The Developed Patient Healthy Questionnaire-8 with a Greater Impact on Quality of Life Compared with the Somatic Symptom Scale-8 in Functional Dyspepsia

Background: To adapt insufficiencies of the Somatic Symptom Scale-8 (SSS-8) measuring somatization in functional dyspepsia (FD) to develop PHQ-8, of which reliability, validity and the effects of somatization evaluated by the developed PHQ-8 on quality of life (QoL) were further assessed. Methods: 612 FD patients completed a 25 items questionnaire. 8 items were selected from 25 items to constitute the PHQ-8 by discrete degree, correlation coefficient, factor analysis and Cronbach coefficient four methods. Reliability and validity for the PHQ-8 and the SSS-8 were compared by principal component and confirmatory factor analysis. The effects of somatization, depression and anxiety on the Nepean Dyspepsia Index (NDI) for QoL were explored by Pearson correlation coefficient and linear regression analysis. Results: Cronbach’s α coefficients for the PHQ-8 and the SSS-8 were 0.601, 0.553, and cumulative contribution rates of three extracted factors were 55.103%, 51.666%, respectively. Somatization evaluated by the PHQ-8(r=0.309, P<0.001) and the SSS-8 (r=0.281, P<0.001) were related to the NDI. The model for the PHQ-8 showed χ2=31.247, RMR=0.01, RMSEA=0.042, GFI=0.984. Linear regression analysis showed that somatization measured by the PHQ-8 (β=0.270, P<0.001), anxiety (β=0.163, P<0.001) and depression (β=0.136, P=0.003) were determinants of the NDI; somatization measured by the SSS-8 (β=0.250, P<0.001), anxiety (β=0.156, P<0.001) and depression (β=0.155, P =0.001) were determinants of the NDI. Conclusions: The developed PHQ-8 had a better reliability and validity, which assessing somatization appeared to have a greater

These factors may interact with each other under the participation of brain-gut axis, FD is a disorder of gut-brain interaction [1,3,15]. Rome IV classified FD into three subtypes: (1) epigastric pain syndrome (EPS): upper abdominal pain and/or burning discomfort of upper abdomen; (2) postprandial distress syndrome(PDS): postprandial fullness and early satiety ; (3) The overlapped group of EPS and PDS [2].

FD patients with common somatization symptoms
In addition, FD patients often have dizziness, back pain, sleep disorders, fatigue [26] and other digestive system symptoms that cannot be explained by biochemical and structural abnormalities. Clinically, these symptoms are called somatization symptoms [27,28]. . Somatization is defined as a chronic mental disorder characterized by the presence of one or more frequently changing somatic symptoms, involving multiple systems and organs of the body [29]. The severity of dyspepsia was affected by somatization. Patients often had incorrect understanding or excessive attention to these symptoms, and had too much anxiety about their physical condition. They repeatedly seeked medical help for these, consuming financial cost [30]. Somatization can coexist with other medical diagnoses such as anxiety and depression, and should be given equal attention to other comorbid diseases, because it often makes other diseases more complex and changeable [31]. FD patients had more somatic symptoms and worse quality of life (QoL) [32,33].

Limitations of questionnaires for somatization
The Patient Health Questionnaire Symptom Group (Patient Healthy Questionnaire-15, PHQ-15) was most widely used to assess somatization symptoms [34]. In FD patients, some items overlapped with FD gastrointestinal symptoms. Therefore, the Patient Healthy Questionnaire-12(PHQ-12) with the removals of three gastrointestinal symptoms was used, but the dysmenorrhea or other menstrual discomfort items in the PHQ-12 and the PHQ-15, which maked the gender score different. The item of syncope was relatively rare, of which the incidence rate was low [34][35][36]. In addition, FD patients often had symptoms such as throat discomfort and dry mouth that were not included in the PHQ-15, which might lead to neglect these symptoms by clinicians.
On the other hand, the Somatic Symptom Scale-8 (SSS-8) with good reliability and validity has been developed in the field of the DSM-5 to evaluate somatization symptoms [37][38][39], which was recommended to be a replacement for PHQ-15 in a limited time [40]. However, the items of the SSS-8 also overlap with gastrointestinal symptoms, and the SSS-8 is not a FD-specific scale for evaluating somatization.
Subsequently, we adapted the SSS-8 to develop the Patient Healthy Questionnaire-12(PHQ-8) by screening the somatic symptoms, and confirmed its reliability and validity, and demonstrated that somatization assessed by the developed PHQ-8 had a possible greater impact on QoL than that of the SSS-8 in specific FD patients.

