Monday, July 29, 2019

Internet Computerized Adaptive Testing to Detect Cheating Respondents: An Example of Bully Prevalence Survey at Workplace



Abstract

Objective: Surveys are often conducted but rare collecting data against cheating behaviors by detecting abnormality responding to items. The aim of this study is to design indices for screening out suspiciously careless cases for improving survey quality and effectiveness.
Methods: We interpreted a result of bully survey on prevalent rates of workplace bullying resulting from respondent’s subjectivity bias in part, simulated data using four indices (i.e., Chi-square test, Z-score, Gini coefficient, and Delta coefficient) for detecting cheating respondents, and finally demonstrating an online computer module that combines model person fit with the study equality indices of personal responding time consumed to items to monitor the behavior abnormality.
Results: We found that prevalent rates of workplace bullying might be overestimated at 7.5% due to cheating behaviors and the inflated self-labeling endorsement on their responses, two equality indices of 1-Gini coefficient (>0.70) and Chi-square (<2.0) are recommended for use in computer online module, and (3)an online computer adaptive testing was designed to join with the suggested indices for detecting abnormality in a survey.
Conclusion: Prevalent rates of workplace bullying should be guaranteed against those suspicious respondents’ cheating behaviors. We recommend using two equality indices in a computer online module to ensure and secure the survey quality in future.
Keywords: Equality index; Computer adaptive testing; Workplace bullying; Gini coefficient; Chi-square deviation indicator
Abbrevations: APP: Application; CAT: Computerized Adaptive Testing; CTT: Classic Test Theory; IRT: Item Response Theory; MNSQ: Mean-Square; MSE: Mean-Squared Error; SD: Standard Deviation; SE: Standard Error

Introduction

During the last 20 years, workplace bullying has been measured and assessed in a range of different studies to investigate mental health issues [1]. Despite all this attention on the bully phenomenon, little is known about how the use of different measurement and estimation methods influences the findings on workplace bullying. The prevalence of bullying was reported at 24% for hospital nurses [2], higher than seen in studies of Japanese nurses (19%) [3], Korean intensive care unit (ICU) nurses (15.2%) [4], and workers in general services (2%-17%) [1].
We have not seen any study checking data in correction (or called purification) to respondents before conducting statistically analyses. That is to remove those suspiciously possible cheating respondents answering questions in a survey. Otherwise, the findings on workplace bullying would be biased and overestimated. Nielsen et al. [5] addressed that self-labelling (i.e., with a single quest to answer whether she/he is a bullied victim [6,7] with definition studies yielded far lower estimates of bullying than self-labelling studies without definitions. For studies using the behavioral method (i.e., with several items to respond with regards to encountered negative acts or behaviors in a workplace [1,8] with an operational criterion, prevalence rates seem to vary between 3% and 17%, depending on the cut-off criterion utilized [9].

Cheating behaviors and cutting points

If the vital few (e.g., victims of bullying as in nominator) was over-counted (e.g. using self-labelling method or a lenient cut-off criterion) or the trivial many (e.g. not bullied and limited work criticism as in denominator) was under-counted, the prevalent rate will be beyond the expectation. A specific definition is thus needed in the self-labelling method, and a statistically scientific detection is required to decrease the over count and the under count phenomenon in a survey. We name it detecting cheating behavior in this study. Some researchers [10-12] proposed person fit statistics to detect non-fitting examinees in a test. But none were seen in exploring an online detection to screen out suspiciously careless cases before conducting analyses for improving study quality and effectiveness. Especially, we are in the age with all forms of web-based technology, advances in mobile health (mHealth) and health communication technology, which are rapid and ubiquitous around the world [13].

The NAQ-R inventory and the computer instrument

A notable behavioral experience inventory used in research on workplace bullying is the version of the Negative Acts Questionnaire-Revised (NAQ-R) [14], which has been validated in several studies and countries [2,8,15,16]. The NAQ-R investigates the frequency and persistency of the respondent’s exposure to 22 different types of unwanted and negative behaviors. The range of negative perceptions is widely included from such subtle and indirect acts as gossiping to such more direct behaviors as threats of physical abuse. All items are described with behavioral terms without the word bullying. Respondents are asked to indicate how often they have been exposed to the 22 negative acts using a response scale ranging from «Never» to «Daily». Hence, the NAQ-R is a behavioral experience tool used for examining the extent to which the psychological aggression and harassment is perceived by the test-taker.
The NAQ-R is evident of a unidimensional construct and can be applied to measure exposure to workplace bullying through the computerized adaptive testing (CAT) administration [2]. The CAT requires fewer items to answer than the traditional pen-andpaper approach (an efficiency gain of 32%), suggesting a reduced burden for respondents [2]. However, the CAT-based NAQ-R is just administered on a computerized nursing cart (i.e., not an online CAT version) and is not equipped with any functionality of detection in monitoring respondents with cheating behaviors in a survey to improve the quality of data collection.

