Expression profiles during honeybee caste determination

Jay D Evans email@example.com
Diana E Wheeler

VDepartment of Entomology
Addresses: *Bee Research Lab
USDA-ARS
20705BeltsvilleMDUSA

University of Arizona
85721TucsonAZUSA

Expression profiles during honeybee caste determination
http://genomebiology.com/2000/2/1/research/0001.1 comment reviews reports deposited research interactions information refereed research Research Correspondence: Jay D Evans.
Background:Depending on their larval environment, female honeybees develop into either queens or workers. As in other polyphenisms, this developmental switch depends not on genomic differences between queens and workers but on the differential expression of entire suites of genes involved with larval fate. As such, this and other polyphenic systems can provide a novel tool for understanding how genomes and environmental conditions interact to produce different developmental trajectories. Here we use gene-expression profiles during honeybee caste determination to present the first genomic view of polyphenic development.Results: Larvae raised as queens or workers differed greatly in their gene-expression patterns. Workers remained more faithful than queens to the expression profiles of younger, bipotential, larvae. Queens appeared to both downregulate many of the genes expressed by bipotential larvae and turn on a distinct set of caste-related genes. Queens overexpressed several metabolic enzymes, workers showed increased expression of a member of the cytochrome P450 family, hexameric storage proteins and dihydrodiol dehydrogenase, and young larvae overexpressed two putative heat-shock proteins (70 and 90 kDa), and several proteins related to RNA processing and translation.Conclusions: Large differences in gene expression between queens and workers indicate that social insect castes have faced strong directional selection pressures. Overexpression of metabolic enzymes by queen-destined larvae appears to reflect the enhanced growth rate of queens during late larval development. Many of the differently expressed genes we identified have been tied to metabolic rates and cellular responses to hormones, a result consistent with known physiological differences between queen and worker larvae.

Background

Social insect colonies are defined in part by reproductive division of labor, whereby some colony members are considerably more fecund than others. The reproductive roles of colony members often are fixed by events that occur during larval development. An understanding of the mechanisms behind role, or caste, determination allows tests of several models for the evolution and maintenance of social life [1][2][3]. Female honeybees (Apis mellifera) are fated to become queens or workers during the first few days of larval development. Despite detailed knowledge of the physiological differences between workers and queens during development [4], relatively little is known of the underlying genetic machinery that drives these changes. Although differences in honeybee larval transcription had been inferred [5], castebiased genes were identified only recently [3,6,7]. On the basis of inferred homology with known genes [3], these genes appear to be involved with diverse metabolic, nutritional and signaling processes during development.

Gene-expression arrays provide a powerful new tool to clarify the timing and nature of genetic events during insect development [8]. Here we use this technique to explore the genetic mechanisms of divergence between social insect castes. We contrast the gene-expression patterns of workerdestined and queen-destined larvae and then compare both castes with younger, bipotential, individuals. These comparisons allow tests of hypotheses concerning the evolutionary relationship between queen-or worker-destined developmental pathways in social insects (see, for example, [2]). More generally, changes in gene expression during insect caste determination can shed light on diverse developmental events such as differences in hormonal titers, the development or apoptosis of reproductive tissues, and developmental rates and metabolism [9]. We present evidence for widespread divergence in gene expression between workers and queens, and identify particular genes that appear to be integral to the production of these distinct adult phenotypes.

Results

We assayed gene expression using an array of gene fragments derived from reciprocal queen and worker larval subtractive cDNA libraries. Of 158 unique, consistently amplified clones isolated from these libraries, 63 showed a significant match to genes with known function. The functions assigned to these genes span approximately half of the major functional groups described by Adams et al. [10] for Drosophila melanogaster, suggesting that we have captured a fairly broad cross-section of the expressed genes in larval bees. Nevertheless, the clones derived from our libraries were biased toward particular functional groups, in a fashion that suggests a relationship between gene function and caste (Table 1). For example, we found an apparent over-representation of both ribosomal proteins and hexameric storage proteins in our libraries, relative to the expected frequencies of these gene families based on the Drosophila sequence. Of the 63 characterized clones, 15 (24%) showed significant similarity to known ribosomal protein genes. In contrast, 128 of the 6,537 annotated genes (2%) in the Drosophila melanogaster genome encode ribosomal proteins [10]. Gene knock-out experiments have implicated several of these as regulators of development rate and body size in Drosophila [11]. Assuming that ribosomal proteins help modulate ribosome activity, they may be indicators of the developmental tempo of larvae, and therefore could help pinpoint the initiation of caste determination or other major developmental events. We also cloned six apparently distinct hexameric storage proteins from the libraries, indicating a strong bias toward this family given the frequencies of hexamerins in the Drosophila genome of <<1% [10].

We raised female honeybee larvae using standard methods, then measured gene-expression patterns for larvae collected at six 24-hour intervals from the embryo stage to the middle of the fifth and final instar. A subset (n = 13) of these larvae was raised as queens, while the others (n = 14) were raised workers. Analyses of covariance in gene expression indicate three primary clusters of genes with shared expression patterns across larvae ( Figure 1). These clusters define genes upregulated primarily in queen-destined larvae relative to the other larvae screened; genes downregulated in queens; and genes upregulated in young, bipotential larvae. Genes within these clusters are more similar to each other in function than expected by chance (likelihood-ratio analysis based on functional group, df = 14, X = 38.2, p < 0.001).

