US Prevalence of Upper Gastrointestinal Symptoms: A Systematic Literature Review

Objectives:

To quantify the prevalence of dyspeptic and gastroesophageal symptoms and peptic ulcer disease (PUD) in the United States and to identify factors affecting their prevalence.

Study Design:

Systematic search of MEDLINE and Web of Science through November 2010.

Methods:

We identified studies of US patients and evaluated a general (not disease-specific) adult sample that reported the prevalence of 1 or more upper gastrointestinal (GI) outcomes of interest, including dyspeptic symptoms, gastroesophageal symptoms, dyspeptic and/or gastroesophageal symptoms, or PUD. Proportions of individuals in each study reporting each symptom were pooled to derive separate prevalence estimates. Qualitative synthesis of data depicting multivariate relationships between covariates and upper GI outcomes was undertaken.

Results:

A total of 36 citations representing 24 studies were included: 9 studies reporting dyspeptic symptoms (n = 14,181), 14 reporting gastroesophageal symptoms (n = 58,701), 5 reporting dyspeptic and/or gastroesophageal symptoms (n = 103,175), and 7 reporting PUD prevalence (n = 269,299). The pooled prevalences of dyspeptic, gastroesophageal, and dyspeptic and/or gastroesophageal symptoms were 16.3% (95% confidence interval [CI] 9.1%-25.1%), 24.2% (95% CI 18.2%-30.5%), and 35.2% (95% CI 14.9%-58.9%). The pooled prevalence for studies asking for shorter-term PUD recall was 3.3% (95% CI 2.2%-4.6%), with lifetime PUD prevalence estimated at 13.8% (95% CI 10.7%-17.0%). The influence of covariates evaluated as part of multivariate analyses was often inconsistent.

Conclusions:

It appears that upper GI symptoms and disorders are common in US inhabitants. We identified patient- and study-level factors that should be considered when assessing upper GI symptom prevalence and conducting future research.

(Am J Manag Care. 2011;17(11):e449-e458)

Systematic review and meta-analysis indicated that upper gastrointestinal symptoms and disorders are common to inhabitants of the United States.

• The pooled prevalences of dyspeptic, gastroesophageal, and dyspeptic and/or gastroesophageal symptoms were 16.3%, 24.2%, and 35.2%.

• In studies asking for shorter-term peptic ulcer disease (PUD) recall, the pooled prevalence was 3.3%; in studies asking for lifetime PUD recall, the prevalence was estimated at 13.8%.

• The influence of covariates on prevalence rates was often inconsistent.

The phrase “upper gastrointestinal (GI) symptoms” is commonly used to describe a wide range of complaints including dyspeptic and gastroesophageal symptoms, as well as peptic ulcer disease (PUD).^1-4 Such symptoms are a common cause of healthcare utilization, resulting in increased direct medical costs⁵ as well as costs to individuals and society due to lost work time and productivity (indirect costs), disrupted social life, and lowered quality of life (intangible costs).^5-7

Currently available studies suggest a high burden of disease due to upper GI symptoms.^8-43 However, due to a lack of standardization of upper GI symptom definitions and differences in methodology used between studies, available prevalence estimates have varied greatly.^1-4,8 Furthermore, data suggest that prevalence of upper GI symptoms can vary markedly between countries.⁴² The decision for managed care organizations to pay for medications depends on the prevalence of the condition in a population. When different studies report different values, it becomes difficult to estimate true population prevalence. Estimates provided by a systematic review and meta-analysis can be helpful in such situations. Despite this fact, no previous systematic review and meta-analysis focusing on US prevalence rates of upper GI symptoms have been undertaken. Finally, it has been proposed that associations between sociodemographic and other covariates can affect upper GI symptom prevalence^9,41; however, no prior attempt has been made to gather and synthesize such data.

In order to gain a better understanding of the prevalence of dyspeptic and gastroesophageal symptoms and PUD in the US population, and to more completely identify factors that affect their prevalence, we sought to conduct a comprehensive and systematic review of the literature on this topic.

METHODS

Literature Search

Appendix 1

A systematic literature search using the MEDLINE (1950 through November 2010) and Web of Science (1994 through November 2010) computerized databases was conducted. The search combined keywords and medical subject headings (MeSH) terms related to upper gastrointestinal, dyspeptic, and gastroesophageal symptoms and PUD, along with “prevalence.” The complete search strategy is available in , available at www.ajmc.com. Additionally, the references of each pertinent article identified were reviewed to locate other relevant published works.

