Pitfalls in the accurate measurement of joint space narrowing in semiflexed, anteroposterior radiographic imaging of the knee

Vol. 50, No. 8, August 2004, pp 2508–2515 2004, American College of Rheumatology Pitfalls in the Accurate Measurement of Joint Space Narrowing in Semiflexed, Anteroposterior Radiographic Imaging Steven A. Mazzuca,1 Kenneth D. Brandt,1 Kenneth A. Buckwalter,1 and Michel Lequesne2 Objective. Computerized measurement of changes
the skin over the head of the fibula to permit estimation
in joint space width (JSW) on serial radiographs of the
of the percentage of radiographic magnification (%Mag)
knee in the semiflexed, anteroposterior (SF-AP) view
and correction of JSW measurements. Measurements of
has been used recently as a primary outcome measure in
the minimum interbone distance (IBD) in the medial
clinical trials of disease-modifying osteoarthritis drugs
tibiofemoral compartment and the %Mag were obtained
(DMOADs). In the use of fluoroscopy to achieve repro-
by an automated method (edge detection) and manually.
ducible alignment of the medial tibial plateau and x-ray
Combinations of automated and manual measurements
beam, the SF-AP radiographic protocol affords greater
of the IBD and %Mag in estimates of magnification-
sensitivity in the detection of joint space narrowing
corrected JSW were compared with respect to their
(JSN) than that achieved by conventional radiographic
reproducibility, agreement, and sensitivity to JSN.
positioning techniques. However, the utility of the
Results. With fully automated measurements,
SF-AP view is compromised by the variation in x-ray
variations in x-ray penetration in analog radiographs
penetration in each examination, which may confound
and edge enhancement in digital radiographs resulted
the correction of the automated measurement of JSW
in the computer “seeing” a metal ball whose diameter
for the radiographic magnification inherent in an AP
was artifactually reduced, resulting in an inflated mea-
view of the knee. A recent DMOAD trial using the SF-AP
surement of JSW. Use of manual measurement of the
protocol showed an improbable increase in JSW of
IBD and %Mag largely eliminated these problems and
>0.50 mm (i.e., greater than the measurement error).
reduced, from 16% to 2%, the frequency of knees exhib-
The present report provides an analysis of this problem,
iting an increase in JSW >0.50 mm. In 14 of the 15
and the study aim was to demonstrate that substitution
knees in which a significant increase in JSW was noted
of the automated estimates of JSW with precise manual
with the manual method, this increase in JSW could be
measurements can markedly reduce the problem attrib-
explained by the development of significant lateral
utable to radiographic magnification.
compartment narrowing during the study or poor align-
Methods. SF-AP radiographs were obtained at
ment of the medial plateau.
baseline and at 16 months and 30 months thereafter
Conclusion. Although automated and manual
from subjects enrolled in a 6-center DMOAD trial. For
methods of JSW measurement of the knee in the SF-AP
each examination, a 6.35-mm steel ball was affixed to
view possess comparable intrareader reproducibility,
the manual method is less susceptible to technical

Supported by grants from the National Institute of Arthritis factors that affect the correction of raw JSW estimates
and Musculoskeletal and Skin Diseases (P60-AR-20582, R01-AR- for radiographic magnification. Until we can identify
practical, effective solutions to these technical prob-
Steven A. Mazzuca, PhD, Kenneth D. Brandt, MD, Kenneth A. Buckwalter, MD: Indiana University, Indianapolis; 2Michel Le- lems, use of any radiographic protocol involving AP
imaging of the knee in a DMOAD trial must be viewed
Address correspondence and reprint requests to Steven A.
with caution.
Mazzuca, PhD, Indiana University School of Medicine, Department ofMedicine, Rheumatology Division, Long Hospital Room 545, 1110West Michigan Street, Indianapolis, IN 46202-5100. E-mail: The development of protocols for standardized knee radiography has been regarded as an important Submitted for publication January 26, 2004; accepted in advance that, when combined with automated measure- MEASUREMENT OF JOINT SPACE WIDTH IN THE OA KNEE flate estimates of the true value of JSW by as much as35% (3).