Genes related to RNA processing and translation showed higher rates of expression in young larvae (first and second instars) than in older larvae (Table 1). RNA helicase was strongly expressed by young larvae, as was an RNA-binding protein and translation elongation factor 2. Interestingly, two heat-shock proteins also were overexpressed in the youngest larvae. One shows a significant match to the Hsp70 family, whereas the second matches Hsp90. Heat-shock proteins are named for their ubiquitous presence following hyperthermy and other stresses [12], but members of this group have a more general role as molecular chaperones, and are involved in the assembly of newly translated proteins [13]. Hsp90 appears to be involved in the assembly of steroid hormone receptors [13]. Expression analyses on a more precise time scale, and at the level of specific tissues, should help determine whether the covariance between the expression of Hsps and agents involved in RNA processing reflects a joint role in producing essential proteins during early larval development. Table 1 Normalized gene expression by functional group and larval class Queen-destined and worker-destined larvae showed broadly similar expression profiles late in the second instar, 24 hours after queens and workers receive differential treatment in colonies. This suggests that most gene-expression changes associated with the caste programs occur after this point. Nevertheless, several genes were expressed differently at this early stage, including dihydrodiol dehydrogenase, which was expressed in lower levels by second-instar queens (normalized x = -0.067, SE = 0.025) than by either bipotential larvae (x = -0.026, SE = 0.009) or second-instar

Figure 1

Cluster analyses showing expression patterns by gene and larval group. Pink, young bipotential larvae; green, worker-destined larvae; blue, queen-destined larvae. Green cells represent relatively low levels of expression, dark gray cells represent moderate expression levels, and red cells represent higher expression. Bars to the left of the array reflect boundaries of genes with relatively high expression in queens (blue), workers and young larvae (pink and green) and workers alone (green). workers (x = 0.001, SE = 0.007). Dihydrodiol dehydrogenase has a general role in deactivating steroid hormones in mammals [14]. Consequently, it is intriguing that higher levels of expression of this enzyme by workers coincide with a period of decreased steroid titers in workers relative to queens. A putative lipid-binding protein also showed higher expression in workers than in queens from the second instar onward.

By the third instar, queen and worker larvae showed many differentially expressed genes (Figures 1,2) and, in each case, retained these different levels of expression through the remaining two instars. A cytochrome P450 (from the CYP4 subfamily) was more strongly expressed by workers than by queens. Members of the CYP4 subfamily have been implicated in the downregulation of steroid levels [15,16] although this subfamily is involved in a diversity of additional functions   related to the metabolism of endogenous and exogenous substrates [17]. As a group, hexameric storage proteins were expressed at significantly higher levels in workers than in queens (Table 1), although a single hexamerin, from clone 1CB6 [3], showed nearly equal levels of expression in queens and workers. Hexamerins have a nutrient storage role during insect development, by bundling amino acids that accumulate during larval development for use during metamorphosis or by the adult insects. The accelerated growth rates of queens may limit their ability to allocate resources to hexamerin storage during the larval stages we assayed, as shown for Manduca sexta larvae [18]. Other genes consistently overexpressed by workers include an oxidoreductase, a fatty-acid-binding protein, aldehyde dehydrogenase and a second lipid-binding protein.

Queens overexpressed two genes directly linked to increased metabolic rates -the nuclear-encoded mitochondrial protein ATP synthase and the mitochondrial gene cytochrome oxidase I. Higher expression of two mitochondrial genes was reported previously [6], and was suggested to be an indicator of higher metabolic respiration in queen versus worker larvae. Interestingly, increased expression of these genes by queen larvae in our study was not apparent until the fifth instar in the bees we followed, a fact consistent with a role in caste-biased respiration. During the final instar, queens show the most extreme differences in growth rates, relative to workers. Queens also showed relatively high expression of a set of structural (cuticular) proteins, a histone acetyltransferase bromodomain, an ortholog to the Smcx/y mammalian sex-differentiation gene, and pyruvate dehydrogenase (Figures 1,2).

Discussion

As well as providing expression information for specific genes, the analyses presented here provide the first look at genome-level processes during the divergence of two social insect castes. Caste-and age-based biases in gene expression were indicated by a strong tendency for independent samples to group together in the clustering analyses ( Figure 1). The castes differed widely in gene-expression patterns, supporting the idea that social insect castes have faced strong directional selection pressures [2]. Workers remained more faithful than queens to the expression profiles of younger, bipotential, larvae. In contrast, queens appeared simultaneously to downregulate many of the genes expressed by bipotential larvae and turn on a distinct set of caste-related genes. This difference could reflect, in part, a common impact of regulatory hormones on gene expression in young larvae and in larvae destined to become workers. Juvenile hormone and ecdysteroids are both much reduced in these larvae, relative to queen-destined larvae [4], and ecdysteroids have been shown to downregulate several genes expressed in the ovaries of developing workers [7].

Honeybees and other social insects provide a novel opportunity to measure the impacts of insect hormones on gene expression [9]. Specifically, hormone levels in different social insect castes are partially decoupled from molting and metamorphosis [19]. This fact can be used to retrieve expression differences caused by hormones per se from differences caused by other developmental events such as metamorphosis [8]. The identification of common transcriptional regulators for these genes, as shown in Drosophila embryos [20], would point to hormonal control mechanisms and unite caste-related genes with genes involved in insect development more generally.

Materials and methods

Array development

To generate the genetic arrays, cDNA clones were isolated from four subtractive libraries derived from worker-and queen-destined larvae collected in the third and fourth instars. We chose 144 clones from worker-biased libraries and 144 clones from queen-biased libraries. These clones were amplified by the polymerase chain reaction (PCR) using endogenous adaptor primers (primers Nest1 and Nest2r, described in [3]), then separated and verified by agarose gel electrophoresis. After being denatured for 5 min at 95°C in a final molarity 0.2 M NaOH, approximately 5 mg DNA from each amplified clone was fixed onto nylon membranes (Hybond N+, Amersham) using a 5 ml slot-pin library replicator (V and P Scientific) followed by UV irradiation. Each of 96 quadrants in a 384-cell printing contained three samples and a negative control. An aliquot of each cDNA clone was purified then sequenced using fluorescent-dye labeling and an ABI Prism 373 DNA analysis machine (Applied Biosystems).

