Osteoarthritis and Cartilage xxx (xxxx) xxx–xxx

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10 Clinical Trial
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12 30 years with the Knee injury and Osteoarthritis Outcome Score (KOOS)
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14 Ewa M. Roos 1
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Center for Muscle and Joint Health, Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
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19 a r t i c l e i n f o s u m m a r y
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Article history: This narrative review describes the development and use of patient-reported outcomes over 30 years, fo­
21 Received 9 August 2023 cusing on the Knee Injury and Osteoarthritis Outcome Score (KOOS). KOOS is a five-subscale patient-re­
22 Accepted 9 October 2023 ported instrument intended for use from the time of knee injury to the development of OA. Numerous
23 studies have confirmed that the psychometric properties of the KOOS and its short-form KOOS-12 are
24 Keywords: acceptable. More recent research has focused on the use and interpretation of KOOS scores in clinical trials
25 Patient-reported outcome measure using thresholds, such as minimal important differences, patient-acceptable symptom states, and treatment
Knee injury and Osteoarthritis Outcome Score
26 failure. As an indication of KOOS’s popularity, the total 3854 PubMed results for KOOS have increased
Interpretation thresholds
27 exponentially since the first KOOS paper was published 25 years ago and now seem to have plateaued at
Minimal important change
28 Patient-acceptable symptom state around 650 annually. The selected articles are not based on a systematic search, but on the author’s own
29 Treatment failure publications, reading, and literature search that grew organically from that.
© 2023 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.
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35 Evaluation of knee injury and Osteoarthritis (OA) thirty years ago Knee Injury and Osteoarthritis Outcome Score (KOOS) 66
36 background and development 67
37 In the mid-nineties, OA was largely evaluated as a cartilage dis­ 68
ease, with few measures of illness (e.g., symptoms) available. At the Department of Orthopedics at Lund University, where I 69
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Western Ontario and McMaster Universities Osteoarthritis Index participated in data collection from the early nineties and conducted 70
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(WOMAC), published in 1988,1 made it possible to evaluate in a re­ my PhD from 1995 to 1999, we studied soccer players and other 71
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liable and valid way the experience of older adults with OA in terms patients treated for knee injury as a model of OA development, 72
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of pain during activities and reduction in activities of daily living. mostly using imaging and biomarkers as outcomes. 73
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At the same time, in knee injury research, the gold standard for My PhD supervisor Professor Stefan Lohmander, former Editor- 74
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the treating surgeon was to fill out an insufficiently developed and in-Chief of Osteoarthritis and Cartilage, and an orthopedic surgeon 75
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validated knee score to evaluate the patient’s perspective and arrive with an impressive research background in cartilage biochemistry 76
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at an aggregated score that was arbitrarily categorized as poor, fair, and biomarkers recognized the need for complementary outcome 77
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good, or excellent. Such practice is associated with interviewer bias, measures to evaluate the patient experience in our knee injury co­ 78
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and studies have shown that treating surgeons always rate the horts at high risk of developing OA, suggesting that it would become 79
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outcome as better than the patient, with increasing discrepancy the topic of my PhD. At the time, no patient reported outcome 80
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with worse patient-reported outcome.2 Questionnaires informally measures (PROMs) existed for younger or more physically active 81
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put together by surgeons risk not taking aspects considered most individuals with knee OA, and no existing PROMs could be used from 82
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important by patients into account, and arbitrarily assigned points to the time of knee injury to severe OA. We, therefore, set out to de­ 83
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questionnaire items may weigh domains of the total score in a way velop a PROM for this purpose, including content related to WHOs 84
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not most relevant to patients. Categorizing the score using arbitrarily classification categories of impairment, disability, and handicap3 for 85
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decided cutoffs may flatten the result and confuse the interpretation young adults with knee injury, middle-aged with emerging OA, and 86
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of the illness perspective in knee injury evaluation. older adults with severe OA. While my main supervisor had, and still 87
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has, an impeccable researcher’s mind, he had at the time little 88
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knowledge and no background in the development of patient-re­ 89
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ported outcome measures. This provided me with an opportunity for 90
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international collaboration. 91
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E-mail address: eroos@health.sdu.dk.
Work with KOOS started during a pre-doctoral fellowship in 92
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ORCID: 0000-0001-5425-2199 1994–1995 in Burlington, Vermont, USA. With collaborators from 93
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https://doi.org/10.1016/j.joca.2023.10.002
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1063-4584/© 2023 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.