We have previously presented data indicating that longitudinal variations in x-ray penetration alter byas much as 20% (7) the projected diameter of a sphericalmarker, which is used as a basis for correcting auto-mated measurements of JSW in the SF-AP view forradiographic magnification. Changes in JSW (both pos-itive and negative) due to x-ray penetration–relatedvariations in the size of the marker, rather than todisease progression, confound the detection of jointspace narrowing (JSN) in the SF-AP view and diminishthe confidence (i.e., statistical power) with which aclinical DMOAD trial of reasonable size and durationcan be expected to detect a true structure-modifyingeffect. Moreover, many clinical radiology departmentshave converted their methods from conventional analogto digital radiographic imaging. The effects of this trendon our ability to correct automated measurements ofJSW from the SF-AP view for radiographic magnifica-tion are unknown.
placebo-controlled clinical trial (RCT) of a DMOAD in Figure 1. Fluoroscopically assisted positioning of the knee for the
which structure modification was evaluated in serial semiflexed, anteroposterior radiographic view requires flexion of the SF-AP radiographs. In the course of this trial, we knee to achieve parallel alignment of the medial tibial plateau and encountered unanticipated problems with the correction central x-ray beam, as indicated by superimposition Ϯ1 mm of the of automated estimates of JSW for magnification, both anterior and posterior margins of the medial tibial plateau. The degree in the analog and in the digital radiographs. These of flexion needed to achieve parallel alignment in most subjects (7–10°)draws the knee away from the x-ray cassette and results in magnifica- problems were highlighted by an inordinately large tion of all features of the joint in the radiograph. To adjust for this percentage of serial pairs of SF-AP radiographs (16%) effect, a magnification marker (a small metal sphere of known in which automated measurements of JSW in analog and diameter affixed to the skin over the head of the fibula) is used to digital images suggested a paradoxical thickening of the estimate the degree of magnification reflected in a radiograph, so that articular cartilage beyond the limits of measurement quantitative measurements can be proportionate.
In the present report, we describe our experience ment of joint space width (JSW) in digitized radio- with the correction of estimates of JSW for radiographic graphs, permits more reproducible estimates of articular magnification, and we examine the extent to which cartilage thickness in knee osteoarthritis (OA) than is substitution of automated estimates of JSW in serial possible with conventional radiographic methods (1).
SF-AP views with precise manual measurements may The semiflexed, anteroposterior (SF-AP) view of the increase the power of a DMOAD trial to detect a knee (2,3) has been used in several clinical trials of difference between the active treatment group and pla- purported disease-modifying OA drugs (DMOADs; i.e., cebo group with respect to the rate of JSN.
doxycycline, risedronate). This protocol uses fluoroscopyto guide positioning (flexion and rotation) of the knee PATIENTS AND METHODS
and is superior to nonfluoroscopic standardization pro-tocols (4,5) in achieving reliable parallel alignment of Subjects for this trial (n ϭ 431) were recruited from 6 the medial tibial plateau with the central x-ray beam in clinical centers for a placebo-controlled RCT of a DMOAD.
serial examinations (6). However, with the SF-AP view, All subjects had unilateral knee OA by the Kellgren andLawrence criteria (OA severity grades 2 or 3 for the index knee in which the knee is not in contact with the x-ray cassette and grades 0 or 1 for the contralateral knee, in a standing AP (Figure 1), quantitative estimates of JSW require cor- view) (8). SF-AP knee radiographs were obtained at baseline rection for radiographic magnification, which may in- and at 16 months and 30 months thereafter (Figure 1). As directed by the protocol for the SF-AP view (2), a magnifica- Intrarater reproducibility of automated and manual mea- tion marker (6.35-mm steel ball encased in methyl methacry- surements of joint space narrowing in the knees of patients with late) was affixed to the skin over the head of the fibula for each examination. The minimum interbone distance (IBD) in the medial tibiofemoral compartment and the degree of radio- graphic magnification (%Mag) were measured by 2 methods, by investigators who were blinded to the treatment group.