Sample collection

Embryos, along with worker-and queen-destined larvae, were harvested from several colonies of A. mellifera ligustica of the same genetic stock maintained in the Bee Research Lab apiary. Two groups of 50 late-stage (2-day-old) embryos were harvested from standard (worker) cells and immediately frozen at -80°C. Four groups of 20 bipotential larvae aged 24 h post-hatching also were pooled and frozen. Fourteen worker-destined larvae aged 48, 72, 96, and 120 h posthatching were also collected, along with 13 queen-destined larvae from the same age groups, raised in natural queenrearing (swarm) cells. The ages of these queen larvae were determined by wet weight and body size comparisons with larvae of known age raised in artificial queen cells. For both worker-and queen-destined larvae, ages were likely to be accurate within 8-12 h, on the basis of wet-weight comparisons with larvae of known age [3]. Total RNA was extracted from these samples using the RNAqueous protocol (Ambion).

Labeling and hybridization

DNA probes were generated from 5 mg total RNA by reverse transcriptase synthesis (Superscript II enzyme, Life Technologies), using oligo-dT primers and biotin-labeled dUTP and dATP (in a 1:10 molar ratio to unmodified dTTP and DATP, respectively). Probes were cleaned by spin filtration, denatured, and then incubated in hybridization buffer (50% formamide, 6´SSPE, 0.5% SDS, 5´Denhardts solution) with 0.1 pmol poly-(A) 25 for 2 h at 42°C. Hybridization was carried out at 42°C, followed by a series of stringency washes, as in [3]. Membranes were washed, bathed in the Avidx alkalinephosphatase conjugate then exposed to the chemiluminescent substrate CDP-star, according to the manufacturers instructions (Tropix, Applied Biosystems). Membranes were next exposed to autoradiographic film for between 10 min and 8 h. Each membrane was used only once, giving an independent hybridization for 2 embryo replicates, 4 bipotential larvae, 13 queen, and 13 worker larval samples.

Data analysis

Cloned sequences were aligned using the CLUSTALW algorithm (Omiga 2.0, Oxford Molecular) to assess sequence quality and identify multiple captures of the same sequence. Each unique clone (167 out of 288) was compared against the GenBank database using the BLAST-X and BLAST-N algorithms at the site maintained by the US National Center for Biotechnology Information [21]. Matches showing a probability score of < 1.0´10 3 were treated as significant matches. Of the 167 unique clones, nine were dropped from the analyses as a result of evidence of multiple bands or inconsistent PCR amplification. Of the remaining clones, 64 showed a match to one or more sequences in GenBank and, of these, 63 could be placed into one of the gene function groups defined in [10] and the Gene Ontology database [22]. All gene fragment sequences used are available, along with their BLAST search results, at the Beenome Project website [23], and in the NCBI dbEST database [24].

Scanned images of exposed films were scored using the software program Zero Dscan (Scanalytics), giving a densitometry score for each cell in the membranes 384-cell matrix. Spreadsheet macros (Microsoft Excel) were then used to generate an average intensity value for each of 158 unique clones that consistently showed a single band in the PCR amplifications. These values were normalized as a proportion of the strongest signal on each membrane, then were further normalized and centered on unity across genes and samples [18]. Centroid clustering was then carried out and visualized using the programs Cluster 1.0 and TreeView 1.0, respectively [25].

Additional data

The following additional data are included with the online version of this paper: raw expression data and normalized data used in cluster analyses.

bold represent groups overexpressed in a particular larval class. Binding proteins were defined as non-metabolic proteins known to bind to other proteins or nucleic acids. SE, standard error.

Figure 2
2Proportional expression levels of specific genes. (a) Genes with high expression in young larvae (Y). (b) Genes with high expression in worker larvae (W). (c) Genes with high expression in queen larvae (Q). Normalized expression levels are shown, with standard error bars. FABP is a fatty-acid-binding protein and 52A9 is an oxidoreductase.
http://genomebiology.com/2000/2/1/research/0001.5
AcknowledgementsWe thank D. Lopez and D. Pham for technical assistance, and A. Collins and B. Tabashnik for comments on the manuscript. G. Hoffman, J. Martin, and colleagues in the Beltsville Bee Research Lab shared insights into honeybees and queen production.
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Service quality, trust, and patient satisfaction in interpersonal-based medical service encounters

Ching-Sheng Chang
Su-Yueh Chen
Yi-Ting Lan
Service quality, trust, and patient satisfaction in interpersonal-based medical service encounters
R E S E A R C H A R T I C L E Open Access
Background: Interaction between service provider and customer is the primary core of service businesses of different natures, and the influence of trust on service quality and customer satisfaction could not be ignored in interpersonal-based service encounters. However, lack of existing literature on the correlation between service quality, patient trust, and satisfaction from the prospect of interpersonal-based medical service encounters has created a research gap in previous studies. Therefore, this study attempts to bridge such a gap with an evidence-based practice study.Methods: We adopted a cross-sectional design using a questionnaire survey of outpatients in seven medical centers of Taiwan. Three hundred and fifty copies of questionnaire were distributed, and 285 valid copies were retrieved, with a valid response rate of 81.43%. The SPSS 14.0 and AMOS 14.0 (structural equation modeling) statistical software packages were used for analysis. Structural equation modeling clarifies the extent of relationships between variables as well as the chain of cause and effect. Restated, SEM results do not merely show empirical relationships between variables when defining the practical situation. For this reason, SEM was used to test the hypotheses. Results: Perception of interpersonal-based medical service encounters positively influences service quality and patient satisfaction. Perception of service quality among patients positively influences their trust. Perception of trust among patients positively influences their satisfaction.Conclusions: According to the findings, as interpersonal-based medical service encounters will positively influence service quality and patient satisfaction, and the differences for patients' perceptions of the professional skill and communication attitude of personnel in interpersonal-based medical service encounters will influence patients' overall satisfaction in two ways: (A) interpersonal-based medical service encounter directly affects patient satisfaction, which represents a direct effect; and (B) service quality and patient trust are used as intervening variables to affect patient satisfaction, which represents an indirect effect. Due to differences in the scale, resources and costs among medical institutions of different levels, it is a most urgent and concerning issue of how to control customers' demands and preferences and adopt correct marketing concepts under the circumstances of intense competition in order to satisfy the public and build up a competitive edge for medical institutions.

