. pylori screening. Described in detail elsewhere, the model is based on natural history parameters derived via empirical model calibration to age-specific precancerous lesions prevalence and Surveillance, Epidemiology, and End Results (SEER) cancer incidence to ensure model outputs are consistent with US epidemiologic data (see Supplemental Materials). For each strategy, we estimated screening test performance, complication rates and treatment effectiveness from the published literature. Costs were based on US Medicare reimbursement rates and SEER-Medicare linked database estimates. Model outcomes included lifetime risk of intestinal-type NCGA, life expectancy, quality-adjusted life expectancy, lifetime costs, and number of cause-specific deaths. To evaluate the relative performance of each strategy, we calculated incremental cost-effectiveness ratios (ICERs), defined as the additional cost of a specific strategy divided by its additional clinical benefit, compared with the next least expensive strategy, and expressed as cost per quality-adjusted life year (QALY) gained. We adopted a societal perspective and discounted all costs and clinical consequences at 3% annually. All costs are reported in 2012 dollars. To identify subgroups for targeted screening, we conducted subgroup analyses based on smoking status at time of screening: never, current and former smokers.
As depicted in Figure 1, the model simulates the development of intestinal-type NCGA through a series of precancerous lesions, which may progress to dysplasia and eventually invasive cancer. At the start of the simulation, 20-year old individuals enter the model and are assigned a risk factor profile for H. pylori and smoking status. Based on epidemiologic data , we assumed that precancerous lesions were already present in a subset of 20-years olds, with a greater proportion among those infected with H. pylori. Based on monthly probabilities derived via model calibration (Supplemental Table 1), individuals transition among the health states and are followed throughout their lifetime.
We based H. pylori prevalence and smoking profiles for a 1961–65 birth cohort (corresponding to 50-year old men between calendar years 2011 and 2015) on National Health and Nutrition Examination Survey and National Health Interview Survey data.[30–33] Specifically, we estimated that 31% of the birth cohort was infected with H. pylori and assumed the following: H. pylori infection is established by age 20, causes gastritis and increases the risk of atrophy, and remains unchanged throughout one’s lifetime.[36, 37] We assumed that an individual’s smoking status may change over their lifetime and estimated that 23% of individuals at age 50 were current smokers (a decline from a peak prevalence of nearly 40% at age 30).[32, 33] We assumed that smoking increases the risk of progression to intestinal metaplasia and dysplasia,[11, 12] and that the magnitude rises with smoking intensity (defined as <10, 10–19, ≥20 cigarettes per day). Upon quitting, individuals face former smoker-specific disease progression rates.
For individuals who developed intestinal-type NCGA, stage-specific mortality rates were based on SEER estimates. Competing cause mortality was based on US birth cohort-specific life tables [39, 40] and adjusted for smoking intensity using published relative risk estimates.
To assess the face validity and projective validity of the model, we compared model outputs to data not used for model parameterization or calibration. Model estimates of the relative risk of intestinal-type NGCA associated with H. pylori infection (3.6) and smoking (1.6) were consistent with published estimates (95% CI, 2.7 to 7.2 and 1.5 to 1.8, respectively).[7, 42] The proportion of all cancers occurring in H. pylori-positive individuals (60%) fell within the calculated population attributable fraction range for the cohort (38–65%). Modeled estimates for prevalence of precancerous lesions and 10-year cancer risk for individuals with dysplasia also approximated published estimates (see Supplemental Materials for full details).[15, 44]
Compared to no screening, we evaluated the following one-time screening strategies at age 50: 1) serum pepsinogen screening, 2) endoscopic screening, and 3) H. pylori screening.
For serum pepsinogen screening, all individuals with a positive assay test result for atrophy (defined as serum pepsinogen I levels ≤70 μg/l together with pepsinogen I/II ratio ≤3.0) were followed up by endoscopy with 7 to 9 random biopsies of the gastric mucosa. All individuals with a positive endoscopy for dysplasia or asymptomatic localized cancer (detected either macroscopically via endoscopy or histologically based on gastric biopsies) underwent EMR treatment to remove lesions; those with a negative endoscopic result returned for a follow-up endoscopy in 10 years. Individuals with an initial negative serum pepsinogen test result received no further treatment or follow-up. As part of standard practice, we assumed that individuals would also be tested for H. pylori and all individuals who tested positive for the infection would receive standard triple therapy (20 mg omeprazole, 1 g amoxicillin, 500 mg clarithromycin, twice daily).