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Please cite this article as: E.M. Roos, 30 years with the Knee injury and Osteoarthritis Outcome Score (KOOS), Osteoarthritis and Cartilage,
https://doi.org/10.1016/j.joca.2023.10.002i
 2 E.M. Roos / Osteoarthritis and Cartilage xxx (xxxx) xxx–xxx

1 from the audience, more so in the orthopedic environment than in the 66

2 field of rheumatology where some giants in the field had paved the road 67
3 Arabic for Egypt with the introduction of PROMs such as Health Assessment 68
4 Arabic for Saudi Arabia Questionnaire and Arthritis Impact Measurement Scale already in the 69
5 Bengali for India early eighties.4 My first PROM papers concerned the development and 70
Cantonese for Hong Kong
6 use of KOOS in young athletes with major knee injury and consequently, 71
Chinese for Singapore
7 Croatian for Croatia I submitted my papers to journals in orthopedics and sports medicine. 72
8 Czech for Czech Republic Examples of editor and reviewer comments serve to illustrate the 73
9 Danish for Denmark skepticism felt by many towards research suggesting that the patient is 74
Dutch for the Netherlands
10 an expert on their own symptoms: 75
English for USA
11 English for Singapore 76
“Your paper stimulated considerable interest and discussion. The use
12 Estonian for Estonia 77
of self administered questionnaire was welcomed, cautiously, but it
13 Farsi (Persian) for Iran 78
Filipino for the Philippines was felt that in the knee the number of variables which might in­
14 79
Finnish for Finland fluence outcome was such that it was difficult to assess patients after
15 French for Canada
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arthroscopy by this method” (part of rejection letter from the
16 French for France 81
Editor of a major orthopedic journal, July 14, 1998).
17 Georgian for Georgia 82
18 German for Austria “I realize that the Lysholm score was completed by the patients 83
German for Germany
19 without the help of an observer. This may have made an impact on 84
Greek for Greece
20 Gujarati for India the scores, making them lower than they actually are in this group. 85
21 Hindi for India Why not omit the whole paragraph on this score?” (reviewer 86
22 Hungarian for Hungary comment on PROM-paper rejected for publication in a major 87
Icelandic for Iceland
23 sports medicine journal, November 10, 1998). 88
Indonesian for Indonesia
24 Italian for Italy 89
Thirty years later, the culture has changed dramatically. There is
25 Japanese for Japan 90
today a consensus that illness is the primary perspective in clinical
26 Kannada for India 91
Korean for Korea research, that the patient is an expert on their own symptoms, and
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Latvian for Latvia validated patient-reported outcome measures are required by the
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Lithuanian for Lithuania FDA in clinical trials.5 Value-based healthcare, where the value is
29 Malay for Malaysia 94
derived from measuring health outcomes, is gaining traction as a
30 Malayalam for India 95
Marathi for India healthcare delivery model. Disease measures, such as imaging or
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Norwegian for Norway knee laxity, are often considered proxy outcomes, signifying a
32 Persian for Iran
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complete turnaround of how the different aspects of OA and knee
33 Polish for Poland 98
injury are valued and evaluated compared to 30 years ago.
34 Portuguese for Brazil 99
Portuguese for Portugal Today, the role of PROMs is accepted by most, but some are still
35 100
Romanian for Romania skeptical, and perhaps to an extent, rightly. Patient-reported outcomes
36 101
Russian for Russia are influenced by mood, expectations, and other internal and external
37 Slovak for Slovakia 102
factors not directly related to the condition or treatment itself. This can
38 Slovenian for Slovenia 103
Spanish for Peru
be frustrating for the clinician who feels that the treatment was suc­
39 104
Spanish for Spain cessful when evaluated by other means such as imaging or clinical tests
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Spanish for the USA in a patient who self-reports little improvement. In particular, the per­
41 Swedish for Sweden 106
ception of pain is susceptible to placebo or contextual factors, and stu­
42 Tamil for India 107
dies have shown that, on average, 75% of the pain reduction seen in knee
43 Tamil for Singapore 108
Telugu for India OA trials is attributable to contextual effects.6 One way of improving
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Thai for Thailand illness evaluation is to use complementary measures, for example, apply
45 Turkish for Turkey 110
both a patient-reported measure of function and functional tests such as
46 Ukrainian for Ukraine 111
a walking test or one leg hop test.7,8 This broadens the evaluation of the
47 Urdu for India 112
Urdu for Pakistan aspect ‘function’ as patient-report and functional tests measure related
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Vietnamese for Vietnam but distinctly different aspects of function. If both patient-reported and
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objectively measured function change in the same direction, this finding
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may increase the trust that a ‘true’ change in function occurred. The
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Table I evaluation of pain remains a challenge, and collecting PROMs at multiple
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time points has been suggested as a means of reducing variability.9
53 Languages/countries with available KOOS versions (updated July 118
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17, 2023).