Background

The interaction between service provider and customer is the primary core of the service businesses of different natures. The intimate contact between service provider and service recipient is involved in the scenario of service, and such contact opportunity shall definitely and greatly influence the customer's evaluation process and focal point. One of the important factors is that inseparability exists between production and consumption in such services. Oftentimes, the service encounter system, including service personnel, physical facility, and other tangible elements, is regarded by customers as a part of the service [1]. In addition, the enhancement of service quality places emphasis on the actual service process, and the discussion of service encounter has obviously been the focus of service management [2,3]. Scholars have proposed that trust may allow customer behavior to be more predictable, reduce customer attrition rate, and create higher customer value [4,5]. In addition, trust may further save cost to increase customer satisfaction by creating customer value [6,7], and establish long-term customer relationships [8,9]. Researchers have pointed out that trust imposes positive influence on satisfaction [6,10,11]. Therefore, the influence of trust on service quality and customer satisfaction could not be ignored in interpersonal-based service encounters. However, the lack of existing literature on the correlation between service quality, patient trust, and satisfaction from the prospect of interpersonal-based medical service encounters has created a research gap in previous studies. Therefore, this study attempts to bridge such a gap with an evidence-based practice study.

In the process of service delivery, replacing the simple concept of medical service quality with the concept of interpersonal-based medical service encounters will enhance the dynamic nature and specificity of connotation. Therefore, in recent research, the original service quality studies were replaced by the interpersonal interactive connotation of service encounters [2,9]. However, past studies of the service industries focused mainly on such areas as how to establish long-term seller-buyer relationships, consumer behaviors or customers' satisfaction with the service quality [1,5]. As for the nature of relationship between the business proprietors and consumers during the process of service delivery, and the phenomenon of different interactive quality between the two, few studies have been conducted, and thus these areas are not sufficiently interpreted. This is particularly true for industries with relatively high level of interaction between the service deliverers and service recipients, such as the ever more prevalent professional service industries in recent years: doctors, lawyers, accountants, etc., in which relatively few empirical studies have been conducted. Nonetheless, it is important that practitioners of the above-mentioned professional services understand customers' needs during their interaction with the customers, and provide appropriate services to ensure the service quality, so that an edge tool of critical influence can be secured in this highly competitive market today [2]. This is also why the study chooses to explore how the service recipients feel and judge the behavioral performance of professional service providers on the basis of "professional interpersonalbased medical service encounters". The study aims at seeking to develop and design high-quality medical service solutions, measures, training or public relation activities, etc., in order to improve the medical service quality and the patients' satisfaction with medical services.

Hypotheses development and structural framework

Relationships among interpersonal-based medical service encounters, service quality, and patient satisfaction

Research has been conducted [12] on service encounters from the viewpoints of customer and service personnel that concluded service personnel and service behavior are both factors for customer's satisfaction and service quality on service encounter [13]. Therefore, the firstline service provider's behavior is important in customer's evaluation of service. Many scholars have suggested that the physical environment where services occur may be helpful to service marketing and it has affected service behavior since earliest trading times, indicating the necessity of proper planning and design of such a physical environment. However, what influence does a service environment have on customers? For general industries, pricing, advertising, and promotion activities are usually more able to attract customers and allow them to feel satisfied with the services more than the physical settings. This phenomenon indicates that physical settings simply play an auxiliary role in terms of the internal corporate goals and external marketing goals for an enterprise. For the service industry, however, things may be different since customers usually arrive and stay at the place where services occur. Hence, strategic planning and space design are apparently more important in the service industry than in other industries.

Booms and Bitner [14] have proposed that the newly added 3Ps in the 7Ps for service industry, physical evidence, participant, and service procedure, might compensate the shortcomings of the traditional 4Ps in marketing: product, place, promotion, and price. Bitner [15] has proposed the "Service Encounter Evaluation Model" to describe the causal variables that influence customer satisfaction or service awareness in the process of service encounter. The 7 Ps of service encountered in consumers' evaluation of service encounter will influence the contributing factors of the awareness of service performance, service expectation, service quality, and customer satisfaction. From the above statements, the following hypotheses are formed:

Hypothesis 1 Perception of interpersonal-based medical service encounters positively influences service quality.

Hypothesis 2 Perception of interpersonal-based medical service encounters positively influences patient satisfaction.

Relationships among service quality, patient trust, and satisfaction Rodolfo et al [16] have conducted an empirical study on tourism businesses and explored the functional quality facet and customer trust in service quality. The result suggests that when functional quality of service quality is perceived as superior by consumers, the employees of a service business are more trusted. Foster and Cadogen [17] have confirmed that perceived service quality will significantly and positively influence customer trust. Coulter and Coulter [18] have proposed that service quality is an important preliminary factor to customer trust [19,20]. In their study on service quality and relationship quality, Chang and Chang (2011) [21] and Wong and Sohal (2003) [22] have pointed out that service quality has positive, significant influence on relationship quality (trust, satisfaction, and commitment). Ribbink et al [23] have suggested that service quality has significantly positive influence on trust in their study.