Patients
Patients from June 2017 to June 2018, the outpatient department of gastroenterology, who were suspected to be FD, should improve the examination of digestive endoscopy, blood routine, biochemistry and abdominal ultrasonography. According to CONSORT guidelines, inclusion criteria: (1) Rome IV criteria [1]: upper abdominal pain, upper abdominal burning sensation, postprandial fullness, early satiety of one or more symptoms, and no organic diseases' evidence that can explain the above symptoms; the above symptoms exist for at least 6 months, and nearly 3 months meet the above diagnostic criteria; (2)  showed that anxiety, depression and somatization had mutual effects [21,33]. Thus the patients with anxiety and depression were included in the clinical application study of the PHQ-8,.  [35], each item scored by three-level as 0 ("not bothered at all"), 1 ("bothered a little"), or 2 ("bothered a lot") (past 2 weeks).The Items of the developed PHQ-8 were completed by discrete degree method, correlation coefficient method, factor analysis method and Cronbach's alpha.

Items for development of the PHQ-8 selected by four methods
Discrete degree method: when the degree of dispersion of the selected items is low revealing the poor ability for evaluation to distinguish, so the items with high degree of dispersion should be selected, and the degree of dispersion is measured by the standard deviation of the item scores, excluding the standard deviation of the items was < 0.5 [44].
Correlation coefficient method: an item with a correlation coefficient > 0.3 is selected according to Cohen's criteria [39].
Factor analysis: using the principal component method, the common factor is extracted according to the feature root greater than 1, and the variance is maximized by orthogonal rotation to select an item with a factor load greater than 0.4. The KMO and spherical test are performed. The KMO value< 0.5 is unsuitable factor analysis, and Bartlett's spherical test P<0.01 can negate the zero hypothesis that the correlation matrix is a unit matrix, that is, there is a significant correlation between the variables [45] .
Cronbach ɑ coefficient method: the items are screened from internal consistency, and the Cronbach ɑ coefficient of the initial total scale is calculated. If the ɑ coefficient is increased after the deletion of an item, it indicates that the existence of the item reduces the internal consistency [46].

Dyspepsia symptoms severity
The Dyspepsia Symptoms Severity (DSS) score is the sum of all eight symptoms: postprandial fullness, early satiation, epigastric pain, burning, bloating, belching, nausea and vomiting by 3-point scale (absent, mild, moderate, severe) [33] . The relationship between the DSS, the SSS-8 and the PHQ-8 were evaluated, and the effects of somatization, anxiety and depression on DSS were analyzed.

Disease-specific quality of life (QoL) measurement
The Nepean Dyspepsia Index-Short Form (NDI) measure the influence of dyspepsia symptoms on FD patients' QoL: inference with work/study, tension, inference with daily activities, disputation to daily eating/drinking, knowledge toward/control over disease symptoms over the past 2 weeks. Each item is assessed with a 5-point scale from 0 (not at all), 1 (a little), 2 (moderately), 3 (quite a lot) to 4 (extremely) [43]. The relationships between the NDI, the SSS-8, the PHQ-15 and the PHQ-8, and the effects of somatization, depression and anxiety on QoL were assessed in FD patient.