For endoscopic screening, individuals with a positive screen result (based on biopsy sampling) for dysplasia or asymptomatic localized cancer received EMR treatment; those with a negative biopsy result received no additional follow-up care.
For both the serum pepsinogen and endoscopic screening strategies, we assumed: 1) only asymptomatic localized cancers detected via endoscopy benefited from screening (i.e., negligible survival benefit for detected regional and distant cancers), 2) all dysplastic lesions (detected macroscopically and/or histologically) and submucosal localized cancers (American Joint Committee on Cancer (sixth edition) stage IA) were eligible for EMR treatment; all other localized tumors were surgically treated, and 3) all individuals treated with EMR returned for post-treatment surveillance via endoscopy for recurrence in 10 years.
For H. pylori screening, all individuals with a positive test result received standard 10-day triple therapy (described above).
We evaluated the screening strategies for the overall cohort and smoking subgroups based on smoking status at time of screening (never, current, or former smokers).
For each strategy, we estimated screening test characteristics, complication rates and treatment effectiveness based on data from published clinical studies (Table 1).[18, 20, 24, 46–64] For the serum pepsinogen test, sensitivity and specificity were based on the ability to detect atrophy (with and without more advanced precancerous lesions), with dysplasia and asymptomatic cancerous lesions identified via subsequent endoscopy and random biopsy sampling. All endoscopic procedures, including EMR, were associated with a risk of severe bleeding or perforation requiring surgery.[51, 53] After EMR treatment, individuals faced a risk of recurrence from incomplete resections and, for cancerous lesions, metachronous lesions (which we assumed stemmed from undetected dysplasia).[52, 53, 57] For H. pylori treatment, we assumed standard triple therapy reduced the risk of progressing from gastritis to atrophy to H. pylori-negative rates  with 80% efficacy.
To reflect quality of life, we used sex- and age-specific population-based weights and disease-specific weights. We also assumed that endoscopic procedures and surgical procedures were associated with a 50% utility reduction for 1 day and 2 weeks, respectively.
For each strategy, we estimated direct medical costs based on 2012 Medicare reimbursement rates (Table 1). Costs included physician costs, pathologist costs (for biopsy evaluation), and facilities and/or hospitalization costs associated with endoscopic or surgical procedures. We used phase-specific treatment costs for gastric cancer. Drug costs were based on median Wholesale Acquisition Cost among leading manufacturers. Indirect patient costs were based on time lost from work, including phase-specific time costs for cancer treatment.
We conducted sensitivity analyses on key variables to explore how results varied across plausible ranges established from published studies. To reflect the impact of uncertainty surrounding disease natural history on results, we conducted analyses with a subset of 50 good-fitting natural history parameters identified via model calibration (Supplemental Table 1) and report the range across all parameter sets for all model outcomes. In addition, we conducted a probabilistic sensitivity analysis using 1000 second-order Monte Carlo simulations, in which key model parameters, including natural history parameter sets, were simultaneously varied.
For a hypothetical cohort of 20-year old men, the modeled lifetime risk of intestinal-type NCGA was 0.24% (Table 2). The relative reduction in intestinal-type NCGA lifetime risk was 26.4% with serum pepsinogen screening (range, 22.3% to 34.5%), 21.2% with endoscopic-based screening (range, 17.0% to 30.1%), and 0.2% with H. pylori screening at age 50 (range, 0.0% to 1.2%) (Figure 2). The gain in life expectancy was greatest for serum pepsinogen screening (2.7 days; range, 2.4 to 4.2 days) compared to endoscopy with EMR (2.4 days; range, 2.1 to 3.9 days) and H. pylori screening and treatment (0.01 days; range, 0.00–0.07 days) (Table 2). Among individuals with a positive serum pepsinogen result, the life expectancy gain was 1.2 months, and among those with a positive follow-up endoscopy for dysplasia or asymptomatic cancer, 1.2 years.