55 KOOS popularity 120
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57 two countries, KOOS was simultaneously developed in two lan­ Using the search term “KOOS[TIAB] OR "Knee Injury and 122
58 guages: US English and Swedish. 30 years later, KOOS is available in Osteoarthritis Outcome Score"[TIAB]” 3854 results were identified in 123
59 more than 50 language versions, Table I. PubMed (search date October 4, 2023). The number of results has 124
60 increased exponentially since the first KOOS paper was published in 125
61 Acceptability of PROM use has changed dramatically over 30 1998, and over the last two years (2021–2022) seems to have pla­ 126
62 years teaued at around 650 results annually (Fig. 1). In support of KOOS’ 127
63 frequent use, the two initial validation papers of the simultaneously 128
64 In the nineties when I worked on developing and validating KOOS, developed English10 and Swedish11 versions of KOOS have been cited 129
65 the topic of my academic presentations was often met with skepticism 2417 and 451 times, respectively (Web of Science May 29, 2023). 130
 E.M. Roos / Osteoarthritis and Cartilage xxx (xxxx) xxx–xxx 3

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Fig. 1 86
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Number of publications including ‘KOOS’ in PubMed from 1998 to 2022.
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25 Of the total 3854 results, 471 results were categorized as we comprehensively search for papers reporting on psychometric 90
26 ‘Randomized Controlled Trial’, the first publication appearing in properties of the KOOS and synthesize the data from the available 37 91
27 2002. Surgical, pharmacological, and rehabilitation interventions papers, using meta-analysis when possible, we also evaluated the 92
28 have been evaluated with the KOOS in younger, middle-aged, and methodological quality of these papers using the COnsensus-based 93
29 older patients with knee injury, OA, or the combination thereof. Standards for the selection of health Measurement INstruments 94
30 250 results were categorized as ‘Meta-Analysis’, ‘Review’ or checklist (https://www.cosmin.nl/). We found ‘adequate content 95
31 ‘Systematic Review’. The first systematic review and meta-analysis validity, internal consistency, test-retest reliability, construct validity 96
32 including KOOS appeared in 2010. A systematic review and meta- and responsiveness for age- and condition-relevant subscales’.12 97
33 analysis from 2016 identified 37 studies establishing KOOS psycho­ We also found structural validity, cross-cultural validity, and 98
34 metric properties.12 measurement error to require further evaluation. Based on the re­ 99
35 sults of our study, we advise future users to a priori decide in what 100
36 KOOS psychometric properties order to test the KOOS subscales for older adults with OA and 101
37 younger adults with knee injury, respectively, when applying hier­ 102
38 A first of its kind paper on psychometric properties of the KOOS archical testing in clinical trials. The suggested subscale orders are 103
39 was published in Osteoarthritis and Cartilage in 2016.12 Not only did given in Table II. 104
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43 Primary and secondary outcomes Hierarchical testing of outcomes 108
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Young adults with knee injury16 Middle-aged adults with knee injury45 Older adults with knee OA46 Young adults with knee injury10 Older adults with OA10
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Primary: Primary: Primary: 1. Sport/Rec 1. Pain
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KOOS4 KOOS4 KOOS4 2. QOL 2. ADL
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(Pain,Symptoms, Sport/Rec, QOL) (Pain,Symptoms, Sport/Rec, QOL) (Pain,Symptoms, ADL, QOL)
48 Secondary: Secondary: Secondary: Pain 3. QOL 113
49 Pain Pain Pain Symptoms Sport/Rec 114
50 Symptoms Symptoms Symptoms ADL Symptoms 115
ADL ADL ADL
51 Sport/Rec Sport/Rec Sport/Rec
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52 QOL QOL QOL 117
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55 Table II 120
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57 Examples of how to analyze and report KOOS results in randomized controlled trials. Examples are from the KANON study testing treatment for 122
58 acute ACL injury in young adults,16 the OMEX study testing treatment for meniscal tear in the middle-aged,45 and the MEDIC study testing 123
59 treatment for moderate to severe knee OA in older adults.46 Please note that different subscales for evaluation of function are included in KOOS4 124
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for younger and middle-aged (subscale Sport/Rec) and older (subscale ADL) adults. Depending on authors’ preference, both KOOS5 and
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KOOS4 have been pre-specified primary outcomes for the evaluation of middle-aged individuals with meniscal injury.45,47 For hierarchical
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63 testing, numbered subscales are recommended to test in the listed order based on results of psychometric properties of KOOS subscales in 128
64 younger and older adults, respectively.10 The orders of the unnumbered subscales are based on the author’s (EMR) suggestions. 129