First, automated measurements from digitized images were obtained by a research associate (computer operator) in the laboratory of 1 of the investigators (KAB), using xJSWsoftware (9). This software uses a semiautomated (operator- * IBD ϭ interbone distance; %Mag ϭ percentage of radiographic assisted) edge-detection subroutine to define the margins of magnification; JSW ϭ joint space width.
the femur and the medial tibial plateau in the medial compart- † Corrected for radiographic magnification.
ment, and then fits circles between the bony margins (edges) toidentify the circle with the smallest diameter (i.e., the mini-mum IBD, expressed in pixels). Another semiautomated sub- JSW in the SF-AP view were compared: fully automated, fully routine estimates the %Mag reflected in the size of the circular manual, and hybrid (i.e., automated estimate of IBD corrected projection of the magnification marker. After the operator manually for magnification). These approaches were evaluated draws a square region of interest (ROI) of known dimensions (e.g., 80 ϫ 80 pixels) around the image of the marker, the First, we compared the automated, manual, and hybrid software counts the number of unexposed pixels within the approaches with respect to the frequency with which the ROI (i.e., pixels that appear white against the black back- 30-month estimate of JSW was Ն0.50 mm as compared with ground). This count is expressed as a percentage of all pixels the baseline value. The value of 0.50 mm represents the upper within the square. Based on the assumption that this percent- limit of measurement error (the 95% confidence interval) for age represents the area of the circle relative to that of the ROI, JSW estimates in repeated SF-AP radiographs obtained over the diameter of the circle (expressed in pixels) is determined an interval of 7–10 days (11). All knee radiographs obtained in arithmetically. Given the known diameter of the marker (6.35 the trial (both knees of subjects in both treatment groups) were mm), the %Mag for each radiograph is expressed as the ratio of the 2 diameters (in pixels/mm). The minimum IBD is then Second, based on data from the placebo group of the divided by the corresponding value of %Mag, to yield a present RCT, we estimated sample size requirements for a magnification-corrected estimate of JSW.
hypothetical 30-month DMOAD trial designed to detect a The manual measurements of minimum IBD and 30% decrease in the rate of JSN in the active treatment group, %Mag were then obtained directly from the radiographs, in in comparison with the placebo group, with 80% statistical accordance with the method of Lequesne (10). Manual mea- power and ␣ ϭ 0.05. The mean and SD values of the 30-month surements were performed by an investigator (SAM) who was JSN in the placebo group derived from automated, hybrid, and blinded to the results of the automated measurements. The manual approaches were the bases for alternative sample-size minimum IBD and the diameter of the projected marker were gauged with a screw-adjustable divider and transferred to ablank sheet of paper as pin pricks. A magnifying lens fittedwith a 1-cm graticule (Ϯ0.2 mm) was then used to measure the distance between each pair of pin pricks. The manual mea-surement of IDB was then adjusted proportionately, based on The intrarater reproducibility of measurements the ratio of the measured diameter of the marker to the known derived from automated and manual methods is shown diameter (%Mag), providing a magnification-corrected esti- in Table 1. The intraclass correlation coefficients (ICCs) for the repeated automated measurements of the IBD For the purpose of establishing intrarater reproducibil- ity, a second set of automated measurements of the IBD and and %Mag were 0.993 and 0.968, respectively. When %Mag were obtained in a random sample of 30 digitized combined to produce a magnification-corrected esti- images, with the operator blinded to the results of the first set mate of JSW, the result also possessed remarkable of analyses. Similarly, 2 investigators (ML and SAM) each intrarater reproducibility (ICC 0.991). For the repeated generated 2 sets of manual measurements of the IBD and manual measurements conducted by each of 2 raters, the %Mag from a separate random sample of 30 radiographs, witheach rater blinded to his own initial measurements as well as to intrarater reproducibility was comparable with that seen those of the other rater. Automated and manual methods of in automated measurements, with ICCs of 0.973 and measurement were then compared with respect to reproduc- 0.980 for IBD, 0.989 and 0.998 for %Mag, and 0.986 and ibility and agreement (Pearson correlation) of the estimates of 0.996 for JSW. Moreover, the interrater reproducibility IBD, %Mag, and magnification-corrected JSW.
for manual measurements of the IBD was only slightly To evaluate the discrete contributions of the measure- ments of IBD and %Mag to the sensitivity with which serial smaller (ICC 0.953) than the corresponding estimates of estimates of magnification-corrected JSW reflect the thinning intrarater reproducibility (Table 1). In contrast, the of articular cartilage (i.e., JSN), 3 approaches to estimating correlation between manual measurements of the diam- MEASUREMENT OF JOINT SPACE WIDTH IN THE OA KNEE Pearson correlations between automated and manual measurements among the clinical centers eter of the ball (the %Mag) by the 2 raters was much of the joint space (from 41% to 16%) occurred in the smaller (ICC 0.785) than that for the measurements of clinical center with the highest percentage of such errors the IBD. However, given that the SF-AP radiographic in fully automated data. Notably, digital radiographic technique results in radiographic magnification of the images, rather than analog images, comprised a far knee within a relatively narrow range (10–35%) (3), the greater proportion of the SF-AP radiographs from this lesser level of agreement with regard to the degree to center than from the other 5 centers. Furthermore, a which the estimates of IBD required correction for temporal trend was observed in the digital radiographs magnification did not affect the interrater reproducibil- from this center; in contrast to the radiographs acquired ity of estimates of JSW (ICC 0.956).