To be included in this systematic review, studies had to (1) be conducted in the United States (as clear differences in GI symptom prevalence exist between countries); (2) be published in English; (3) evaluate a general (not disease-specific) adult sample selected without prior knowledge or suspicion of the presence or absence of GI symptoms or disorders; and (4) report the prevalence of at least 1 upper GI outcome of interest, including dyspeptic symptoms (eg, postprandial fullness, early satiety, localized epigastric pain, diffuse epigastric pain, belching, nocturnal/fasting pain, abdominal distention), gastroesophageal symptoms (eg, heartburn, regurgitation), dyspeptic and/or gastroesophageal symptoms (at least 1 related dyspeptic or gastroesophageal symptom), or PUD (eg, gastric or duodenal ulcer). Database studies evaluating only the rate of healthcare utilization for upper GI symptoms or disease were not included. Only fully published manuscripts were considered. In studies with more than 1 published report on the same study population, the most recent publication was selected for analysis to avoid double-counting participants, although previous publications were reviewed to supplement for missing data where applicable. When studies with nonidentical but overlapping populations were identified, the most recent publication was again selected for analysis.

Upon determination of inclusion, studies were further assessed to see whether they reported on the relationship between any sociodemographic or other covariates and upper GI symptom prevalence. To be included in this second portion of the systematic review, studies had to have (1) conducted multivariate analysis and (2) reported the results of at least 1 relationship between a covariate and upper GI symptom prevalence.

In all situations, 2 investigators (DMS and SMC) determined study eligibility independently, with disagreements resolved by discussion or by a third investigator (CIC).

Data Extraction

Two investigators (DMS and CIC) performed all data extraction. Data collected for each study included authors, year of publication, sample size, US geographic region in which the study was conducted, population studied including setting, use of random or convenience sample, age and sex, method of study data collection (eg, postal, Internet, selfcompleted or interviewer-administered questionnaire), response rate, duration or recall of symptoms, time frame of population sampling/study, criteria used to define upper GI symptoms (including whether a validated tool was used), upper GI symptom prevalence estimates, P value for the univariate relationship between a covariate and upper GI symptom, and effect size and P value for the multivariate relationship between a covariate and upper GI symptom.

Validity Assessment

The methodological quality of prevalence studies was assessed using the following attributes: (1) adequacy of sampling by assessing whether participants were sampled randomly or by convenience, (2) use of a validated questionnaire or tool to define upper GI disorders, and (3) sufficiently high response rate (>70%).⁴⁴ We did not attempt to give a summary validity rating to each individual study in this systematic review, but rather used each criterion in sensitivity analysis as described below.

Data Synthesis

Numerators (n = number of patients reporting the symptom) and denominators (N = total number of patients evaluated) were extracted from each study in order to compute symptom prevalence with accompanying 95% confidence intervals (CIs) using the Wilson score method without continuity correction.⁴⁵ The proportions of individuals in each study reporting symptoms were combined using a random-effects model to derive separate pooled prevalence rates of dyspeptic, gastroesophageal, or dyspeptic and/or gastroesophageal symptoms for all studies.⁴⁶ Due to the wide variance identified in requested disease recall periods for PUD (upon endoscopy, the prior 12 months, or lifetime prevalence), an analysis pooling all studies was not conducted.

Between-study heterogeneity was assessed using the I2 statistic with a threshold of 50% used to define a statistically significant degree of heterogeneity. To assess for the potential for publication bias, we reviewed Egger’s weighted regression statistic P values (with P <.05 suggesting a higher likelihood of publication bias) and constructed funnel plots in which the standard error of each study was plotted against its prevalence (with an asymmetrical funnel plot suggesting publication bias; funnel plots available from authors upon request).

We conducted various subgroup and sensitivity analyses to examine the effect on dyspeptic, gastroesophageal, and dyspeptic and/or gastroesophageal symptom prevalence of various study characteristics and validity assessment criteria such as sampling (random or convenience); required duration or symptom recall (for dyspepsia, upper GI symptoms, and gastroesophageal symptoms, shorter recall included studies with <3-month disease recall; for PUD, shorter recall included studies with <12-month disease recall); US geographic region (national or regional sample); questionnaire/tool to ask about symptoms (validated or not); response rate (>70% or <70%); and year of publication (2006 to present or prior to 2006). For PUD, studies with shorter disease recall durations were pooled separately from studies with longer disease recall durations, and these analyses served as this outcome’s base-case results. No other PUD analyses were conducted due to the limited number of data points. The Cochran Q statistic was used to determine whether a statistically significant difference existed between subgroups. We considered P <.05 statistically significant for all analyses. All analysis was conducted using Stats- Direct version 2.7.2 (StatsDirect Ltd, Cheshire, England).