Among a cohort of 10 million 20-year old men, the model estimated that serum pepsinogen screening would prevent 5,126 (range, 4,687 to 8,316), or 27.0% (range, 23.2 to 34.7%), of the projected 19,014 intestinal-type NCGA deaths (range, 16,576 to 26,255) (Table 3). The estimated number needed to screen to prevent 1 intestinal-type NCGA death was 1,813 (range, 1,117 to 1,982). The estimated number of endoscopies needed was 295 (range, 216 to 378). Table 3 depicts additional results.
The relative reduction in lifetime intestinal-type NCGA risk was greatest among current smokers (Figure 2). Targeting current smokers at age 50 reduced the lifetime risk (0.35%) by 30.8% with serum pepsinogen screening (range, 27.0 to 38.5%), 25.5% with endoscopy and EMR (range, 21.5 to 34.8%), and 0.1% with H. pylori screening and treatment (range, 0.0 to 1.0%). The number of days gained for each strategy was higher for current smokers (Table 2). Current smokers with a positive serum pepsinogen screen test result also had a greater gain in life expectancy compared to never or former smokers (1.4 months versus 1.1 to 1.2 months, respectively).
Among the approximately 2.10 million individuals who were current smokers at age 50, serum pepsinogen screening would prevent 1,810 (range, 1,602 to 2,476), or 31.4% (range, 27.8 to 38.5%), of the projected 5,758 intestinal-type NCGA deaths (range, 4,836 to 7,344). The percent reduction in number of intestinal-type NCGA deaths prevented was similar for never and former smokers, reflecting the reduced risk of progressing to invasive cancer associated with smoking cessation. The model estimated that approximately 1,157 current smokers (range, 846 to 1,307) would need to be screened to prevent 1 intestinal-type NCGA death. The corresponding number of endoscopies needed was 218 (range, 174 to 297).
For the overall cohort, compared to no screening, serum pepsinogen screening had an ICER of $105,400 per QALY gained (Table 2). Serum pepsinogen screening dominated the other screening strategies, as it was either less costly and more effective (endoscopic screening) or more effective and more cost-effective (H. pylori screening).
ICERs were more attractive for current smokers ($76,000 per QALY gained) and former smokers ($94,500 per QALY gained), and less attractive for never smokers ($137,800) (Table 2).
For the overall cohort, results for the serum pepsinogen screening strategy were most sensitive to H. pylori prevalence, screen age, serum pepsinogen test sensitivity, and costs associated with endoscopic follow-up (Figure 3). Results were moderately sensitive to serum pepsinogen screening costs and test specificity. Results remained largely unchanged over the plausible range for endoscopic sensitivity for dysplastic and cancerous lesions, EMR treatment effectiveness and complication risks, and proportion of EMR-eligible localized cancers.
We conducted scenario analyses for the overall cohort to explore alternative model assumptions. In our base case, we used estimates for surgical mortality risks among asymptomatic individuals in good health; if age-specific risks for symptomatic patients undergoing surgery were used instead, the ICER for serum pepsinogen screening increased to $128,400 per QALY gained. If 5% of endoscopic procedures required hospitalization (related to complications or incidental findings that required follow-up care), the ICER increased to $120,600 per QALY gained. Similarly, if follow-up endoscopic surveillance was based on only macroscopic findings (i.e. no gastric biopsies were taken), both the reduction in cancer risk (21% vs. 26% in base case) and attractiveness of serum pepsinogen screening ($130,000 vs. $105,400 per QALY gained in base case) declined. If we assumed that after EMR treatment, individuals still harbored intestinal metaplastic lesions (which could progress to invasive cancer), serum pepsinogen screening was also less attractive (ICER = $116,000 per QALY gained). For all these scenarios, ICERs remained less than $93,000 per QALY gained for current smokers.
To assess the impact of H. pylori prevalence, we determined the threshold value needed for serum pepsinogen screening to be considered cost-effective. At a $100,000 per QALY gained threshold, 40% of the cohort would need to be H. pylori infected (base case = 31%) (Supplemental Figure 1). For current smokers, screening was considered cost-effective at nearly all prevalence levels. In contrast, for never smokers, the ICER exceeded the $100,000 per QALY threshold at all prevalence levels.