at baseline, the digital images acquired at 16 months and Correlations between the automated and manual at 30 months were processed with edge enhancement, measurements of the IBD and %Mag in all radiographs which is an adjustment of the digital image that high- from the trial are presented in Table 2. In radiographs lights bony margins and the perimeter of the magnifica- from each of the 6 clinical centers, the correlation tion marker but decreases the intensity of the interior of between automated and manual measurements of the IBD was very strong (0.88–0.93; P Ͻ 0.0000 for all).
In the fully manual measurements of both the However, the %Mag estimates by the 2 methods were IBD and the %Mag, the frequency with which JSW only moderately correlated (0.40–0.47) in 5 of the 6 values increased beyond the limits of measurement error was reduced to Յ5% in each of the clinical centers, and The percentage of index and contralateral knees to only 2% overall (Table 3). Notably, of the 15 knees in in which the automated measurements over 30 months which manual measurements indicated an increase in indicated an increase in medial JSW beyond the margin JSW Ն0.50 mm, the results in 5 were found to have been of measurement error (i.e., Ն0.50 mm) (11) varied from due to progression of JSN in the lateral compartment 7% to 41% across the 6 clinical centers, and this increase that could not have been anticipated at baseline, and the was seen in 16% of knee radiographs overall (Table 3).
results in 9 were attributable to longitudinal changes in Substitution of the automated estimate with the manual knee flexion or rotation that occurred despite the posi- estimate of %Mag (i.e., the hybrid approach) reduced tioning standards of the SF-AP protocol.
only moderately the frequency of this type of measure- The effect of measurement-related error varia- ment error in estimates of JSN (to 6–23% across the 6 tion in JSN by these 3 approaches on the sample-size clinical centers and 10% overall). The greatest decrease requirements for a hypothetical DMOAD trial can be in the frequency of knees showing significant widening extrapolated from data from the placebo group of the Changes in magnification-corrected joint space width (JSW) in the index and contralateral knees, by method of measurement, in a 30-month, randomized clinical trial of doxycycline versus placebo in knee osteoarthritis detected would decrease to 424 subjects per treatmentgroup.
Clinical trials of DMOADs, hindered until re- cently by the absence of reliable radiographic methodsby which to document structure modification, have beenfacilitated greatly by the development of protocols forstandardizing the position of the knee in serial radio-graphic examinations (1). The SF-AP view was the firstsuch protocol to be described (2). The primary advan-tage of the SF-AP view, compared with conventional Figure 2. Radiographic images of the magnification marker, a
radiographic methods, was the reproducibility with 6.35-mm steel ball encased in methyl methacrylate, used to correct which the knee could be positioned and repositioned measurements of joint space width (JSW) for radiographic magnifica- under fluoroscopy to achieve parallel alignment of the tion in the semiflexed, anteroposterior view (2). Upper panels, Re-peated analog images of the stationary marker taken at 70 kVp with a medial tibial plateau and central x-ray beam (superim- fixed focal distance, but with varying exposures (in milliampere- position Ϯ1 mm of the anterior and posterior margins of seconds). Increasing x-ray penetration burns away the margin of the marker, resulting in underestimation of the degree of radiographic In a DMOAD trial, the benefit of reliable radio- magnification and corresponding overestimation of JSW. A and B,
anatomic positioning of the knee is remarkable precision Digital radiographic images of the marker. The image shown in B was
processed with edge enhancement, which brightened the perimeter but
(i.e., reproducibility in repeated examinations) of esti- dimmed the interior of the projection. Edge enhancement does not mates of the minimum JSW in the SF-AP view after the affect the accuracy of manual measurements of the diameter of the measurement of the minimum IBD is corrected for projection. However, it may result in underestimation of the degree of radiographic magnification (3). In theory, increased radiographic magnification if digital image analysis relies upon the precision in serial measurements of JSW should permit number of unexposed (white) pixels within the perimeter to estimatemagnification.