Objectives

First, we interpreted a result of bully survey on prevalent rates of workplace bullying that show the over-count in response to the subjectivity bias in part. Second, a simulation study was conducted to explore possible and feasible indices that can help us detect cheating respondents on a CAT-based NAQ-R. Third, an online CAT NAQ-R was developed by combining model person fit with the study equality indices together to ensure data purification and survey quality.

Methods

Study participants

The study sample was recruited from three hospitals (Hospital A: 1236-bed medical center; B: 265-bed local hospital; C: 877-bed region hospital) in southern Taiwan in the summer of 2012. No incentive for participation was offered. A total of 963 nurses completed a pen-and-paper format of NAQ-R questionnaire. This study was approved and monitored by the Research Ethics Review Board of the Chi-Mei Medical Center. Demographic data were anonymously collected including gender, work tenure in hospitals of all types, age, marital status, and education level.

Scales used for reporting exposure to bullying

The 22-item NAQ-R with 5 response alternatives (1=never, 2=occasionally, 3=monthly, 4=weekly, 5=daily) was used to measure exposure to workplace bullying within the past 6 months. A single self-labeling victimization question was additionally provided to respondents for answering their experience being bullied (without a specific definition of workplace bullying) during the last 6 months in order to calculate the prevalent rate of workplace bullying for each study hospital. With permission from the author [17], the NAQ-R was professionally translated into Chinese by authors in Taiwan using a back-translation technique (English-Chinese-English).
According a study in Belgian employees[18], six different groups of respondents were identified based on their exposure to negative behaviors: Not bullied (35% ), Limited work criticism (28% ), Limited negative encounter (17% ), Sometimes bullied (9% ), Work related bullying (8% ) and Victims of bullying (3% ). Using the study sample, we combined the aforementioned six categories as three ones and calculated prevalent rates for each hospital in following four formats:
a) Using cutting points at > -2 logits according to the threshold step difficulties for the NAQ-R assessment of the previous paper [2].
b) Using cutting points of raw summation scores at >33 according to previous study [18].
c) Dividing study sample into two clusters (bullied and not bullied) using self-labelling method.
d) Separating the bullied in (iii) into two parts at a cutting point of summation score >30, defined in the previous paper [2], to know how many percentages are classified as bullied, but with low scores (i.e., with possible cheating behaviors in response).

Simulation to select viable indices for detecting cheating respondents

We simulated data for analyzing thresholds of the study four indices (i.e., Chi-square test, Z-score, Gini coefficient [19], and Delta coefficient [20] as described in Equations below) used for detecting abnormality of responding time consumed to items.
Where Oi is observed time spent on each item, E is the mean of all time spent averaged on an item, I is the item length a respondent answers, Xi is the observed time spent in second on items, X-bar is the mean of observed time spent on items, and k is the number of item length. For detail information of calculations on Delta and Gini, interested readers are recommended referring to see Multimedia Appendix 1. A simulation study was performed onto 28 scenarios (i.e., four kinds of item length across 5, 10, 20, and 30 quests and data following six uniform distributions with a range of standard deviation from 0.5 to 3.0 for widely dispersing item difficulties, and one normal distribution, (Table 1A & 1B) with a 10-category scale (i.e., seconds spent on items ranging from 1 to 10). Three hundred persons were first extracted from a normal distribution representing their true scores in speed answering items. Accordingly, we could simulate four indices on 28 scenarios to generate Rasch [21,22] simulation responding data [23], and then record their medians and 95% confidence intervals under conditions on different scenarios of item difficulties and item length.
Note: Random seconds were generated by the simulation of Rasch model when samples follow normal distribution and item difficulties are dependent of the study scenarios.