In regard to the relationship between trust and satisfaction [20,24], it has been found that the degree of trust positively influences satisfaction, and furthermore [25,26], that prior trust directly and positively affects consequent satisfaction. Much service-related literature also demonstrates that trust positively influences customer satisfaction. Coulter and Coulter (2003) [19] have indicated that trust is an important factor for the service industry to maintain customer satisfaction. Chiou et al (2002) [27] have proposed in their basic model for customer loyalty that trust will positively influence satisfaction. It has been confirmed in much service-related literature that trust is an important factor in the maintenance of the relationship between service provider and customer satisfaction [13]. Thus, the importance of trust for enterprise and service provider is beyond any doubt. Medical service is a type of intangible product with service encounters; both medical care personnel and general service personnel must develop a trust relationship with patients to enhance patients' satisfaction. Combining all of the above, the following hypotheses are formed:

Hypothesis 3 Perception of service quality among patients positively influences their trust.

Hypothesis 4 Perception of trust among patients positively influences their satisfaction.

Structural framework of the theoretical relationships

We thus derive conclusions from the motive, purpose, and article review that the perception in interpersonalbased medical service encounters positively influences service quality and patient satisfaction; the perception of service quality positively influences patient trust; and patient trust positively influences patient satisfaction. The overall research framework is shown as Figure 1.

Methods

Research design and participants

In this study, the convenience sampling method was applied to select two medical centers each from northern Taiwan, central Taiwan and southern Taiwan, as well as one from eastern Taiwan, totaling seven medical centers (each was a teaching hospital and medical center, and each had more than 1200 sickbeds). There were a total of eight variables (four constructs) in this study. According to the suggestions provided by Hair et al (1998) [28] regarding sampling in different units of a study, the number of  samples should be at least five to ten times the number of research variables in addition to the number of samples for each unit should be more than 30 (that is, a large sample size). Therefore, a unit was then randomly selected from each medical center, where 50 copies of questionnaires were distributed by one trained interviewer of the selected each unit to the outpatients who voluntarily completed the questionnaires. A total of three hundred and fifty questionnaires were distributed between June 2011 and August 2011, and 285 valid ones were collected after incomplete and incorrect questionnaires were filtered out, with a valid response rate of 81.43 %. Israel (2003) [29] has proposed that the more samples drawn, the more statistical significance will be found (but probably the identification of this statistical significance will be meaningless from a management perspective, and it may lead to statistical misrepresentation), thus, they suggested that when the population size is more than 100,000, then, theoretically, the sample size should lie between 204 (95% confidence level and ±7% precision) and 400 (95% confidence level and ± 5% precision). Therefore, the number of questionnaires gathered in this work is consistent with the theoretical sample size.

Instrument

Because patients directly filled in the questionnaires in the independent variable and dependent variable sections, a single source bias (the deviation caused by the common method variance) might occur [30]. Thus, to avoid and reduce the occurrence of common method variance which might raise the possibility of overestimation and underestimation by the patients, we adopted: 1) a participant information confidentiality approach, using an anonymous method to reassure the participants; 2) a concealed purpose approach, by not revealing the variables of every aspect in the questionnaire to reduce the doubts and suspicions that participants may have. The following is the explanation of the questionnaire, which comprised questions already developed in foreign studies that were modified to serve the study purposes.

First, dimensions of questionnaire forms were obtained from the literature and used to compile questionnaires. Second, the dimensions were slightly modified to create initial questionnaires based on the research purposes and industry features. Third, tests were repeatedly administered to three professors in the industry, and to two medical specialists and five patients; a pilot run of the questionnaire was administered to 37 patients. A total of 32 valid questionnaire forms were gathered, and the results indicated that the reliability was 0.72 to 0.87 (except for one item for the interpersonal-based medical service encounter, two items for patient trust and satisfaction, therefore, these items were deleted) meeting the acceptable standard of more than 0.6 recommended by Chang and Chang (2009) [31]. Finally, the questionnaire was officially released. The questionnaire employed a 5-point Likert scale from 1, for "strongly disagree" to 5, for "strongly agree." Table 1 summarizes constructs and Professional Personnel Patients' perceptions of the medical professional skill and communication attitude of the physicians and nurses in the service encounter.

0.92

General Administrative Personnel

Patients' perceptions of the communication attitude, sympathy, and empathy of the general service personnel in the service encounter.

0.89

Patients' perceptions of the other tangible factors that may help the implementation of medical service in the service encounter.

0.90

Service Quality [34,35] Response Hospital's capabilities of providing services that instantly and rapidly respond to patients' demands in the service encounter.

0.88

Reliability Hospital's capabilities of providing services that correctly delivery the service requested by patients in the service encounter.

0.90

Assurance Hospital's capabilities of providing services that really earn patients' confidence in the service encounter.

0.93

Patient Trust [19,36] Patient Trust Patients' perceptions of the confidence in the reliability and integrity of medical service in the service encounter.

0.91

Patient Satisfaction [37,38] Patient Satisfaction The psychological state of patient involves their positive or negative feelings or attitudes toward their experience and some specific aspects in the service encounter.

0.91

variables, including operational definitions for all variables. Questionnaires were examined for reliability and validity as follows:

1. Reliability analysis: Principal component factor analysis was used to extract major contributing factors, and varimax of the orthogonal rotation was performed to maximize the differences in factor loading carried by every common factor after the rotation to help recognize common factors. Thus, as Table 1 illustrates, the analytical results indicated that all Cronbach's α values exceeded 0.6 [28,31,32]. 2. Construct convergent validity (confirmatory factor analysis): The confirmatory factor analysis could gain higher recognition than expert content validity [28], and the results for all dimensions are listed in Table 2. All of the adequacy indicators were close to the ideal. Parameters (λ) between each latent variable and manifest variable were estimated to determine the significance of the estimated parameter (λ) in order to evaluate convergent validity. Thus, as  Table 3 shows, the Chi-square values of limited patterns in fact exceeded those of unlimited patterns, and reached a level of significance, indicating discriminant validities among all dimensions.