increased sensitivity to JSN; however, longitudinal stud-ies of the radiographic progression of JSN in knee OAusing highly standardized radiographic methods have yet present RCT. In the fully automated, serial measure- to be reported in the literature (1). The choice of ments of JSW, the mean Ϯ SD JSN over 30 months was automated measurements of JSW at the outset of this 0.30 Ϯ 0.92 mm (Table 3). Based on these data, if a trial was predicated on the fact that the original demon- hypothetical DMOAD trial were designed to have 80% stration of the reproducibility of the SF-AP view was power to detect, with a P value Ͻ0.05, a rate of JSN in based on data derived from digital image analysis of the active treatment group that was 30% slower than JSW (3). However, the conclusions of that study and that in the placebo group, then 1,642 subjects per those of subsequent reports have been inconsistent with treatment group would be required. If automated esti- respect to whether semiautomated measurement soft- mates of the %Mag were replaced with manual mea- ware is superior to manual methods with respect to surements of the diameter of the magnification marker, reproducibility of JSW estimates and sensitivity to JSN neither the hybrid measurements of the 30-month JSN in the placebo group (mean Ϯ SD 0.35 Ϯ 0.99 mm) nor The data in the present study came from one of the sample-size requirements (1,397 subjects/group) for the first clinical DMOAD trials to use the SF-AP view.
the hypothetical DMOAD trial would change apprecia- This trial was designed to have Ն80% power to detect a bly. However, because the fully manual estimates of JSN 30% decrease in the rate of JSN in the active treatment were relatively free of instances of inexplicable widening group, relative to the placebo group, provided that loss of the medial joint space, manual estimates of JSN to followup was less than 15% and that the mean and SD yielded a larger mean value and smaller SD (mean Ϯ SD JSN values (a composite of biologic variability and 0.45 Ϯ 0.70 mm) than did the automated or hybrid measurement error) in the placebo group accrued in approaches (Table 3). Accordingly, with fully manual roughly equal proportions over 30 months, as suggested measurements of JSN, the sample size needed to afford by the literature (14,15). At the completion of the trial, 80% confidence that a true 30% DMOAD effect will be the former condition regarding minimal loss to followup MEASUREMENT OF JOINT SPACE WIDTH IN THE OA KNEE was achieved (16). However, with automated measure- moot when, during the course of our clinical trial, the ments, the SD value for JSN in the placebo group at 30 radiology departments in 5 of our 6 clinical centers months was 3-fold larger than the mean JSN value converted from analog to digital radiography.
(Table 3), and the power to detect a true DMOAD The advent of digital radiography posed 2 addi- effect was only 17%. In contrast, with fully manual tional problems for measurement of JSN in this trial.
measurements, the increase in mean JSN and concur- First, in 24% of subjects, JSW was measured in an rent decrease in between-subject variability of JSN in analog radiograph at baseline and in a digital radiograph the placebo group restored much of the intended power in 1 or both followup examinations. In the remainder of of the present study (i.e., from 17% to 53%). It should subjects, all 3 radiographs were either analog (60%) or be recognized that suboptimal power does not preclude digital (16%). Second, within the subset of digital radio- detection of a significant DMOAD effect (17), although graphs, unanticipated variations were noted with respect it does increase the risk of failing to detect a true to whether the printed images were processed with or DMOAD effect when one exists (Type II error).