An online NAQ-R assessment APP was designed for use on smart phones

An online routine was designed for participants to report their estimated measures (i.e., in a unit of logit, log odds), the more measure, the higher probability to group into a bullied victim. The item parameters (i.e., overall item difficulties and threshold difficulties) use for constructing an online CAT were extracted from the previous paper [2] and then uploaded to the website. The first CAT item will be randomly selected from the item pool. The next item to be answered is the item with the maximal variance among the remaining items according to the provisional person ability [24,25]. All the responses will be automatically saved in the study website database.

Statistical tools and data analyses

MedCalc 9.5.0.0 for Windows (MedCalc Software, Mariakerke, Belgium) were used to calculate prevalent rates of workplace bullying for each hospital.

Results

Prevalent rates for hospitals

Low prevalent rate in panel A: It can be seen in Table 2 (panel A) that Hospital B has a highest prevalent rate (=15%) of workplace bullying higher than those two counterparts (8%, respectively). Prevalent rates in panel A are apparently far lower than those in panel B and panel C, indicating some possible cheating behaviors in response might be in existence in in this study. That is over-count in the denominator (i.e., eligible sample size).
High prevalent rate in panel C compared to panel B: An incremental quantity of 6% in panel D in comparison to panel C is found. We ascribed the high prevalent rates to the reason of up-self-labelling without a definition of bully before when answering the single question. After removing these 6% from panel C, the prevalent rates are equivalent to those in panel B.
A positively skewed sample: We drew a scatter plot in Figure 1. The study sample is dispersed on two axes (bullied theta on the vertical axis and the Rasch outfit mean square errors of person fit statistics [10] on the horizontal axis). Apparently, person estimates are not following a normal distribution (i.e., a positively skewed one), vital few (e.g., victims of bullying as in nominator) at the top and trivial many (e.g., not bullied and limited work criticism as in denominator) at the bottom. We are convinced to have some cheating respondents (7.5% with outfit MNSQ greater than 2.0) at low scores resulting in low prevalent rates in panel A.
Phenomenon of up-self-labelling as bullied: Fifty-three nurses were self-evaluated as being bullied with low scores below a cutting point at 30 [2], indicating a phenomenon of upself- labelling as bullied inflating the prevalent rates in panel C. The issue is whether we have additional indices to detect those cheating respondents in a survey besides the model’s person fit statistics [10,26] are used in (Figure 1).
The simulation to select viable indices for detecting abnormality: The simulation results in Figure 2 show that (1) Delta coefficient is dependent of item length, the more number of items and the higher Delta value. (2) The index of Z-score is also dependent on the dispersion of item difficulties and the item length. (3) The (1-Gini) coefficient is ideal and acceptable as an index for detecting abnormality when setting criterion at lower than 0.60. (4) The Chi-square can be set at the value greater than 2.0, also some arguments are raised in dependence of item length. In all, we recommend using these two equality indices of (1-Gini) and the Chi-square to detect cheating respondents.

Online CAT assessment

By scanning the QR code (Figure 3, bottom right), the CAT icon appears on the smart phone. The mobile CAT survey procedure was demonstrated item-by-item in action Figure 3. Person fit (i.e., infit and outfit mean square [MNSQ]) statistics showed the respondent behaviors. Person theta is the provisional ability estimated by the CAT module. The MSE in Figure 3 was generated by this formula as below: 1/√ (Σ variance (i)), where i refer to the CAT finished items responded to by a person [27]. In addition, the residual (resi) in Figure 3 was the average of the last 5 change differences between the pre-and-post estimated abilities on each CAT step. CAT will stop if the resi value is less than 0.05. The corr refers to the correlation coefficient between the CAT estimated measures and its step series numbers using the last 5 estimated theta (= person measure) values. The flatter the theta trend, the higher the probability that the person measure is convergent with a final estimation.
After finishing the online CAT NAQ-R assessment, a repot of time spent on each item is shown on the mobile screen Figure 4 along with both suggested equality indices (i.e., 1-Gini <0.60 and Chi-square>2.0), which can be another form of detection utility saved in the website server as an indicator we examine whether the respondent had a cheating behavior in the NAQ-R assessment. Interested readers are recommended to see the multimedia at reference [27].

Discussion

Key findings

The results from this study indicate that some cheating or up-self-labelling behaviors might be in existence in a survey, two equality indices of (1-Gini) and the Chi-square are recommended to users for detecting cheating respondents in practice, and an online CAT NAQ-R is required to combine model person fit with the equality indices jointly together to ensure data purification and survey quality.