Two-way threshold analysis on serum pepsinogen test characteristics similarly found that the range of possible values for which serum pepsinogen would be preferred was much broader for current smokers compared to the other subgroups (Figure 4). For current smokers, if sensitivity was greater than 60%, serum pepsinogen screening was the preferred strategy as long as test specificity was greater than 94%. For never smokers, serum pepsinogen screening was preferred only if the test had nearly perfect performance.
For the overall cohort, probabilistic sensitivity analysis suggested that at a cost-effectiveness threshold of $100,000 per QALY gained, the probability that serum pepsinogen screening was the preferred strategy was 0.47 (Table 2 and Figure 5). The probability was 0.97 for current smokers and 0.85 for former smokers.
Although intestinal-type NCGA incidence has declined over the past century, disease risk is largely determined by H. pylori infection acquired in childhood and the number of cases is projected to remain considerable for decades. To provide insight into this important public health and clinical problem and explore options for secondary prevention, we employed a model-based approach to estimate the comparative benefits and cost-effectiveness associated with several screening strategies. Our findings suggest that although a one-time serum pepsinogen screening (with endoscopic follow-up and EMR treatment if needed) at age 50 can prevent as many as 1 in 4 intestinal-type NCGAs among US men, general population-wide screening is unlikely to be a high-value strategy for improving cancer outcomes. However, screening targeted to current smokers who are at elevated risk for premature death may be an effective and cost-effective strategy to reduce NCGA mortality.
Our study is the first simulation model-based analysis to evaluate the clinical benefits and economic consequences of serum pepsinogen screening in the US. Previous model-based studies have focused on high-risk populations in Asia, or estimated the short-term economics of serum pepsinogen testing as a follow-up strategy for individuals diagnosed with atrophy or intestinal metaplasia. Neither study estimated the clinical benefits associated with serum pepsinogen screening in terms of a reduction in cancer risk, or provided estimates for smoking subgroups which can be used as the basis for targeting screening efforts. Consistent with published studies (Supplemental Table 2),[46, 70–75] our model-based estimates of serum pepsinogen screening performance underscore the potential usefulness of the test to detect and distinguish individuals at higher risk for developing cancer from those at lower risk.[76, 77] Furthermore, our estimates of the number needed to screen (NNS) to prevent one intestinal-type NCGA death (1157 US male smokers) suggest that serum pepsinogen screening may have similar benefits to mammography screening among 50–59 year old women (NNS = 1339 to prevent 1 breast cancer death), albeit smaller benefits than low-dose computed tomography (NNS = 320 to prevent 1 lung cancer death)[78–80] or flexible sigmoidoscopy (NNS = 871 to prevent 1 colorectal cancer death). However, our findings should be cautiously considered given the notable uncertainty surrounding serum pepsinogen test performance, limited evidence in low-risk populations, and concerns surrounding the translation of clinical findings in high-risk populations to low-risk populations. As better data become available, our model can be refined and recalibrated to reflect these data, and as such, can serve as an iterative tool to provide updated assessments of the likely health and economic outcomes associated with secondary gastric cancer control efforts.
The serum pepsinogen test has also been proposed as the basis for screening for intestinal-type NCGA itself (in contrast to identifying individuals with atrophy who are at elevated risk for NCGA as in our analysis). Our model found, however, that such a strategy, with a 77% sensitivity and 73% specificity for dysplastic and cancerous lesions, would not be cost-effective in the US, even among current smokers (Supplemental Table 3). While such a test would lead to similar reductions in cancer risk as regular screening, nearly 30% as opposed to 2% would have a false positive test and receive treatment unnecessarily leading to higher costs and possible harm without a commensurate gain in benefits. Similar to our threshold analyses on screening test characteristics (Figure 4), these results highlight the importance of accurately detecting the absence of atrophy or precancerous lesions for any serum pepsinogen test-based screening strategy.