Data analysis methods

The SPSS 14.0 and AMOS 14.0 (structural equation modeling) statistical software packages were used for data analysis and processing, including:

1. Descriptive statistical analysis: To see the sample characteristics.

1. Structural equation modeling (SEM): According to Scholars [31,43], structural equation modeling clarifies the extent of relationships between variables as well as the chain of cause and effect. Restated, SEM results do not merely show empirical relationships between variables when defining the practical situation. For this reason, SEM was used to test the Hypotheses. This study also used several indices, including Chi-square ratio (< 3), goodness of fit index (GFI> .9), adjusted goodness of fit index (AGFI> .8), normal fit index (NFI> .9) and root mean square of standardized residual (RMSR< .08) to evaluate overall model fitness.

Ethical approval

Approval for the project was obtained from the Institutional Review Board, the study was then carried out with participants'written consent; each participant's personal data was kept anonymous and confidential and used only for research purposes to comply with the spirit of the Declaration of Helsinki, 2008. The response period was limited to two months. An introductory letter was attached to the questionnaire to explain the purpose of the study and to ensure respondent confidentiality. Anyone who was also interested in learning about the result of this study was able to request a copy through the contact address provided in the questionnaire.

Results

Characteristics of Samples

The respondents included male (50.9%) and female (49.1%) respondents. The demographic data revealed that 30.5% of participants were between 41-50 years of age. Furthermore, most respondents had a senior high school degree or university / college level (36.1% and 31.9% respectively). In terms of occupation, there was considerable variety: service sector (49.5%), commerce (15.1%), industry (11.2%), military, public servant, teacher (10.5%), agriculture (6.0%), freelance (4.2 %), and student (1.1%). Concerning the department in which patients were to receive medical treatment, the internal medicine department and cancer center (38.9% and 20.0% respectively) were visited most frequently by the outpatients (see Table 4).

Results of structural equation modeling (SEM)

As Table 5 illustrates, Hypotheses in this study are also demonstrated to be statistically significant. Perception of interpersonal-based medical service encounters positively influences service quality (γ 11 = 0.57) and patient satisfaction (γ 31 = 0.23). Perception of service quality among patients positively influences their trust (β 21 = 0.49). Perception of trust among patients positively influences their satisfaction (β 32 = 0.33). Table 5 also shows the results of SEM in this study and the model goodness of fit. In short, it can be concluded that the research model is applicable for the data.

Discussion

Theoretical Implications

The major results in this study are: Perception of interpersonalbased medical service encounters positively influences service quality and patient satisfaction, perception of service quality among patients positively influences their trust, and perception of trust among patients positively influences their satisfaction.

The conclusions are discussed, as follows: Our findings support the statement that perception of interpersonal-based medical service encounters positively influences service quality and patient satisfaction. This agrees with the assertions of previous relevant studies. For example, Booms and Bitner (1981) [14] and Bitner (1990) [15] have respectively suggested that participants play an important role in service quality, including professional personnel, general administrative personnel, and environment and space (physical symbol). As suggested by a previous study by Bitner et al (2000) [44], role expectation and role performance all have an influence on an assessment of service quality and satisfaction by customers after services are delivered and the payment is settled. Also, the role has a significant influence throughout the whole course of a service encounter, and a friendly attitude taken by the service encounter personnel toward customers also has a great influence on service quality and customers satisfaction.

Our findings also support the statement that perception of service quality among patients positively influences their trust and perception of trust among patients positively influences their satisfaction. This agrees with assertions made in previous studies, such as that by Wong and Sohal (2003) [22], which have suggested that service quality is an important antecedent of customer trust. Josep and Velilla (2003) [20] and Singh and Sirdeshmukh (2000) [26] also have indicated that prior trust directly and positively affects consequent satisfaction.

Practical implications

The results of the study concluded three points to illustrate the importance of the interaction between service provider and patients: 1) the term of role has its meaning in social background. In role theory, any service transaction can be an interactive exchange; 2) the concept of role expectation and the predictability of role may help the understanding of the nature of service transaction; and 3) the element of role in service industry may provide other more useful methods for categorizing service and the marketing method to develop marketing management strategy. Therefore, the results of the study point out the content and structure of the role of professional service provider from the aspects of professional service provider, such as professional personnel as well as the general administrative personnel, and the study also concluded that patients will distinguish between ideal role and expected role and describe professional service role according to the traits of professional ethics, professional skill, communication skull, interpersonal skill and personal characteristic.

Deserving of special attention is that, as interpersonalbased medical service encounter will positively influence service quality and patient satisfaction, and the differences for patients' perception of the professional skill and communication attitude of personnel in the interpersonal-based medical service encounter will influence patients' overall satisfaction in two ways: (A) interpersonal-based medical service encounter directly affects patient satisfaction, which represents a direct effect; and (B) service quality and patient trust are used as intervening variables to affect patient satisfaction, which represents an indirect effect. According to the above findings, we learn that patients' perception of the professional skill and communication attitude of professional personnel in the interpersonal-based medical service encounter also positively influences their satisfaction, with the requirement of service quality and patient trust as the intervening variables. This finding varies from the previous assumption that service quality alone can positively influence patient satisfaction. The results of the study reveal that the higher the patients' perception of the professional skill and communication attitude of personnel, the better the service quality, patient trust, and patient satisfaction shall be. Based on such findings, the hospitals are recommended to enhance professional skills and communication attitudes of personnel to retain patients and build up a competitive edge for medical institutions as competitive pressure increases. This study shows that service quality has a positive influence on customer trust, and customer trust also has a positive influence on customer satisfaction. Medical service is a type of intangible product with service encounters; therefore, both medical care personnel and general service personnel must develop a relationship of trust with patients to enhance patient satisfaction. After all, the safety and honesty of the results of diagnosis in the service encounters are now an importance issue due to the openness of the Internet. Customers are anxious about the credibility of the health care provider they deal with, besides illegal interception of their transaction information; therefore, medical institutions must build up customers' psychological trust in the service encounters. Intangibility of the service industry makes customers unable to predict the result of service; they can only become aware of risk when consumption occurs. Also, consumers of service lack sufficient information and knowledge, and therefore a high level of risk and uncertainty are often inevitable. For the medical service industry, both medical service personnel and general service personnel play an important role in communication, and establishing a relationship of trust with patients is very important.