What this adds to what was known

The prevalence of bullying was reported at nearly 20% panel in Table 2, similar to the previous published paper at 24% for hospital nurses [2], higher than seen in studies of Japanese nurses (19%) [3]; and ICU nurses in Korea (15.2%) [4], and workers in general services (2%-17%) [1]. The reason for higher prevalent rates of workplace bullying might be attributed to those who self-labelling as being bullied without a definition of the concept beforehand to over-count the perception of a victim bullying [5,9]. If we remove those possible up-self-labelling cases, the prevalent rates will be decreased from panel C to panel B.
On the other hand, if we conduct the data purification process (i.e. discarding those sample with cheating behaviors) before conducting statistical analyses, our findings for prevalent rates can be increased to a higher level (i.e., from panel A to panel B) and consistent with the level in literature: in Japan at 19% [3], ICU nurses in Korea (15.2%) [4], and workers in general services (17%) [1]. Rasch-based CAT is generally different from the traditional pen-and-paper test for which all items are answered while providing little information to use for analyzing the CAT users’ responses. For instance, outfit MNSQ values of  2.0 [26] in Figure 1 can be a threshold when examining whether patient responses are distorted or abnormal, i.e., whether respondents unexpectedly do not fit the model’s requirements and are deemed highly possibly careless, mistaken, cheating, or awkward [28-30] (e.g., the outfit MNSQ of 4.02 is shown in Figure 3 as cheating or awkward behaviors). This is another advantage of IRT over the traditional classic test theory (CTT): it gives more useful information to readers. That is, any significantly aberrant or cheating behavior on CAT will be detected and found by the CAT module algorithm [2,11,31].

What it implies and what should be changed

It can be seen in Figure 1 that many respondents with low bully scores suffer a high outfit MNSQ, indicating a possible cheating behavior might be in existence. Additional other indices, such as (1-Gini) and Chi-square algorisms in line with time spent on items, are required in use for detecting cheating respondents to gain an accurate prevalent rate of workplace bullying. An online CAT based NAQ-R routine can be equipped with Rasch outfit MNSQ, (1-Gini) and Chi-square equality indices in a survey Figure 3. Cut points can be used for respondents to identify the degree of workplace bullying. We provided a way to determine the cut points of person strata for CAT-based NAQ-R assessment using the Rasch threshold step difficulties [2]; Figure 3-5 which is theoretically based on the expected response counts that are different from the traditional CTT using the summation counts to calculate the cutting points. Furthermore, the most straightforward approach in tradition is to compute an overall sum score on the base of the individual items. This sum score may then be applied as a measure of the level of exposure to bullying, which can be further included in correlation analysis, regression analysis, and so on. It is problematical to use the raw score for further statistical analysis instead of using the Rasch interval estimated measures [22].

Strengths of this study

Many studies have reported the advantage of CAT over the traditional pen-and-paper one. That is, traditional questionnaires have a large respondent burden because they require patients to answer questions that do not provide any information for the patient estimation [32]. However, we have not seen any online CAT that can be used for smartphones with audio and multimedia as well as incorporated with a detection functionality using respondent’s consumption time across all items on internet. It is very easy to apply the online CAT to other kinds of health-related assessment if the designer uploads relevant parameters into the database (e.g., definitions about threshold difficulties; the number of questions in the item bank). It is worth noting that item overall (i.e., on average) and step (threshold) difficulties of the questionnaire must be calibrated in advance using Rasch or other item response theory models, and pictures and the corresponding audio files used for the subject or response categories for each question should be wellprepared with a web link that can be shown simultaneously with the item appearing in the animation module of CAT. Further, the parameters corresponding to the exact fields of the database need to be correctly uploaded. As with all forms of web-based technology, advances in mobile health (mHealth) and health communication technology are rapid. Mobile online CAT is promising and worth promoting the patients’ health literacy in future. Interested readers are recommended to see multimedia appendix for the calculation of Delta and Gini coefficients [33].