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1 The KOOS five-subscale structure can be viewed as both KOOS as primary outcome in RCTs, KOOS4, and hierarchical 66
2 advantageous and problematic testing of subscales 67
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4 Typically, serious knee injuries occur early in life, in women in To avoid multiplicity in trial evaluation, at least two different 69
5 their late teens, and some years later in men. Physical capacity and approaches can be used: hierarchical testing of individual KOOS 70
6 expectations of function differ widely between young athletes and subscales or applying an aggregate subscale score (KOOS4 or KOOS5, 71
7 middle-aged and older or more sedentary adults. In addition, while depending on the number of included subscales) as the primary 72
8 acute symptoms associated with serious knee injury and symptoms outcome, complemented by all KOOS subscales as secondary out­ 73
9 from OA have some overlap, they also differ. These and other aspects comes.18 KOOS4 is the average score of the four (or five for KOOS5) 74
10 may impact differently on quality of life (QOL), an important aspect equally weighted subscales included and was introduced as the pri­ 75
11 of the patient’s experience that was not included in the previously mary outcome to avoid multiplicity in the 2-year trial report of the 76
12 available PROMs available for people with knee injury only or OA KANON trial. The KANON trial compared a strategy of early ACL re­ 77
13 only. After an extensive literature review, and input from patients, construction followed by rehabilitation to a strategy of rehabilitation 78
14 physical therapists, and orthopedic surgeons, a list of 42 items was alone with the option of having surgery later.19 We argued that Sport 79
15 developed and with the use of classical test theory the five-subscale and recreation function and QOL subscales were more likely to be 80
16 structure was confirmed.10,11 The five subscales Pain, other Symp­ improved by surgery since mechanical stability is restored by sur­ 81
17 toms, Activities of Daily Living (ADL), Sport and recreation function gical reconstruction while we argued Pain and Symptom subscales 82
18 (Sport/Rec), and knee-related QOL are validated for individual use, would be more improved with non-surgical treatment since surgery 83
19 and it is up to the user to decide what KOOS subscales are relevant to induces a second trauma to the joint. Including these four equally 84
20 apply in their clinic or study context. For example, the use of the weighted subscales in an aggregate score would therefore be a fair 85
21 Sport and recreation subscale is often considered less relevant in and relevant primary outcome in our KANON trial. The KOOS4 has 86
22 individuals having total knee replacement, but on the other hand, as not been formally validated and is only intended as the primary 87
23 many as three out of four patients having total knee replacement outcome to allow statistical testing without risking multiplicity in 88
24 expect improvement of items included in the Sport and recreation clinical trials. To enable meaningful interpretation of results all the 89
25 function subscale after surgery.13 Similarly, the ADL subscale is less individual KOOS subscales were reported as secondary outcomes.19 90
26 relevant in younger adults following knee surgery, but evaluating Use of KOOS4 under other circumstances should be avoided. The 91
27 ADL function from the start may be of importance to create a aggregate KOOS4 is not validated, and an aggregate score cannot be 92
28 baseline for difficulty with ADL function when following patients for clinically interpreted because it cannot be teased out if the included 93
29 a longer time. A major knee injury increases the risk of knee OA by subscales have changed to a similar extent and in the same direction. 94
30 4–6 times.14 With the five-scale structure where scores are calcu­ Giving equal weight to four (or five) subscales, as in KOOS4(5), is 95
31 lated and presented for each subscale individually, it is possible to better (assuming all included subscales are equally important to 96
32 evaluate domains relevant to people with knee injury and OA se­ patients) than calculating a total summary score where subscales 97
33 parately and at different stages of their lives. This aspect may be will have unequal weights, but it does not make KOOS4/5 more 98
34 important in the future as prevention and treatment of early OA gets clinically interpretable because a score change will represent the 99
35 increasing attention.15,16 change in the average of Pain, Symptoms, ADL and/or Sport and 100
36 The multi-subscale structure of the KOOS can be viewed as both recreation function, and QOL. 101
37 advantageous and problematic when used in research. Keeping do­ 102
38 mains separate is helpful for clinicians because it is straightforward Interpretation of KOOS scores 103
39 to see what domain(s) patients have concerns about and discuss 104
40 how future treatment may help alleviate bothersome aspects. It is an Scoring direction 105
41 advantage in the clinic and in research with a multi-scale structure, 106
42 as it increases relevance and validity for the diverse population Each KOOS subscale is scored from 0 to 100, on a worst to best 107
43 KOOS is intended to evaluate, spanning from children with knee scale (Fig. 2). This follows the orthopedic tradition, where more 108