Qualitative synthesis of data depicting the relationship between various covariates and upper GI symptoms is reported using descriptive statistics.

RESULTS

Study Identification and Characteristics

Figure

Our literature search revealed 3096 nonduplicate citations. Upon title and abstract review, 3328 citations were excluded, leaving 578 citations for full-text review. Upon full-text review, 542 were excluded (). Of note, 14 studies conducted in the Olmsted County, Minnesota, population were excluded from this analysis as they drew random samples out of the same study population and therefore were likely to have overlapping patient populations. A total of 36 citations, representing 24 unique studies, met our inclusion criteria.^9-43 These included 9 studies reporting dyspeptic symptoms, 14 reporting gastroesophageal symptoms, 5 reporting dyspeptic and/or gastroesophageal symptoms, and 7 reporting PUD prevalence. These studies were all observational in nature and were published between 1991 and 2010. Of the 24 studies, 11 (45.8%) reported results of multivariate analysis with an upper GI symptom as the dependent variable (Appendixes 2-15, available at www. ajmc.com).

Table 1

Key characteristics of included studies can be found in. Study sample sizes ranged from 248 to 226,953 patients. The total sample size for dyspeptic, gastroesophageal, dyspeptic and/or gastroesophageal symptoms and PUD studies was 14,181, 11,790, 58,701, and 284,922, respectively. Of the 24 unique studies, 9 (37.5%) used a randomly drawn sample, while the remaining 15 used convenience samples. Eleven studies (45.8%) sampled a national population, while the remaining studies drew participants from a regional area (city, state, or county). Eleven studies (45.8%) used validated questionnaires to elicit prevalence data on upper GI symptoms, with response rates from those reporting ranging between 17% and 92% (median of 70%).

Dyspeptic Symptoms

Appendix 16

Nine studies (n = 14,181) reported prevalence data (symptom recall ranging from 1 to 12 months) on dyspeptic symptoms (, available at www.ajmc.com).^{10,15,16,31,32,34,36,37,41-43} The mean age range for these studies was 42 to 62 years, and females made up 27% to 100% of the studies’ populations. The prevalence of dyspeptic symptoms varied between 2.9% and 34.4%, with a pooled prevalence of 16.3% (95% CI 9.1%- 25.1%) (Appendix 17, available at www.ajmc.com). Significant heterogeneity between studies was observed (I² = 99%). Review of the funnel plot (not shown, available upon request from authors) and Egger’s weighted regression statistic P values suggested the possibility of publication bias in the l symptom analysis (P <.05).

Upon subgroup analysis, it appeared that the prevalence of dyspeptic symptoms was greater in studies with longer symptom recall periods (22.8% vs 5.8% for shorter periods, P<.001), when participants were drawn from a regional sample (23.2% vs 5.8% for national sample, P <.001), and when validated questionnaires were used (20.7% vs 4.7% for nonvalidated questionnaires, P <.05) (Table 2).

Four studies reported results of multivariate analysis with dyspeptic symptom prevalence as the dependent variable (Appendix 18, available atwww.ajmc.com).15,16,31,32,36 A single study suggested increasing age was an independent negative predictor of dyspeptic symptoms.¹⁵ Various psychiatric disorders (including anxiety, depression, and posttraumatic stress disorder) were consistently found to be associated with an increased prevalence of dyspeptic symptoms.³⁶ Use of prescription acid-suppressing medication,¹⁵ tobacco use,¹⁵ higher household income,^31,32 larger family size (5 persons),^31,32 and irregular or no church attendance^31,32 were also found to be positive predictors, although they were only evaluated by 1 study each. Data on sex and race were inconsistent: 1 of 2 studies (50%) indicated that females had a higher prevalence of dyspeptic symptoms,^31,32 and among studies reporting data on race, Caucasians had a higher prevalence in 1 study,^31,32 a second study reported no difference,¹⁵ and a third study reported lower prevalence in Caucasians.¹⁶ Alcohol use and education level were not shown to be associated with an increased or decreased prevalence of dyspeptic symptoms.^15,31,32