Limitations and future studies

Our study has some limitations. First, although we believe that all respondents’ bully perception scores do not follow a normal distribution, there is no evidence to support our assumption of cutting points suitable to other different workplaces, which might influence the classification of workplace bullying for the NAQ-R scale. We recommend additional studies to compare and explore the cut point determination using Rasch analysis in future. Second, equality indices are recommended in this study, but not necessary in these two, because there may be other more evidence based indices that can be efficient and effective to detect abnormal pattern of those cheating respondents in a survey. Third, the CAT parameters were based on a previously published paper [2]. All of the person measures were estimated from those released parameters. If any one set (either item or threshold parameters) were different from the real world for nurses in Taiwan, the classification will be problematic in analysis in Table 2. That is, parameters from one hospital will be different from those in other hospitals, and those from other cultures will be different from those with other nations. Additional studies are needed to reexamine whether the psychometric properties of the NAQ-R suitable for other types of workplaces.

Conclusion

Prevalent rates of workplace bullying should be guaranteed against those suspicious respondents’ cheating behaviors. We recommend using two equality indices in a computer online module to ensure and secure the survey quality in future.

Additional Files

Multimedia 1

Online NAQ-R assessment using Rasch computerized adaptive testing.

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Friday, July 26, 2019

Prostate Volume, Size Does Matter. Growth Dynamics of the Acini and the Stroma using a “Prostatocrit” Model

JOJ Urology & Nephrology    Juniper Publishers



Abstract

Background: Analysis of prostatic growth has focused on the whole gland volume. However there are distinct zones which grow at different rates which can be further divided into acini and stroma.
Objective: Measuring the principal sub-zones of the gland and taking into account their intrinsic asymmetry of glandular acina density, one can develop the prostatocrit model, similar to the haematocrit. This generates four new zones which better define the differential growth of the gland. This has implications for benign and malignant glands, response to drugs and need for surgery.
Design, setting, participants: Retrospective data was collected from 409 men undergoing TRUS and biopsy in a district general hospital. Whole gland and zonal volumes were recorded along with IPSS scores. Rates of growth for conventional and prostatocrit volumes were compared using univariate analysis. The relative amount of PSA secretion per zone was estimated using the model. The PSA densities and ratio of zone to whole gland were plotted.
Outcome measurements and statistical analysis: Univariate analysis to measure slopes of rate of growths of zones and relation to PSA. Multivariate analysis was used to find significant predictors of PSA secretion. IPSS scores of whole gland and zones.
Results and limitations: Age (P<0.0001) and the transition zone stromal volume (P=0.0001) were the only significant factors for PSA secretion. None of the conventional volumes were included in the model. Limitations include 1. TRUS estimations are probably inferior to MRI.2. Some negative biopsies will prove to have missed cancer.
Patient summary: This new prostatocrit model is consistent with known gross and microscopic anatomical differences in the gland. It potentially reveals a more logical, intuitive and easily measured account of the zonal and sub-zonal growth patterns.
Keywords: Benign prostatic hyperplasia; PSA; Acini; Stroma

Introduction

The role of prostate volume in diagnosis and aetiology of benign hyperplasia and need for treatment has been fraught with uncertainty and conflicting information. The view that has prevailed was that size was completely unimportant [1]. We propose the converse, that size or volume of the gland and its subdivisions do matter. By noting the asymmetry of acini within the principal zones, peripheral and transitional, we generate four new zones and reveal their differential growth and influence on PSA. We plot the growth of each zone and their relation to PSA. We also document the change in IPSS with whole gland and principal zones.

Size measurement of zones

Previous methods to determine size have used the DRE, transabdominal US, TRUS and MRI. We discuss what we mean by size. There has been an almost universal use to refer to the whole gland volume. The gland is quite complex and composed of several divisions each with varying amounts of secretory acinal cells and fibromuscular non-secretory elements [2]. The peripheral zone stays relatively constant in structure whereas the transition zone varies dramatically with ageing [3].
We can measure the contribution of each element due to the fact that the epithelial components have a secretory product, the PSA. This yields an "acinar density" which we can use to model growth [4]. Conversely we highlight the importance of the transition zone stromal volume which does not secrete PSA.

Zone measurement and acinar asymmetry

The gland can be divided into two distinct zones, the peripheral zone which is composed principally of epithelium and the inner gland which is mainly stroma [2,3]. Using this asymmetry of macroscopic and microscopic differences one can develop a new concept, the "prostatocrit" [4] to model the relative growths of epithelial and stromal components. The peripheral zone will have a higher prostatocrit than the transition zone and this ratio is key to the model. This has proven to be more accurate in prostate cancer diagnosis than traditional methods of PSA densities [4].