44 injury to older adults with knee OA. In research, it is also an ad­ points usually represent a better outcome (‘the more the better’) and 109
45 vantage that different subscales can be selected as primary out­ is similar to the scoring direction of some commonly used generic 110
46 comes, depending on the intervention tested. For example, in a drug health measures, such as the SF-36. PROMs, developed in the field of 111
47 trial, the KOOS subscale Pain may be considered the primary out­ rheumatology, often apply in the reverse direction, where 0 is the 112
48 come, while in an exercise trial, one of the KOOS function subscales best score indicating the absence of disability. To compare PROM 113
49 may be considered the primary outcome. In either case, the re­ results, the directions of KOOS (developed in an orthopedic context) 114
50 maining KOOS subscales should be evaluated as secondary outcomes and WOMAC (developed in a rheumatology context) are sometimes 115
51 to enhance the clinical interpretation (Table II). reversed. This practice increases the risk of misinterpretation of 116
52 Unfortunately, to ‘simplify’ some users report a total KOOS score scores, since KOOS and WOMAC are scored in opposite directions to 117
53 instead of reporting the five KOOS subscale scores separately. A total start with; in KOOS, 100 represents an excellent result, while in 118
54 score is not validated and is advised against.17 The KOOS’ five sub­ WOMAC, 0 represents an excellent result. 119
55 scales hold from 4 to 17 items each and a summary score will weigh 120
56 the individual subscales very differently. Reporting a total score Categorization into no, mild, moderate, severe, and extreme difficulty 121
57 threatens the validity of KOOS for both younger and older adults. For 122
58 younger individuals, the subscales Sport and recreation function and The individual KOOS items are rated on a 5-point Likert scale 123
59 QOL are of greatest relevance,12 and a total of nine items in these two ranging from 0 to 4. The five response options are 0=no difficulty/ 124
60 subscales will only contribute 21% to a total summary score. For pain, 1=mild difficulty/pain, 2=moderate difficulty/pain, 3=severe 125
61 older individuals, the KOOS subscale Pain is equally relevant to the difficulty/pain, and 4=extreme difficulty/pain. After applying the 126
62 ADL subscale,13 but will get comparatively less weight in a total KOOS scoring algorithm, a subscale score of 0 represent extreme 127
63 score because it holds only five items compared to the 17 items in difficulty/pain, etc.; a subscale score of 25 represent severe diffi­ 128
64 the ADL subscale. culty/pain on average, a subscale score of 50 represent moderate 129
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26 Fig. 2 91
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28 A. KOOS is scored on a 0–100, worst to best, scale. Interpretation of KOOS scores exemplified using different thresholds; B. average response 93
29 categories based on wording on Likert scale used to respond to individual KOOS items, and C. Patient Acceptable Symptom State (PASS) and 94
30 Treatment Failure (TF) thresholds from studies by Ingelsrud et al.27 and Roos et al.33 Patient acceptable symptom state is defined as reporting a 95
31 KOOS score including or higher than the PASS thresholds. KOOS subscale scores in between PASS and TF thresholds are categorized as 96
32 ‘undecided’. Treatment failure is defined as reporting a KOOS score at or lower than the TF thresholds. Minimal important change thresholds 97
33 cannot be meaningfully visualized on a 0–100 scale, credible estimates for KOOS are presented in a review by Macri et al.31 98
34 99
35 100
36 difficulty/pain on average, a subscale score of 75 represent mild beneficial and that would mandate, in the absence of troublesome side 101
37 difficulty/pain on average, and a subscale score of 100 represent no effects and excessive cost, a change in the patient’s management’. Since, 102
38 difficulty/pain, Fig. 2. Using the patient’s response on a Likert scale up to 86 variations of the MCID concept have been identified with as 103
39 supported by words (as opposed to a numerical rating scale) allows many combinations of terms, abbreviations, definitions and methods 104
40 for a relatively straightforward interpretation of the patient’s per­ used.21,24 We may think of this development as a reflection of the 105
41 ception of their reported problems. Using this approach, KOOS complexity of the concept ‘minimal clinically important difference’ 106
42 subscale scores can be categorized into on average no, on average and indeed the terminology and methods have been criticized.21,25 107
43 mild, on average moderate, on average severe, and on average ex­ With time, ‘clinically important’ has become a statistical matter 108
44 treme difficulty/pain, using cut-off values of 12.5, 37.5, 62.5, and where preferably anchor-based methods are used to arrive at a 109
45 87.5, respectively (Fig. 2). specific threshold for a given PROM, and the concept has conse­ 110
46 quently been narrowed down to only include treatment effect, and 111
47 The concept of ‘minimal important difference’ not taking risk, cost, harms, patient’s preferences, and accessibility 112
48 of the treatment being offered into account.25 Likewise, the quali­ 113
49 Clinician scientists would like a single number to put into sample tative aspect (comparison of score change with treatments of known 114