Gastroesophageal Symptoms

Appendix 19

Fourteen studies (n = 58,701) reported prevalence data (symptom recall ranging from 3 to 12 months) on gastroesophageal symptoms (, available at www.ajmc.com).^{9-11,14-16,21,27,33,35,37,40,41,43} The mean age range for these studies was 42 to 66 years, and females made up 14% to 100% of the studies’ populations. The prevalence of gastroesophageal symptoms varied between 10.0% and 58.3%, with a pooled prevalence of 24.2% (95% CI 18.3%-30.5%) (Appendix 20, available at www.ajmc.com). Significant heterogeneity between studies was observed (I² >99%). Review of the funnel plot and Egger’s weighted regression statistic P values suggested the possibility of publication bias in the gastroesophageal symptom analysis (P <.05).

Upon subgroup analysis, it appeared that the prevalence of gastroesophageal symptoms was greater in studies published during or after 2006 (31.4% vs 19.1% for studies published prior to 2006, P <.05).

Four studies reported results of multivariate analysis with gastroesophageal symptom prevalence as the dependent variable (Appendix 21, available at www.ajmc.com).^15,16,27,37 Of 2 studies, 1 (50%) suggested increasing age was an independent negative predictor of gastroesophageal symptoms.¹⁵ We also found conflicting data regarding the association between race and gastroesophageal symptom prevalence, with 1 of 2 studies (50%) suggesting an increased prevalence in Caucasians. ^15,37 Larger body mass index and increases in body mass index were consistently found to be associated with higher gastroesophageal symptom prevalence in numerous studies. ^27,37 Current nonsteroidal anti-inflammatory use,¹⁵ use of prescription acid-suppressing medication,¹⁵ and living in the Western United States¹⁶ each were found to be associated with increased gastroesophageal symptom prevalence (1 study each), while female sex,³⁷ alcohol or tobacco use,^15,37 family history of gastroesophageal reflux disease, and increasing fat (total and saturated) intake³⁷ were not (1 study each).

Dyspeptic and/or Gastroesophageal Symptoms

Appendix 22

Five studies (n = 103,175) reported prevalence data (symptom recall ranging from 1 to 12 months) on dyspeptic and/or gastroesophageal symptoms (, available at www.ajmc.com).^{9,12,26,37,41} The mean age range for these studies was 42 to 46 years, and females made up 51% to 100% of the studies’ populations. The prevalence of dyspeptic and/ or gastroesophageal symptoms varied between 11.0% and 44.5%, with a pooled prevalence of 35.2% (95% CI 14.9%- 58.9%) (Appendix 23, available at www.ajmc.com). Significant heterogeneity between studies was observed (I² >99%). Review of the funnel plot and Egger’s weighted regression statistic P values suggested a lower likelihood of publication bias (P = .30).

Upon subgroup analysis, no analysis was shown to statistically significantly affect dyspeptic and/or gastroesophageal symptom prevalence (P >.05 for all).

Only 1 study reported results of multivariate analysis with dyspeptic and/or gastroesophageal symptom prevalence as the dependent variable (Appendix 24, available at www.ajmc.com).²⁶ This study, which was conducted only in women, identified being in menopause as an independent positive predictor of increased symptom prevalence.

Peptic Ulcer Disease

Appendix 25

Appendix 27

Seven studies reported prevalence data on PUD with the disease diagnosed upon endoscopy (1 study, n = 203), or disease recall asked for the prior 12 months (4 studies, n=15,623)^24,25,30,37 or over the study participants’ lifetimes (3 studies, n = 269,299) (, available at www.ajmc. com).^15,23,27 The prevalence of PUD varied between 2.2% and 4.2% in the shorter duration studies (upon endoscopy to 12-month recall), with a pooled prevalence of 3.3% (95% CI 2.2%-4.6%) (Appendix 26, available at www.ajmc.com). In the lifetime recall studies, the prevalence of PUD ranged between 8.4% and 26.1%, with a pooled prevalence of 13.8% (95% CI 10.8%-17.0%) (, available at www.ajmc.com). Significant heterogeneity between studies was observed in both analyses (I² >93% for both). Review of funnel plots and Egger’s weighted regression statistic P values suggested a lower likelihood of publication bias (P >.72).