Previous studies refer to the entire gland

The growth, proliferation rate of the gland is under the influence of both hormones and ageing. The evidence is conflicting. Regarding Ki67, there was no significant correlation between ageing and proliferation rates in stroma and epithelium. They concluded that a large whole gland volume is not always associated with a high proliferation rate [5]. However, most studies all refer to the global volume of the gland with no discrimination between the subzones. Longitudinal growth rates of the whole gland, not zones, have been assessed [6] using ultrasound. They found an average increase of 1.6%/year. A baseline volume of 29cc showed a general trend to increase with time from 0.3cc/year for younger men and 0.6cc/year for older men. The bigger the baseline volume, the bigger the yearly increase.
Regarding size and symptoms, the Olmsted study [7] described treatment and relation to an enlarged whole gland volume of 30cc. Others have classified BPH as an overall volume of 20g [8]. They did not find a strong correlation (0.22) between volume and symptoms. A weak relation (correlation coefficient 0.185) was found when using a cut-off of 50mls for symptoms and flow rate [9]. Regarding obstruction, it is dependent on three parameters, whole gland volume, maximal flow rate and mean voided volume [10] and this is used to generate a bladder outflow obstruction number.

PSA as a proxy for whole gland volume

The Krimpen study [11] used a similar population of biopsy negative men and found increasing accuracy of PSA for increasing size of gland. They used 30cc as a cut-off for dichotomisation of whole gland volume. This gave as good area under the curve as higher volumes.
Whole gland volume and PSA are significantly correlated (0.54) and increase with age [12]. They found no influence of volume on symptoms. Whole gland volume on its own is not useful to estimate disease severity. Whole gland volume and serum PSA have an age dependent log-linear relation in those without cancer. The relation is stronger with increasing age and there is a greater increase in overall volume per unit of PSA leading to a "dilution" effect in context of the whole gland volume [13].
Nevertheless, 42% of the variance of whole gland volume can be explained by PSA and age [14]. This has implications for pharmacological outcomes when the whole gland volume is a prognostic factor of treatment.

Pharmacological outcomes

Trials such as CombAT [15] have classified glands as being enlarged if over 30cc and concluded that a combination of drugs, Tamsulosin and Dutasteride, are efficacious in treating symptoms. MTOPS [16] examined the effects of Doxazosin to relieve tone and Finasteride to induce epithelial atrophy. The risk of progression increased with increasing baseline PSA and whole gland volume of 40mls. The decrease in volume of 19% in those receiving Finasteride refers to whole gland volume only. The reduction in acute retention and need for surgery was attributed to reduction in overall gland volume. Using the PLESS data it was shown that, by dividing men into differing overall gland volumes, that volume and PSA were predictive of the natural history of symptoms and flow rates [17]. In addition, Finasteride gave a better improvement in bother score than placebo [18] after PSA stratification. PLESS was also used to analyse, by volume and PSA, the risk of acute urinary retention and the need for surgery. The risk was higher in those with high baseline PSA and/or whole gland volume.

MRI measurement

More recently focus has been on zonal volumes using MRI [19]. They used zonal contouring to measure the whole gland and the central and peripheral zones. They found a positive correlation between whole gland and central gland volumes and patient age. No correlation with the peripheral zone. Similarly there was a positive correlation of whole gland and the central gland with PSA and with IPSS. They point out that ellipsoid assumptions in calculating the prostate volume are inaccurate. T2 weighted MRI readily distinguishes between peripheral and central zones. They also document how the peripheral zone is relatively static with ageing. They state that the central gland is the major determinant on BPH and elevation of PSA.
Similar techniques using zonal volumes and adjustment of PSA for whole gland and central gland have improved the diagnostic accuracy and personalised risk of cancer [20]. The level of abnormal PSA is a longstanding problematic issue and leads to over-diagnosis and overtreatment of cancer [21]. The accuracy of early changes in PSA as a predictor of lethal cancer is poor [22].
There is a need to better relate the PSA production to the growth dynamics of the normal and the abnormal gland. We propose that all gland volumes and PSA related phenomena can be better characterised, with better risk stratification, with this new more detailed and intuitive model of the gland.