50 size calculations and I often get the question “What’s the minimal effect) suggested by the early developers as a method to judge what 115
51 important difference for KOOS?” This question does not have a score change defines an ‘important improvement’ is no longer pre­ 116
52 straightforward answer. To illustrate the complexity of the question, sent. Today, increasingly complicated statistical methods are applied 117
53 we need to look back to 1987 when the concept of ‘minimal clinically to arrive at credible PROM-specific thresholds of effect, which are 118
54 important difference’ (MCID) was introduced by Guyatt et al.20 In the used to make a sharp distinction between treatment success and 119
55 introduction of their paper they say “The thesis of this paper is that the treatment failure in clinical trials. 120
56 usefulness of instruments designed to measure change within persons The reality is that minimally important thresholds vary widely 121
57 over time is dependent not only on reliability and validity, but also on within the same group of patients with, for example, the anchor 122
58 their ability to detect minimal clinically important differences, a prop­ question used, cut-off level applied for the anchor question, corre­ 123
59 erty we shall call responsiveness”.20 They did not define MCID beyond lation of anchor question and PROM of interest,26 and statistical 124
60 ‘the ability of evaluative instruments to detect minimal clinically methods used.27 Commonly used methods, listed from older to 125
61 important differences’ and the method they used was ‘change in­ newer, include the mean score change method, receiver operator 126
62 duced by an intervention of known efficacy’.21 When applying this characteristic, and (adjusted) predictive modeling.27 Development is 127
63 approach it has been suggested that the MCID for KOOS is 8–10 ongoing with the introduction of longitudinal item response theory, 128
64 points.22 The most commonly used definition of MCID was published taking aspects such as floor/ceiling effects and measurement error in 129
65 by Jaeschke in 1989:23 ’the smallest difference that patients perceive as PROM scores and anchor questions into account.28 Additionally, 130
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1 thresholds are not only specific to a given PROM but also highly established using absolute post-treatment KOOS scores.33 While an 66
2 context-dependent and may differ, for example, between young improvement in score relates to whether a patient feels better, an 67
3 adults with knee injury and older adults with knee OA, or between absolute post-treatment score relates to whether a patient feels 68
4 those undergoing surgery and those undergoing exercise therapy. good (PASS), is undecided, or thinks the treatment has failed (TF). 69
5 Considering this complexity, it is not surprising that you can always To facilitate the interpretation of the outcome in an RCT in young 70
6 find a published threshold for your preference. In RCTs, where the adults with knee injury, we applied minimal important difference, 71
7 same threshold is applied to all groups, one could argue that while PASS, and TF thresholds to the KANON trial results.33 Interestingly, at 72
8 the level of success reported in the trial is shifted upward or 2 years we found that 90% in the two treatment arms reported 73
9 downwards depending on the threshold chosen, the difference be­ themselves to feel better (be minimally but importantly improved, 74
10 tween groups will be unaffected. Because of the complexity and the achieve the minimal important difference threshold), while only 75
11 difference in conceptual and methodological rigor in this area, a about 50% reported themselves to feel good (achieving the PASS 76
12 recent paper authored by methodological giants in this area sug­ threshold).33 It seems to be minimally but importantly improved is 77
13 gested ‘a step-by-step approach for selecting an optimal minimal not enough to feel good about your knee. These findings call for 78
14 important difference’.29 This is a commendable effort to tidy up a further reflection. The common standard for the evaluation of suc­ 79
15 messy field, but it does not change the fact that ‘clinically important’ cess in RCTs is to achieve the minimal important difference, which 80
16 has been narrowed down to treatment effect only, determined as does not necessarily reflect that patients feel good about their knee. 81
17 reaching a pre-defined specific threshold on a 0–100 scale, as op­ One could wonder if the universal acceptance and use of ‘minimal 82
18 posed to also including risk, adverse events, cost, etc. as important important difference’ partly reflects the clinician’s and researcher’s 83
19 aspects of the concept ‘clinically important’.25 As a result we may desire to see an improvement from their given or studied treatment 84
20 unconsciously tend to weigh treatment effect as more important rather than asking the patient if their post-treatment result is ac­ 85
21 than treatment-related risk, adverse events (harms), and costs when ceptable to them. 86
22 interpreting study results and when engaging in shared decision- In support of the PASS concept, experienced clinicians find that 87
23 making with patients. every other patient feeling good about their knee 2 years after 88