Upon subgroup analysis, it appeared that the prevalence of gastroesophageal symptoms was greater in studies with longer disease recall periods (13.8% vs 3.3% for shorter periods, P <.001).

Appendix 28

Five studies reported results of multivariate analysis with PUD prevalence as the dependent variable (, available at www.ajmc.com).^15,23,24,38 Conflicting data regarding the associations between age, sex, and race and PUD prevalence were found. Of 5 studies, 3 (60.0%) suggested a positive relationship between increasing age and increasing PUD prevalence,^15,23,38 1 study suggested a trend in this direction,²⁴ and 1 suggested no effect.²⁵ Of 5 studies, 1 (20.0%) suggested that females had a higher prevalence of PUD,²³ 2 trended in a similar direction but failed to reach statistical significance,^24,25 while another (20.0%) suggested an independent negative association between female sex and PUD prevalence.³⁸ While a single study (20.0%) suggested Caucasians had a higher prevalence of PUD,³⁸ 4 others showed no significant relationship. ^15,23-25 African Americans were shown by 1 study to have a higher prevalence of PUD, while in the same study Hispanics had a lower prevalence.²³ A third study suggested “minority” races had a higher prevalence of PUD.²⁵ Data on marital status from 3 studies also were conflicting.^24,25,38 Higher income appears protective against PUD, with both studies that evaluated the association suggesting a negative correlation.^25,38 High level of education also was found to be associated with a decreased prevalence of PUD in 1 study,³⁸ with another suggesting a trend in this same direction²⁵ and a third showing no association at all.²⁴ Most studies (3 of 4, 75%)^15,23,38 suggested tobacco use was associated with an increased prevalence of PUD; however, the association between alcohol use/abuse and other types of substance abuse were not as consistent.^15,23-25

As with other upper GI symptoms discussed, increased body mass index was found to be independently associated with increased PUD prevalence in a lone study.²³ Studies evaluated a host of medical comorbidities to assess their association with PUD. Among those found to be associated with an increased prevalence of PUD include heart disease, kidney disease, chronic obstructive pulmonary disease, diabetes (in 1 of 2 studies), recurrent stomach problems, migraine, hernia, seeking care from a doctor 3 or more times a year, and poorer“perception of health.”^23,24 Psychiatric disorders including generalized anxiety disorder, bipolar disorder, and specific phobias were found to increase PUD prevalence²⁵; however, the association was not seen as consistently with PUD as with other upper GI symptoms. Of 14 separate PUD—psychiatric disorder associations evaluated as part of 2 studies, only 3 (21.4%) were found to be statistically significant.^24,25 Finally, while use of prescription acid-suppressing drugs was associated with increased PUD prevalence, current nonsteroidal antiinflammatory drug use was associated with decreased PUD prevalence.¹⁵

DISCUSSION

To our knowledge, this is the first published systematic review and meta-analysis that was restricted to US prevalence studies, included dyspeptic and gastroesophageal symptoms as well as PUD as outcomes of interest, and comprehensively evaluated factors that affect upper GI symptom prevalence. Thus, our systematic review and meta-analysis help to put into focus the US population prevalence of these GI symptoms and provide valuable information to healthcare decision makers. We identified 24 unique US upper GI symptom prevalence studies, and although estimates were variable, our analysis suggests that upper GI symptoms are common in Americans. Meta-analysis of studies revealed PUD to have the lowest prevalence (3.3% in shorter-term recall studies and 13.8% lifetime). Dyspeptic symptom prevalence was estimated to be 16.3% (range: 2.9%-34.4%) and gastroesophageal symptom prevalence 24.2% (range: 10.0%-58.3%). Not surprisingly, the outcome of dyspeptic and/or gastroesophageal symptoms had the highest reported prevalence (35.2%; range: 11.0%-44.5%), as it includes the broadest number of qualifying symptoms. High statistical heterogeneity was seen in all analyses (I² >93% for all). Prior meta-analyses attempting to pool prevalence rates of dyspeptic or upper GI symptoms have encountered similar degrees of heterogeneity.^8,47

Our a priori subgroup analyses revealed that the use of longer symptom recall periods (dyspeptic symptoms and PUD), regional sampling (dyspeptic symptoms), validated questionnaires (dyspeptic symptoms), and later year of study publication (gastroesophageal symptoms) resulted in increased prevalence rates. While the finding that longer symptom recall periods resulted in higher prevalence rates was not unexpected, it was somewhat surprising that the trend was not seen with all upper GI symptom outcomes. It is possible that this is a result of “recall” or “memory” bias (longer recall periods being prone to respondent error and underreporting) or type 2 statistical error (underpowered comparisons). It was also notsurprising that the use of a validated questionnaire resulted in higher prevalence rates due to the comprehensive nature of the questions asked in these tools. Finally, the finding that studies published in 2006 and later reported higher gastroesophageal prevalence rates compared with earlier published studies may suggest that symptom prevalence is on the rise.