Suggestions and recommendations

As the competition in the medical service industry is intense and a large number of medical institutions have to share a limited medical market, medical service marketing (encounter) now plays an important role in hospital management. Also, medical services are still a kind of services, and it is widely recognized that there is inherent difference between medical services and tangible products. Therefore, medical service providers are faced with management challenges about how to overcome specific properties thereof to cater for individual requirements and needs. Since each patient has his/her own demographics, such as cultural background and values, there is significant difference in key factors affecting patients' choosing medical institutions of different levels as well as decision-making. Owing to the difference in the scale, resources, and costs among medical institutions of different levels, it is the most urgent and concerning issue of how to control customers' demands and preferences and adopt correct marketing concepts under the circumstances of an intense competition in order to satisfy the public and build up a competitive edge for medical institutions. The following recommendations are made for hospital administrators according to the conclusions of this study:

1. Increasing satisfaction with medical professional personnel will bring the largest rise in overall satisfaction. Nonetheless, "treatment effect" and "doctors' consultation attitude" are difficult to control, and so top management of hospitals should take doctors' experience, medical skills and ethics as important criteria when recruiting doctors.

Limitations and future studies

Our findings should be considered in view of certain limitations. Firstly, we only investigated the correlation between interpersonal-based medical service encounters, service quality, patient trust, and patient satisfaction in a sample of outpatients. Other factors influencing service quality and patient satisfaction such as the hospital offering convenient transportation, parking, reputable physicians, complexity of disease, and the waiting time, and so on, await further study. Secondly, Cooper and Schindler (2003) [45] and Culyer and Newhouse (2000) [46] have proposed that using aggregation data for inference of individual behaviors might lead to biases. When individual data cannot be observed, using the average value for inference would easily result in biases, because average values cannot reflect individual differences. Therefore, the demographic variables (characteristics of the respondents) were taken as the control variables in this study, but it is expected that individual medical difference can be used as the unit of analysis in future studies to estimate its flexible influence, and hence to conclude the differences in various aspects (constructs) between different hospitals or different specialist departments, etc. Thirdly, the primary research instrument was the questionnaire, which has a certain degree of validity and reliability. However, the results would have been subject to numerous factors that could cause variations in the results, such as defensiveness, misrepresentation, personal emotion and other attitudes. Finally, we examined only one period, which would not reveal factors having long-term effects. A multiple period approach is suggested for follow-up study. Analyzing multiple periods of data would achieve more complete and objective statistical data.

Conclusions

The 21 st century is a new starting point of medical science for Taiwan and other Western countries alike. Since people are giving increasing emphasis to the quality of living, and the demand for medical and health care is growing, Taiwan's medical care system and the ecology of hospitals have seen changes since the implementation of the National Health Insurance Scheme on March 1, 1995 and the inclusion of some of the medical staff in the applicable scope of the Labor Standards Act: large hospitals have expanded tremendously, with excessive number of beds; this coupling with the general shortage of medical and nursing manpower in hospitals has added enormous workload onto the medical personnel. Hospitalization rate at regional hospitals has dropped significantly, and the number of base-level clinics has increased drastically. All these have resulted in major changes in the internal management and external contingencies of hospitals. The overall operational environment of hospitals is increasingly difficult and full of uncertainties. In response to this drastic change in the operational environment, hospitals are invariably involved in institutional reform and organizational re-engineering by actively strengthening internal quality enhancement, external marketing, forming merger or strategic alliance, etc., in order to boost their own competitiveness. However, escalating costs of medical expenditure and medical insurance have created new problems. Apart from making tighter controls on personnel costs, medical care institutions must also keep their operating costs below a certain percentage while maintaining the level of medical service quality. Hence, in addition to grasping the correct way of development, hospitals should also explore the trend of human resource application in their operation, to make the most out of the manpower at the most economical personnel costs. How to flexibly adjust the number of staff, working hours and manpower structure, making timely rotation of staff, providing sufficient education and training, and making effective distribution and utilization to adapt to the rapid changes in the overall environment and market at any time have become essential issues. This study focuses on "professional interpersonal-based medical service encounters" as the major issue, just in a hope to remind hospitals of the understanding that medical care institutions are a tertiary industry that emphasizes "interaction with people", that service orientation is demanded, and that patients are of top priority. However, medical care institutions have put too much emphasis on "sales-oriented" rather than "customer-oriented" tasks in the past. In view of the evergrowing patient awareness today, in addition to the current status of supply exceeding demand, medical managers should not only achieve the maximum manpower efficiency and effectiveness with the most streamlined manpower costs, but also adopt a "customer-oriented" operational philosophy, create the "patient value", work towards the goal of enhancing "patient satisfaction", and hence actively strive for patient revisits on the basis of "professional interpersonal-based medical service encounters" perspective, so that the ultimate ideal of sustainable operation of the medical care institutions can be achieved.

Figure 1
1Structural framework of the theoretical relationships.