24 treatment of a major knee injury fits much better with reality than 89
25 Minimal important difference for KOOS 90% of patients feel better. Supporting the PASS concept (feeling 90
26 good) over achieving a minimal important difference (feeling better) 91
27 To determine the minimal important difference for a PROM, it is is the finding that anchor items of change often have a higher cor­ 92
28 recommended to use an anchor item in which patients rate their relation with the absolute post-operative treatment score than with 93
29 change.30 In our studies of KOOS, subscale specific anchor questions have the change score it is supposed to be reflective of.27 Complementing 94
30 been used, as an example for the subscale Pain the following wording the usual group-based reporting of change and absolute scores in 95
31 was used: “How is your knee pain now compared to prior to your op­ RCTs with the proportions achieving minimal important difference, 96
32 eration?” responded to on a 7-point Likert scale: “Better, an important PASS and TF will enhance the interpretation of study outcomes and 97
33 improvement; Somewhat better, but enough to be an important im­ may be helpful in discussions with future patients about realistic 98
34 provement; Very small change, not enough to be an important im­ expectations of different treatment choices.33 99
35 provement; About the same; Very small change, not enough to be an PASS thresholds from multiple studies in young adults with a 100
36 important deterioration; Somewhat worse, but enough to be an im­ major knee injury are within a 10-point range for KOOS Symptoms, 101
37 portant deterioration; Worse, an important deterioration.27 The two first KOOS ADL, and KOOS QOL.31 KOOS PASS and TF thresholds from 102
38 response options indicate an important improvement representing at Ingelsrud et al.34 and Roos et al.33 are plotted in Fig. 2. Reaching PASS 103
39 least minimal important treatment effect. We calculated the minimal thresholds for the five KOOS subscales and KOOS4 correspond to on 104
40 important change estimates using three methods: the (adjusted) pre­ average no or mild difficulty/pain. The TF thresholds indicate that 105
41 dictive modeling approach, receiver operating characteristic method, young adults with major knee injury only accept on average mild 106
42 and mean score change method. In short, we recommended using the difficulty with ADL activities to feel that treatment has failed, while 107
43 estimates from predictive modeling because these estimates are the for QOL and Sport and recreation function on average severe diffi­ 108
44 most precise with smaller 95% confidence intervals around the esti­ culty is required to reach the threshold for TF, Fig. 2. 109
45 mates, this method being less sensitive to low correlation with the an­ 110
46 chor question, taking the reliability of the anchor question into account, 111
47 and having the possibility to adjust when the proportion of improved Responder analysis of study results 112
48 patients differ from 50%, a finding common in knee injury and knee OA 113
49 research.27 Responder analysis is a concept in which participants are cate­ 114
50 In a recent systematic review, we synthesized and assessed gorized as responders or non-responders. In such analyses of within- 115
51 credibility (or trustworthiness) of thresholds that define meaningful individual changes, one can argue that the best threshold is the 116
52 scores for PROMs applied in young adults with a major knee injury.31 mean of a group’s individual thresholds derived from a study with 117
53 Only one study27 was rated ‘high’ using the MID Credibility Assess­ high credibility. In theory, using the mean from such study would 118
54 ment Tool.32 In that study a minimal important change of 18 was give the correct proportion of patients who have improved, without 119
55 found for the KOOS subscale QOL.27 From multiple studies with ‘low’ pinpointing which individual patients have improved. Others sug­ 120
56 credibility, thresholds within a 10-point range were found for KOOS gest using the upper end of the range of estimates available.35 121
57 Symptoms, KOOS ADL, and for the International Knee Documenta­ In an RCT, the proportion of participants categorized as re­ 122
58 tion Committee Subjective Knee Form. Other PROM thresholds sponders would be compared and presented as a complement to the 123
59 varied up to 30 points.31 between-group comparison of mean change scores. The dichot­ 124
60 omization of continuous outcomes applied in responder analysis 125
61 Patient-acceptable symptom state (PASS) and treatment failure results in loss of power, a statistical reason in favor of comparing 126
62 (TF) for KOOS between-group mean change scores in the primary analysis.36 127
63 Complementary responder analyses are recommended by the FDA,5 128
64 While a minimal important difference is calculated based on as they are more meaningful to clinicians and patients than group- 129
65 longitudinal KOOS data (follow-up minus baseline), PASS, and TF are level results. 130
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1 Confusingly, the MCID concept is used interchangeably to inter­ respond to KOOS and conducted qualitative interviews to uncover 66
2 pret group-and individual-level changes. However, in the PRO how well KOOS was understood from the perspective of developing 67