without edge enhancement. As noted above, edge en- We became aware of the potential for excessive hancement of the digital image of the magnification error variation in JSN estimates when automated JSW marker alters its appearance, decreasing the intensity of measurements from interim (16-month) analog radio- the interior of the circular projection (Figure 2). Be- graphs of many of the early enrollees in the trial cause the subroutine of the measurement software indicated frequent increases in JSW beyond the limits of counts only unexposed (white) pixels within the sur- measurement error (Ն0.50 mm). Visual inspection of rounding square ROI as representing the magnification these radiographs rarely confirmed an appreciable in- marker, dimmed interior pixels are not counted, result- crease in joint space (due, for example, to a longitudinal ing in an underestimation of the %Mag and overestima- change in alignment of the medial tibial plateau or to tion of the JSW—a result similar to that seen in over- progression of lateral JSN). In almost all cases, the penetrated analog radiographs. This problem occurred increase in JSW obtained with semiautomated measure- almost exclusively in digital radiographs from a single ment software was not observed in manual measure- clinical center, and coincided with the turnover of radi- ments of the IBD and %Mag. The evaluation of serial ology technologists who, in the absence of specific radiographs led to the observation that the worst cases instructions to the contrary, used or did not use edge of a false increase in JSW occurred in pairs of images in enhancement according to their individual professional which the followup radiograph was notably darker than the baseline member of the pair. This prompted an In general clinical practice, a moderate degree of investigation into whether uncontrolled, longitudinal irreversible edge enhancement is applied routinely to variations in x-ray penetration compromised the capac- the raw digital image prior to reproduction on film or ity of the magnification-correction subroutine of the electronic display. Unfortunately, many image process- measurement software to estimate the %Mag. We found ing techniques are nonlinear and the processing algo- that overpenetration irretrievably “burned away” the rithms are proprietary, making it virtually impossible to margin of the radiographic image of the marker, causing reverse the processing in order to make measurements a spurious reduction in size as measured by the com- from the original “raw” untransformed image. Although puter software, and resulting in underestimation of the it is now possible to save digital copies of the original %Mag and corresponding overestimation of the JSW untransformed image data, this capability did not exist at (Figure 2); indeed, variations in exposure altered the the beginning of our RCT, when analog radiographs automated estimate of %Mag by as much as 20% (7).
were routine. In addition, to maintain consistency of We also showed that adjustment of the %Mag for study procedures, all images analyzed in this RCT, the optical density of the analog radiograph in the black regardless of acquisition method (e.g., analog or digital), area surrounding the marker (a surrogate for x-ray were digitized from filmed images prior to determina- penetration) could counteract this confounder to a significant degree (7). Other investigators also have Although the many sources of variation in recognized this problem in analog radiographs and magnification-related error in measurements of JSW developed a remedy based on adjustment of the sensi- may have been remedied to an acceptable degree by use tivity of the film digitizer (Beary J: personal communi- of specific approaches (e.g., manual measurement of the cation). However, solutions to the limited problem of %Mag in edge-enhanced digital radiographs, adjust- magnification correction in analog radiographs became ment of the %Mag in analog radiographs for optical density), it was axiomatic that all measurements of JSW the knee have been described (4,5,18). However, only in this RCT be obtained by a single, reproducible the Lyon schuss protocol (18) uses fluoroscopy to method. Accordingly, we obtained a parallel set of achieve parallel radioanatomic alignment of the medial manual measurements of JSW carried out in accordance tibial plateau and central x-ray beam, with a frequency in with the method of Lequesne (10), and determined that serial examinations comparable with that seen with the automated and manual measurements of JSW in SF-AP SF-AP view. Parallel radioanatomic alignment of the radiographic views possess comparably high intra- and medial tibial plateau is the only element of positioning interrater reproducibility (Table 1). Whereas the 2 that is consistently related to sensitivity in detection of methods produced highly correlated measurements of JSN in knee OA (15,19). For this reason, the Lyon the minimum IBD, estimates of the %Mag by the 2 schuss view has been demonstrated to be more sensitive methods were only moderately correlated. Magnifica- to JSN than the conventional standing AP view on tion correction of the automated measurement of IBD with manual estimates of the %Mag (the hybrid ap-proach) yielded only a small improvement in the overallsensitivity of serial JSW measurements to JSN, com- REFERENCES
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Pharmaceutical analysis and Quality control Ph-343 Submitted to: Submitted by: Date of submission: 20 – 02 - 07 APPLICATIONS OF HPLC 1.The wide verity of packing materials allows the separation ofmost chemical species. Chemical Separations can be accomplished using HPLC by utilizing the fact that certain compounds have differentmigration rates given a particular co

Holyrood-house 20th january 1603

Extracts from the records of the Privy Council of Scotland Sederunt- Chancellor ; Mar; Uchiltrie; Elphingstoun; Fyvie; Neubottle; Spynie; Treasurer; Halirudhous; Tracquir; Conservator; Elimosinar. Inasmuch as, "upoun occasioun of the rebellioun and dissobedyence professit and avowit within the bounds of Angus be a nowmer of undeutifull and disloyall subjectis," who seem to be "

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