Statistical analysis
SPSS 24.0 statistical software was used. Quantitative data were expressed as (mean ± standard deviation), t-test was used for comparison between two groups, and one-way ANOVA was used for comparison above two groups. The qualitative data were expressed by rate, and chi-square test was used for comparison. Principal component analysis was used for exploratory factor analysis; AMOS 22.0 was used for confirmatory factor analysis; Pearson correlation coefficient was used for correlation analysis; influencing factors such as somatization, anxiety and depression on NDI were analyzed by linear regression analysis; Two-sided test, P<0.05,the difference had statistically significant . Among the somatic scores evaluated by the three scales, there was a significant difference in genders (P<0.05). There were no significant differences between different educational levels and ages (P<0.05).

Items for the developed PHQ-8 selected by four methods
By a discrete degree method dysmenorrhea or other discomfort during menstruation, chest pain, shortness of breath, fainting, palpitations, sexual life pain or other discomfort, numbness/tingling, sweating, heavy hands/foot, bursts of cold/fever, memory loss/forgetfulness, frequency of micturition, urodynia /dysuria, blurred vision, neck and shoulder pain, musce pain were removed due to the standard deviation of the items was < 0.5.
According to factor analysis the KMO value of the initial scale was 0.668, and the Bartlett spherical test chi-square value = 366.894, P < 0.01, which was suitable for factor analysis showing that each item had a factor loading of more than 0.4 in its dimension except for headaches and chest pain.
A Cronbach ɑ coefficient method showed that the ɑ coefficient increased after removing fainting, urodynia / dysuria.
The screened items of the developed PHQ-8 were shown in Table 2 by the discrete degree, a Cronbach ɑ coefficient, correlation coefficient method and factor analysis , including back pain, limb or joint pain, dizziness, fatigue, dry mouth, feeling tired or having low energy, insomnia or other sleep problems, throat discomfort.

Intrinsic reliability analysis
To measure whether the problem of the questionnaire is the same concept, The Cronbach coefficient is generally used to test the internal consistency. It is generally believed that when the coefficient is greater than 0.7, the reliability is good [47]. The Cronbach ɑ coefficient of the developed PHQ-8 and the SSS-8 were 0.601,0.553, respectively. The correlation coefficient between each item and the total score were 0.426 0.652,0.359 0.573,respectively.

Criterion validity analysis
The PHQ-15 and the NDI as classic scales, the correlation coefficient between the total score of the PHQ-8, the SSS-8 and the PHQ-15 were (r=0.739, P=0.000), (r=0.835, P=0.000), respectively. Table 3 showed the Nepean Dyspepsia Index as a classic QoL criterion, the developed PHQ-8 appeared to be superior to the SSS-8.

Structural validity analysis for the developed PHQ-8 and the SSS-8
Exploratory factor analysis: the developed PHQ-8 had a KMO=0.668, Bartlett spherical test chi-square = 366.894, P<0.01; the SSS-8 had a KMO=0.680, Bartlett spherical test chisquare = 236.445, P<0.01, of which factor analysis was suitable. The exploratory factor analysis was carried out on the scale, and the principal component method was used to maximize the orthogonal rotation through the covariance matrix and the variance, and the common factor was extracted by using the Kaiser criterion(Eigen value > 1). 3 common factors of the developed PHQ-8 was extracted, the cumulative contribution rate was 55.103%, and the factor load range on the common factor. It was 0.482 0.802, which was higher than the minimum standard of structural validity test 0.4 [45,47]; 3 common factors for the SSS-8 were extracted, the cumulative contribution rate was 51.666%, and the factor load range on the common factor was 0.353 0.881. The PHQ-8 and the SSS-8 specific factor loads were shown in Table 4 and Table 5.  Table 6.

Correlation analysis of anxiety, depression, somatization and the DSS for the developed PHQ-8 and the SSS-8 scores in 612 patients
A further clinical application study was carried out, assessing anxiety, depression and somatization mutual effects for the DSS and the NDI, and somatization assessed by the PHQ-8 and the SSS-8 in 612 patients . Correlation analysis showed that anxiety, depression, and somatization were positively correlated with DSS ( Table 7). The correlation coefficient between the DSS and somatization assessed by the SSS-8 appeared to be higher than that of the developed PHQ-8.