3 Guidance by the FDA from 2009, the focus was on individual-level a pediatric version of KOOS (KOOS-Child). We found that many 68
4 changes in responder analysis.5 Although the FDA does not suggest children had difficulty understanding several terms and mis­ 69
5 applying MCID in group-level comparisons, this is commonly done, interpreted items or found them irrelevant. Most children under­ 70
6 especially when conducting sample size calculations.37 stood how to use the 5-point Likert response scale but found 71
7 When comparing the proportion of responders, another aspect to instructions accompanying KOOS confusing.47 We consequently de­ 72
8 consider is whether 10%, 20%, or any other difference in proportion be­ veloped a 39-item pediatric version of KOOS including drawings to 73
9 tween groups is considered representative of a clinically relevant dif­ illustrate some functional activities. When tested in girls and boys 74
10 ference. In our responder analysis of the KANON study, we took into aged 7–16, we found the psychometric properties to be good.48 We 75
11 consideration clinical reasoning about the difference needed to re­ recommend using KOOS-Child when assessing school-aged children 76
12 commend one treatment over another for young adults with a major with major knee injury. 77
13 knee injury.33 We arrived at a 10% difference in proportions achieving 78
14 important change or a patient-acceptable symptom state would be re­ Administration of KOOS©, KOOS-12© and KOOS-Child© 79
15 levant. TF is a more serious outcome and consequently, we considered a 80
16 5% difference in proportions experiencing TF between groups could Administering popular PROMs is a resource and time-consuming 81
17 impact clinicians on what treatment to recommend.33 task. After making the KOOS, KOOS-12, KOOS-Child, and more than 82
18 50 translations freely available for more than 20 years to all users via 83
19 KOOS-12, a 12-item short version of KOOS a personal website, the time has come to manage KOOS more pro­ 84
20 fessionally. In May 2023, a contract was signed with MAPI Research 85
21 In 2019, three papers reporting on the development of short Trust, which will administer the KOOS and my other PROMs in the 86
22 forms of the KOOS and HOOS were published in Osteoarthritis and future (https://eprovide.mapi-trust.org). While a license is always 87
23 Cartilage.38–40 The work was initiated and led by Barbara Gandek, a required, KOOS will be free to use for non-funded and funded aca­ 88
24 highly experienced statistician and psychometrician who worked demic users in the future, but health organizations and commercial 89
25 closely with John Ware on the health status measure SF-36 for users must pay a fee. 90
26 decades. Item response theory and computer adapted test (CAT) si­ 91
27 mulations were used to arrive at KOOS-12, a three-subscale short- Funding 92
28 form holding a total of 12 items primarily intended for use in older 93
29 adults with OA evaluated in surgical registries.39 We also developed No funding was obtained for this work. 94
30 a ‘Summary joint impact score’ in addition to the three subscale 95
31 scores Pain, Function, and QOL to allow for report of a ‘simple’ ag­ Declaration of Competing Interest 96
32 gregated and validated score. Items were chosen based on qualita­ 97
33 tive feedback from patients, clinicians, and KOOS translators and ER is the copyright holder for KOOS. Since May 2023, royalties are 98
34 analysis of data from more than a thousand older adults with knee collected by MAPI Research Trust when KOOS is used by commercial 99
35 OA who responded to the KOOS before and after total knee re­ companies and healthcare organizations. 100
36 placement. The three subscale domains were chosen as they are 101
37 recommended core outcomes by OARSI/OMERACT and ICHOM in­ Declaration of Generative AI and AI-assisted technologies in the 102
38 itiatives.41,42 The final 12 items were chosen based on content, writing process 103
39 coverage of a wide measurement range, high item information, item 104
40 usage in CAT simulations, scale-level properties such as reliability, During the preparation of this work, the author used ‘Paperpal’ in 105
41 validity, responsiveness, and qualitative information.39 We found order to improve English language and grammar. After using this 106
42 that KOOS-12 was a reliable and valid alternative to the full-length tool/service, the author reviewed and edited the content as needed 107
43 KOOS in patients having total knee replacement with substantially and takes full responsibility for the content of the publication. 108
44 reduced respondent burden.38 Psychometric studies from Australia 109
45 have confirmed the good psychometric properties of KOOS-12,43 but References 110
46 note that there may be missing content, particularly for high-func­ 111
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48 19. Frobell RB, Roos EM, Roos HP, Ranstam J, Lohmander LS. A nificance and responder analyses should be reserved as sec­ 113
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10 43. Ackerman IN, Soh SE, Harris IA, Cashman K, Heath E, Lorimer M, 47. Ortqvist M, Roos EM, Brostrom EW, Janarv PM, Iversen MD. 27
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15 et al. Implications for research and clinical use from a Rasch Psychometric properties of the Knee injury and Osteoarthritis 32
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