TRUS measurement

TRUS is quick, simple and safe and not only is useful for volume measurement but also for cancer diagnosis [23]. On the other hand, TRUS has been criticised for being inaccurate [24].
Previous studies all have used the whole gland volume as the entity in question. We propose using the easily measured peripheral zone and the asymmetry in epithelial, acinar, content to generate a prostatocrit (similar to a haematocrit) to better describe prostatic growth.

Methods

This is a retrospective cross-sectional study. We analysed 409 patients who had negative prostate biopsies who were referred for elevated PSA, abnormal DRE or anxiety of cancer 2006-2013. The patient filled out an IPSS questionnaire. One surgeon performed the biopsies using a BK medical Hawk 2102XD1 machine. The whole gland and the zonal volumes were documented. We ascribed the peripheral zone a density of 80% acini (as it has to be richer in glands than the overall prostate). We then subtracted this from the overall gland density to generate the transition zone density which is much more variable due to nodular hyperplasia. See Figure 1, see formula (4), see Table 1 of densities. To ascertain accuracy of imaging, 547 radical prostatectomy specimens with documented gland volumes from histology were documented. We compared the whole gland volume with MRI measurements to estimate if there were any significant difference.
Statistics were performed using medcalc. We used univariate analysis to monitor trends of each zone and subcomponent and related them to IPSS, PSA, growth, densities and ratio with ageing. We then performed multivariate analysis for prediction of PSA.
Bland-Altman plot of MRI v TRUS in estimating volume (Figure 2). There were 319 TRUS volumes documented pre operatively with 34 MRI volumes documented pre operatively. There was no significant difference in accuracy between the two imaging modalities.

Results (Table 2-9Figure 3-8)

Discussion

Previous studies all reference the whole gland volume as the important entity. We use a "prostatocrit model (Figure 1) which generates four new zonal entities. The acinal (epithelial) volume of the peripheral zone, the acinal volume of the transition zone, the stromal volume of the peripheral zone and the stromal volume of the transition zone. In our previous study it was shown that none of the traditional zonal densities (whole gland, transitional or peripheral zone) were included in a model to predict high grade cancer or all grades of cancer [4]. However, the prostatocrit peripheral zone acinal volumes were included and so we extend this concept to benign growth of the gland predicting that the transition zone stromal volume will be the most significant element in PSA secretion. We made the growth measurements using TRUS with no significant difference found when comparing MRI measurements for whole gland volumes (Table 1Figure 2).

Cohort characteristics (Table 2)

The age range is from 40 to 84 years with the first quartile at 58 and the third at 68.5 years. The PSA ranges from 0.47 to 83 (clearly an outlier given where the third quartile is) with first quartile at 4.6 and third quartile at 9.1. The IPSS ranges from 0 to 35 with first quartile at 11 and the third at 15. The whole gland volumes range from 10cc to 220cc. the transition zone ranges from 2cc to 156cc. the peripheral zone ranges from 3cc to 104cc. Thus we see less range in the peripheral zone compared to the transition zone despite a similar mean volume.

Asymmetry in the principal glandular zones (Table 2)

Using the Prostatocrit model, we can estimate the key indice, the proportion of acini in the peripheral zone (0.8x27.7cc=22.2cc). From this we can deduce that the remaining volume is stroma (27.7cc-22.2cc=5.5cc). We estimate the whole acina mass as 0.7x57.6cc=40.3cc. We deduce the transition zone acinal volume by subtracting the peripheral acina volume from the total acina volume (40.3cc-22.2cc=18.1cc).
There is a greater relative amount of stroma in the transition zone. The peripheral zone has less than half the stroma of the transition zone (5.5cc v 11.7cc) and the two zones have similar acini volume (22.2cc v 18.1cc). Here lies the asymmetry.

PSA (Figure 3a & 3b)

The whole gland volumes and PSA are high (right skewed). There is an increase in PSA of 0.23ng/ml/year.
When we compare our PSA values with Oesterlings (Table 3) age groups [25], we see almost twice the level for every age group. Our population appears to be twenty years older. This is a population referred because of elevated PSA.

Symptoms and conventional volumes (Table 4Figure 4a-4d)

There is no significant increase in the IPSS score with ageing (deterioration of 0.025IPSS units/cc) (P=0.56). However, when we look at the deterioration of IPSS with overall gland volume we do see a significant effect of 0.025IPSS units/cc (P=0.006). This is due to a highly significant transition zone affect of 0. 047IPSS units/cc (P=0.0004) compared to a non significant association with the peripheral zone of 0.02IPSS/cc (P=0.355). The peripheral zone, which is mostly acini, is not associated with a deterioration in symptom score. The transition zone which has a greater amount of stroma is associated with a deterioration of symptom score with increasing size. The slope is twice as steep for the transition zone compared to either whole gland or peripheral zone.