Linear regression analysis of the effects anxiety, depression, somatization on the DSS
Anxiety, depression and somatization as independent variable the DSS, the DSS was taken as dependent variable, and linear regression analysis was carried out by backward method to further study the effects of anxiety, depression and somatization on DSS. After adjusting for factors such as gender, age, FD type, education level and employment situation, Table 8 showed that depression and somatization were the influencing factors for the DSS , Three model adjusted R 2 for the PHQ-8 and the SSS-8 were 0.263, 0.263, respectively, all p<0.001 .The role of somatization might be more important than depression. The standardization β for the SSS-8 seemed to be higher than that for the PHQ-8.

Correlation analysis of anxiety, depression, somatization and QoL
Correlation analysis showed that anxiety, depression, and somatization were positively correlated with the NDI (Table 9). Compared to the SSS-8, the correlation coefficient between NDI and somatization for the developed PHQ-8 seemed to be higher.

Linear regression analysis for the effects of anxiety, depression, somatization on QoL
The Nepean Dyspepsia Index for QoL was taken as dependent variable, anxiety, depression and somatization as independent variable, and linear regression analysis was carried out by backward method to further study the effects of anxiety, depression and somatization on QoL. After adjusting for factors such as gender, age, FD type, education level and employment situation, Table 10 showed that anxiety, depression and somatization were the influencing factors for QoL, three model adjusted R 2 for the PHQ-8 and the SSS-8 were 0.224, 0.236, respectively, all p<0.001 .Somatization appeared to be more important than anxiety and depression. The standardization β for the PHQ-8 appeared to be higher than that for the SSS-8.