Table 1
1Factor naming and reliability analysis results of all the constructsConstruct/ variable
Operational definition

Table 2
2shows, the t values for the factor loading of all measurement items reached the level of significance (p< .05), no single factor included only one question, and the composite reliability values for all constructs were greater than 0.6, which demonstrated satisfactory convergent validity[31,33]. 3. Construct discriminant validity: This study performed discriminant validity analysis based on the recommendations of Bagozzi and Yi (1988) and Chang and Chang (2009) [31,33] by limiting the correlation coefficient of the paired dimensions to 1, then performing a Chi-square variance test of the limited and unlimited measurement patterns. If the Chi-square value of the limited pattern exceeds the Chi-square value of the unlimited measurement pattern and reaches a level of significance, then both dimensions have discriminant validity. Thus, as

Table 2
2Confirmatory factor analysis and convergent validity analysis results of all the constructs Goodness of fit: χ 2 / d.f.= 2.79, GFI= .90, AGFI= .87, NFI= .90, RMSR= .068 [33,39-42] * p < .05. AVE= Average variance extracted. χ 2 / df. = Ratio of Chi-square. GFI = Goodness of Fit Index. AGFI = Adjusted GFI. NFI = Normal Fit Index. RMSR = Root Mean Square of Standardized Residual.Construct
Variable / question item
Standard
loading

Composite
reliability > 0.6

AVE
> 0.5

Interpersonal-Based
Medical Service Encounter

Professional personnel
0.85
0.54

1. I feel the physicians are professional during the whole treatment process.
0.71*

2. The physicians will recommend adequate medical treatment according to
patients' needs.

0.71*

3. The physicians are able to provide answers that solve my doubts.
0.74*

4. The physicians will inform patients about treatment plan.
0.79*

5. I feel the nurses are professional during the whole treatment process.
0.72*

General administrative personnel
0.92
0.74

1. Service counter personnel are trustworthy.
0.84*

2. Service counter personnel are able to take the initiative in assisting the procedures
of registration, pharmacy, and cashier to make them smooth and efficient.

0.97*

3. Service counter personnel are able to provide answers that solve my doubts.
0.92*

4. Service counter personnel have a good service attitude.
0.67*

Environment and space (physical symbol)
0.91
0.71

1. The hospital has clear directions inside.
0.85*

2. The hospital has wide and comfortable waiting rooms.
0.77*

3. The hospital has well-illuminated waiting rooms.
0.90*

4. The hospital has clean toilets.
0.84*

Service Quality
Response
0.77
0.53

1. The entire service process has a good feedback system and management.
0.56*

2. The entire service process allows questions to be answered easily.
0.82*

3. The entire service process can complete service in a short period of time.
0.78*

Reliability
0.94
0.83

1. The entire service process has complete record of transaction details.
0.94*

2. The entire service process is able to correctly complete designated service items.
0.85*

3. The entire service process has no error.
0.94*

Assurance
0.81
0.60

1. The entire service process can fulfill its promise to customers.
0.75*

2. The entire service process has a good security mechanism.
0.97*

3. The entire service process is trustworthy.
0.55*

Goodness of fit: χ 2 / d.f.= 2.70, GFI= .96, AGFI= .92, NFI= .96, RMSR= .077 [33,39-42]

Patient Trust
1. Medical care personnel will honestly inform patients about the result of diagnosis. 0.88*
0.87
0.58

2. Medical care personnel will honor the agreement made with the patients.
0.76*

3. My medical issues can be handled through the help from general service personnel. 0.79*

4. I can trust medical care personnel's judgment on my sickness.
0.69*

5. I rely on medical care personnel to solve medical issues.
0.66*

Goodness of fit: χ 2 / d.f.= 2.72, GFI= .98, AGFI= .95, NFI= .98, RMSR= .078 [33,39-42]

Patient Satisfaction
1. The entire service provided by the hospital makes me feel happy.
0.89*
0.89
0.68

2. After consumption, I believe choosing this hospital is a correct decision.
0.85*

3. I will recommend the medical service of this hospital to other people.
0.85*

4. I am very satisfied with the entire service provided by this hospital.
0.69*

Goodness of fit: χ 2 / d.f.= 2.85, GFI= .99, AGFI= .95, NFI= .99, RMSR= .081 [33,39-42]

Table 3
3Discriminant validity analysis results of all the constructsPATTERN

Table 4
4Characteristics of samples (N=285) With the difference in scale, resources, technology, costs, etc., the hospitals may consider their own strengths and weaknesses, and try to upgrade their outpatient clinical service quality and competitiveness by really effective use of their own resources. And hospitals with better facilities and better reputation are usually the first choice of patients and the most important factor.Description
Frequency
Percentage (%)

Gender

Male
145
50.9

Female
140
49.1

Age

20 years and below
19
6.7

21-30 years
26
9.1

31-40 years
68
23.9

41-50 years
87
30.5

51-60 years
56
19.6

61 years and above
29
10.2

Education level

Elementary school and below
27
9.5

Junior high school
53
18.6

Senior high school
103
36.1

University / College
91
31.9

Postgraduate
11
3.9

Occupation

Student
3
1.1

Service sector
141
49.5

Military, public servant, teacher
30
10.5

Industry
32
11.2

Commerce
43
15.1

Agriculture
17
6.0

Freelance
12
4.2

Other
7
2.5

Department

Internal Medicine
111
38.9

Obstetrics & Gynecology
24
8.4

Rehabilitation
39
13.7

Psychiatry (Physical & Mental)
12
4.2

Cancer Center
57
20.0

Ophthalmology
30
10.5

Pediatrics
6
2.1

Other
6
2.1

Table 5
5Results of structural equation modeling Goodness of fit χ 2 / d.f.= 2.19, GFI = .91, AGFI = .89, NFI = .91, RMSR = .058. * p < .05. ** p < .01.Path

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AcknowledgementsThe authors wish to express their gratitude to the study subjects for their participation in this research.Competing interestsThe authors declare that they have no competing interests.Authors' contributions
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Service quality, trust, and patient satisfaction in interpersonal-based medical service encounters. Chang , BMC Health Services Research. 1322Cite this article asCite this article as: Chang et al.: Service quality, trust, and patient satisfaction in interpersonal-based medical service encounters. BMC Health Services Research 2013 13:22.