One of the important aspects of this systematic review was our assessment of potential prevalence modifiers. We found that the influence of most covariates evaluated was often inconsistent both within and between the different upper GI symptom outcomes. Of note, body mass index (for gastroesophageal symptoms and PUD) and psychiatric disorders (for dyspeptic symptoms and PUD) were relatively consistent predictors of increased symptom prevalence. Use of a prescription acid-suppressing drug was also found to be a positive predictor of dyspeptic and gastroesophageal symptoms and PUD, suggesting these drugs could serve as a surrogate marker of upper GI symptom prevalence in future studies. Interestingly, we found that common medical comorbidities including heart and kidney disease, diabetes, and chronic obstructive pulmonary disease were independent predictors of higher upper GI symptom prevalence rates. This association between upper GI symptoms and common medical comorbidities was also clearly depicted in the Domestic/International Gastroenterology Surveillance Study (DIGEST).^41,42 While the multivariate regression results of DIGEST were not included in our systematic review because they were based on an international population,⁴¹ they do serve as confirmation of our findings.

The following limitations to our systematic review and meta-analysis should be noted. Firstly, our meta-analysis results demonstrated the presence of significant statistical heterogeneity, suggesting that there are underlying important clinical or methodological differences between the included studies. While some of this statistical heterogeneity was explained during subgroup and sensitivity analysis, not all was explained or accounted for. Next, when evaluating the results of included multivariate analyses, we often did not know the explanations for the association between these risk factors and symptom prevalence. Often, one covariate may serve as a surrogate for a different but related risk factor. Therefore, wecaution that results must not always be taken at face value. For example, the study by Dominitz and colleagues¹⁵ reported a reduced prevalence of PUD in patients taking nonsteroidal anti-inflammatory drugs (adjusted odds ratio 0.90, 95% CI 0.83-0.97). While these data could be interpreted as indicating a protective effect of these drugs against PUD, this hypothesis seems farfetched. It would seem more reasonable to theorize that patients at risk for PUD were purposely nottaking such drugs, and these data depict avoidance of nonsteroidal anti-inflammatory drugs. A final limitation of our systematic review is our inability to fully rule out the presence of publication bias, although Egger’s weighted regression statistic P values and visual inspection of funnel plots suggest its presence is less likely.

CONCLUSIONS

While estimates of upper GI symptom prevalence are variable, it appears that upper GI symptoms and disorders are common in the US population. Further, this systematic review has identified both patient- and study-level factors that should be considered when assessing the upper GI prevalence literature or when conducting future research. Of note, use of prescription acid-suppressing drugs was found to be a positive predictor of dyspeptic and gastroesophageal symptoms and PUD, suggesting these drugs might serve as a surrogate marker of upper GI symptom prevalence in future studies.

Author Affiliations: From Hartford Hospital (DMS, SMC), Hartford, CT; School of Pharmacy, University of Connecticut (CIC), Hartford, CT.

Funding Source: This research was supported by a grant from Ortho-McNeil-Janssen Scientific Affairs. The authors of this report are entirely responsible for its content.

Author Disclosures: Mr Coleman reports having received grants from Janssen Pharmaceuticals. The other authors (SMC, DMS) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (DMS, CIC); acquisition of data (DMS, SMC, CIC); analysis and interpretation of data (DMS,SMC, CIC); drafting of the manuscript (DMS, CIC); critical revision of the manuscript for important intellectual content (DMS, SMC, CIC); statistical analysis (DMS, CIC); obtaining funding (CIC); administrative, technical, or logistic support (DMS, SMC); and supervision (CIC).

Address correspondence to: Craig I. Coleman, PharmD, School of Pharmacy, University of Connecticut, 80 Seymour St, Hartford, CT 06102.

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