Discussion
Functional dyspepsia (FD) is the result of the interaction of physiological function and psychosocial factors through brain-gut axis changes [2,5].Psychosocial factors such as somatization have effects on health-related QoL after controlling for anxiety and depressive symptoms in FD patients [30,48]. Somatization manifestations can occur in multiple systems, patients often paid too much attention to symptoms and thought that their symptoms were caused by potentially serious physical diseases, thus aggravating anxiety and depression, leading to the deterioration of symptoms, resulting in repeated medical treatment and economic expenses [33]. The PHQ-15 is a good worldwide tool for assessing the severity of somatization and somatoform disorders, which has high reliability and validity not only in the disease population but also in the general population [34,49].
However, the PHQ-15 has some limitations in the study of FD patients. First, the PHQ-15 is not a specificity scale for FD patients, which has three items that overlap with gastrointestinal symptoms (stomach pain, nausea, flatulence or indigestion, diarrhea, loose stools or constipation). Secondly, there is a menstrual problem which is not applicable to menopausal women and cause gender differences. Thirdly, due to cultural differences, patients in the PHQ-15 has poor compliance with questions about sexual issues. Fourthly, the relative incidence of syncope items is low [35], in addition to the symptoms in the PHQ-15, FD patients often have other symptoms: dry mouth, fatigue, and throat discomfort, etc. Finally, most patients with somatic symptoms often visited a general outpatient clinic without non-psychiatric doctors, which may result in less satisfactory results. Therefore, in view of the PHQ-15 above limitations, it is necessary to use a more simple tool to assess FD patient's somatization symptoms and its severity, which is conducive to doctors to give patients better advice, diagnosis and treatment.
The SSS-8 has been used to quickly assess somatization symptoms and their severity, avoiding gender differences caused by menstrual abnormalities, sexual life problems caused by cultural differences, and low incidence of syncope items insufficient [38], but which is a non-specific scale of FD patients and has gastrointestinal overlap symptoms in the clinical application. In view of the SSS-8 limitations, in this study, the items of the developed PHQ-8 screened by discrete degree, correlation coefficient, factor analysis and Cronbach coefficient four methods had back pain, limb or joint pain, dizziness, fatigue, dry mouth, feeling tired or mentally poor, insomnia or other sleep problems, throat discomfort dryness, foreign body sensation etc.
The results showed that menstrual abnormalities, sexual life, syncope related items and the total score of the scale were poorly correlated. The removal of these three items improved the reliability of the developed PHQ-8, each item of which was significantly related to the total score, showing the reliability of the PHQ-8 appeared be better than that of SSS-8. The Cronbach coefficient of the PHQ-8 and the SSS-8 suggested the internal consistency of the PHQ-8 might be also superior to SSS-8. In the calibration validity analysis, the PHQ-15 and the SSS-8 had been widely used as a classic somatic symptom assessment scale, and NDI which were obviously related. In the exploratory factor analysis, the PHQ-8 had a higher cumulative contribution rate than the SSS-8. Common factor 1"neurological discomfort" includes dizziness, feeling tired or mentally poor, insomnia or other sleep problems, fatigue; common factor 2 "pain discomfort" includes back pain, limb or joint pain; common factor 3 "general discomfort "including throat discomfort, dry mouth. Gierk et al. [40] used confirmatory factor analysis to analyze the validity of SSS-8, and the results showed that the 3-factor model was better than the 1factor model. Similarly, we performed a 3-factor model confirmatory analysis for the PHQ-8 and the SSS-8. The 3-factor model fitting of the SSS-8 seemed to be better than that of the PHQ-8, while the SSS-8 contained gastrointestinal discomfort entries in FD patients.
The developed PHQ-8 score was further evaluated in order to compare with the SSS-8 in 612 FD patients including anxiety or depression, because previous studies showed that anxiety, depression and somatization had mutual effects [21,33]. Correlation and linear regression analysis found that somatization assessed by SSS-8 might play a larger role on the DSS than that by the PHQ-8. However, somatization assessed by the PHQ-8 might play a larger influence on QoL than that by the SSS-8,because of the fact that the PHQ-8 had been removed overlap gastrointestinal symptoms in FD patients.
However, there were some shortcomings in the research process. First, the subjects with FD included in this study were all composed of patients with tertiary hospitals. These patients may have severe symptoms, limiting the prevalence of other people with FD, and whether other FD patients from the community can get the same conclusion required a large scale study. Secondly, this study mainly analyzed the evaluation of specific somatization symptoms of FD patients by the developed PHQ-8, which was not used in other disease patients and healthy people. In addition, only patients with IBS, GERD as main symptoms were excluded. Thirdly, the PHQ-8 had not been tested for retest reliability in all cases, so the external reliability of the scale need to be further analyzed in future large sample research. Fourthly, similar to the SSS-8, the PHQ-8 was used to assess the severity of somatoform disorders, rather than the diagnostic tool for somatoform disorders [34]. Accordingly, further more studies were needed to improve the rationality of the developed PHQ-8 in future. FD patients' somatization was an independent risk factor for impaired QoL, proximal gastric accommodation, gastric emptying and H.pylori infection were not risk factors in a 5-year follow-up study [33].Thus, evaluating somatization is important in a long follow-up study. Our results showed the correlation between the PHQ-8 and QoL appeared to be higher than that of the SSS-8. Further a horizontal study was conducted, in which anxiety, depression and somatization were the influencing factors for the NDI.

Consent for publication
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Availability of data and materials
The data and materials can be available from the corresponding author on reasonable request.

Competing interests
There were not competing interests in this study.

Funding
None.

Authors' contributions
Yuan C and Yong G: conducted conception and design, analysis and interpretation of data, and wrote the manuscript; Wang X: collected and analyzed the data, drafted the manuscript; Xie T, Wang C: participated in analyzing data, editing the manuscript and final approval of the version to be published; Yuan Y: edited and approved the manuscript; He G: planned and conducted study concept and design, statistical analysis and edited and approved the manuscript.