Previous studies have concluded H. pylori screening is cost-effective in the US.[21, 83] Our findings provide updated estimates of the cost-effectiveness of population-based H. pylori screening based on randomized trial evidence that only individuals without existing precancerous lesions benefit from H. pylori treatment. Under this assumption, we found that targeting screening to 20-year old individuals (who are less likely to have precancerous lesions) may be more effective in reducing cancer risk (1.6% vs. 0.2%). However, even with the greater benefit, the strategy would remain unattractive compared to no screening (ICER = $2.7M per QALY) and dominated by serum pepsinogen screening. Recent results from another randomized trial in China suggest that all individuals, regardless of the presence of advanced lesions, may benefit from H. pylori treatment, potentially as a result of eradicating non-H. pylori bacteria that influence the later stages of gastric carcinogenesis . If we assumed that the risk of dysplasia was reduced by 50% among all treated individuals, H. pylori screening was indeed more attractive compared to no screening (21% reduction in cancer risk at an ICER of $85,000 per QALY). Yet, H. pylori screening was still dominated by serum pepsinogen screening as the reduction in cancer risk was also greater for serum pepsinogen screening (44%) and at a more favorable ICER ($70,700 per QALY). As such, despite the considerable uncertainty in H. pylori treatment effectiveness, our findings suggest that serum pepsinogen is likely to be a more effective and cost-effective NCGA screening strategy in the US.
Limitations to our study include using data from multiple sources with varying study designs. We conducted extensive probabilistic sensitivity analyses to account for the uncertainty in variables and assumptions, including disease natural history. We focused on only men, and made the simplifying assumption that the prevalence of H. pylori and smoking were independent because data regarding interactions are not available. We also only focused on one gastric cancer subtype. If we assumed that diffuse and other noncardia tumors (detectable for 24 months on average before becoming clinically symptomatic) were also detected via follow-up endoscopy for a positive serum pepsinogen screen, results were largely unchanged (ICER = $104,100 vs. $105,400 in the base case). This was consistent with our finding that the majority of serum pepsinogen screening benefit was derived from the detection and removal of dysplastic lesions before they progressed to invasive cancer. We found however, that serum pepsinogen screening was less attractive if treated individuals still harbored intestinal metaplastic lesions (common in settings where H. pylori-related atrophy is frequently multifocal) or if endoscopic sensitivity for dysplasia was considerably lower. However, as long as sensitivity was greater than 60% (base case = 81%), serum pepsinogen screening remained attractive for current smokers (ICER = $99,400).
Notably, we based estimates of serum pepsinogen test performance and EMR treatment effectiveness on clinical studies from Japan given the limited data in Western populations. EMR is relative new, availability of and expertise with EMR technology is limited; additional training (and resources) will be needed to realize the projected screening benefits. Not all biopsy-detected dysplasia may be macroscopically visible and therefore, eligible for EMR. We found however that even if the large majority of individuals with dysplasia (60–70%) would require annual or biannual endoscopic surveillance before undergoing EMR treatment, results were largely unchanged. We also did not include the impact of endoscopy-related incidental findings and their downstream effects in our analysis; further analysis of their long-term effects is needed. Proton-pump inhibitors, widely used in the general population, may reduce serum pepsinogen test sensitivity by altering intragastric acidity and biomarker levels. Sensitivity analyses found that even if sensitivity fell to 60% (base case = 71%), as long as test specificity was greater than 94%, the ICER remained attractive for current smokers.
Lastly, our model focused on NCGA screening in the US. Estimates of the clinical benefits and cost-effectiveness associated with screening strategies will vary in high-risk countries, such as Japan, where risk factor prevalence and influence on the multifactorial etiology of gastric carcinogenesis may differ. As the projective validity of our model was consistent with data on precancerous lesions prevalence and cancer risk from the Netherlands, our findings are likely generalizable to this setting and other low-risk European countries with similar H. pylori and smoking profiles.
Our model-based findings suggest that serum pepsinogen screening to reduce NCGA risk is not warranted for the general population. However, targeting high-risk smokers for screening may be an effective and cost-effective strategy to reduce intestinal-type NCGA mortality. Further, the marginal benefits associated with H. pylori screening, even among high risk subgroups, underscore the need for future clinical studies on alternative secondary gastric cancer control strategies, including serum pepsinogen screening, to improve cancer outcomes and overall survival.
Dr. Yeh was supported by the National Cancer Institute (NCI) grant K07CA143044. The funder had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
The authors declare no financial relationships with any organizations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work.
CONTRIBUTIONSJMY, CH, ZW, DS, SJG conceived and designed the study; analyzed and interpreted the data; drafted and critically revised the manuscript for important intellectual content; and approved the version to be published. All authors had full access to all the data and take responsibility for the integrity of the data and the accuracy of the data analysis. JMY is the guarantor.
No additional data available.