Prostatocrit volumes and ageing (Table 5Figure 5a5i)

The whole gland grows at 1.16cc/year mostly due to acini (0.81cc/year). The transition zone grows at a greater rate, x3, than the peripheral zone (0.89cc/year cf 0.27cc/year). However, when one look at the relative acinal and stromal growth patterns, we see the transition zone acini growing x3 that of the peripheral zone acini (0.6cc/year cf 0.21cc/year) with an even more pronounced difference in the stromal components. The transition zone stroma grows at x 6 that of the peripheral zone stroma which is almost negligible (0.29cc/year v 0.05cc/year). This prostatocrit insight confirms what would be predicted from clinical and pathological experience.

Prostatocrit and PSA secretion (Table 6Figure 6a-6f)

PSA secretion is greater in the transition zone acini than the peripheral zone acini (0.134 cf 0.081) despite more acini within the peripheral zone. This is well recognised [26,27] and appears to be due to the paracrine growth factor activity of the stoma on the acini. The TZav (Figure 6d) has a coefficient of 0.286 which explains 53% of PSA secretion.

Prostatocrit and PSA density with ageing (Table 7Figure 7a-7f)

Dividing the PSA into the acinal bulk we get a "true" acinal density. There is a non significant increase in overall density with age whether one considers the entire gland or the acinal bulk itself (P=0.107). Neither does the overall transition zone density increase with time (P=0.425), despite an increase in acini, no doubt due to variable decrements in PSA production. However, when accounting for TZ acinal bulk using the prostatocrit, the PSA density increases significantly (P=0.0001).

Ratio change with ageing (Table 8Figure 8a-8f)

As expected all measurements of relative growth show a consistent and well recognised picture. The rate of peripheral zone, overall, acinal and stromal growth, relative to the whole gland, decreases with time (P<0.0001). The rate of transitional, whole gland, acinal and stromal, increases with time (P<0.0001).

Multivariate analysis and PSA using the prostatocrit (Table 9)

Only age and the stromal component of the transition zone (TZsv) were significant predictors of PSA production. Neither the acini of the transition zone nor the peripheral zone acini/stroma nor whole gland volume were significant. This is consistent with prostatocrit stroma being the chief mediator of BPH and LUTS [26,27].

Conclusion

The prostatocrit model is new and intuitive but supports current theories on the role of the stroma in BPH and lUTS. It has been used to successfully predict the risk of cancer [4] and now we reveal its application to the benign growth of this gland. The transition zone stroma is key to PSA secretion and this was confirmed using the model.
This model is logical and illustrates known attributes and trends in growth of each zone into its acinal and stromal components, and may offer a more intuitive framework to gauge the behaviour of the gland. The decrease in transition zone acinar density and the increase in transition zone stromal/acinal volume are the most likely cause of LUTS.
We would predict stronger relationships for the effects of drugs in trials such as MTOPS, PLESS and COMBAT if this model were adopted. Potentially better stratification of patients i. e., those most likely to respond would be those with large transition zone stromal volumes. We will also be able to compare the different growth dynamics of cancerous glands and we plan to demonstrate this.

Limitations

Many of the negative biopsies will have undetected prostate cancer and finding a cohort without this is problematic. We have not been able to follow up men longitudinally and have had to rely on a cross sectional study. MRI will almost certainly be able to better quantify the zones. Although we have seen no significant difference in MRI and TRUS for whole gland volumes, we do not know that it applies to the zones. The estimation of acini is an approximation based on a standard normal prostate gland in a young man. The amount of acini is not the only factor governing PSA secretion and the relation between epithelium and stroma is difficult to quantify and this is reflected in our low correlation coefficients as well as others [7-9]. This complex relationship lies beyond simple measurement of zonal volumes and acinal asymmetry.

Strengths


The prostatocrit makes logical sense and is based on sound anatomic principles. TRUS can define the zones easily and cheaply and it is readily available although operator dependent. TRUS is a good approximation to the volume even if MRI subsequently outperforms it. Although estimation of acini percentage in the zones is problematic the asymmetry is not.

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