PSYCHO-ONCOLOGY, VOL. 3: 215-222 (1994)

QUALITY OF LIFE QUESTIONNAIRES IN CANCER CLINICAL TRIALS: IMPUTING

MISSING VALUES JENNY MORRIS*? AND DOUGLAS COYLES

t Research Fell0 w, York Health Economics Consortium, University of York, Heslington, York, YO1 5DD, UK; $Research Fellow, Centre for Health Economics, University of York, Heslington, York, YO1 SDD, UK

SUMMARY Quality of life is increasingly being used as a measure of outcome in comparative cancer clinical trials. Even when quality of life studies are well funded vis-h-vis data collection and processing, it is unlikely that data sets will be 100% complete, leading to problems at the data analysis stage. Missing data can arise as a consequence of whole assessments being missed due to death or other reasons, or as a result of single items being omitted from particular questionnaires. This paper addresses the latter category of missing data and examines the effects on subscale scores of imputing values for missing items from the Hospital Anxiety and Depression Scale and the psychological complaints subscale of the Rotterdam Symptom Checklist.

INTRODUCTION

Health-related quality of life is accepted as being an important indicator of outcome and is being used more frequently as a measure of outcome in cancer clinical trials. With the purchaser- provider division being made explicit in the recent National Health Service reforms, there is a need for purchasers and providers of health care to focus more on the quality and effectiveness of care provided. Consequently, health-related quality of life assessments are likely to be used in a wider context than the traditional research domain.

The Hospital Anxiety and Depression Scale (HADS; Zigmond and Snaith, 1983) and the Rotterdam Symptom Checklist (RSCL; de Haes et al., 1990) are the instruments used most fre- quently to assess quality of life parameters in cancer clinical trials in the UK. Both instruments were recommended for use by the Medical Research Council’s Cancer Therapy Committee Working Party on Quality of Life (Maguire and Selby, 1989), although such recommendations may be superseded by publication of the final version of the EORTC core questionnaire (Aaronson et al., 1991, 1993). The HADS and the RSCL were used in a trial of different fraction-

* Author to whom correspondence should be addressed.

ation regimes for palliative radiotherapy (MRC Lung Cancer Working Party, 1991). They are being used in MRC funded trials of chemotherapy in small cell lung cancer patients (unpublished) and are currently being used in two randomized controlled trials designed to compare conven- tional radiotherapy with continuous, hyperfrac- tionated, accelerated radiotherapy (CHART) in patients with head and neck cancer or non-small cancer of the bronchus (Morris and Goddard, 1993). While there are many advantages to using self-report questionnaires to assess quality of life, difficulties can arise at the data analysis stage vis-a-vis the use of statistical tests if there are missing items.

A search of the literature revealed little infor- mation about the handling of missing data. Fur- thermore, the majority of quality of life studies published do not indicate the extent to which data were missing, nor if/how such problems were overcome when using particular statistical tech- niques. In their information sheet about use of the 22-item FLI-C, the authors of the instrument (Schipper et al., 1984) suggest that the total score can be prorated by assigning the mean score of answered questions to unanswered items. They also warn, however, that assigning mean scores in this way may not be a good estimate of the actual score had the question been answered. The authors of the SF-36 (36 items divided into eight subscales) also recommend using average scores

ccc 1057-9249/94/030215-08 0 1993 by John Wiley & Sons, Ltd.

Received 27 September 1994

216 J. MORRIS AND D. COYLE

(person-specific estimates) if a respondent answered at least half of the items in a multi-item scale (or half plus one in the case of scales with an odd number of items (Ware et al., 1993, p. 6:16). In neither case, however, is there any published information on the implications of undertaking such calculations.

There are two main reasons why data may be missing: whole assessments being missed due to death or other reasons; or as a result of single items being omitted from subscales of question- naires. The purpose of this paper is to examine category changes (high or low scores), using the HADS and the RSCL, when values are imputed for items missing from the subscales of these questionnaires.

METHODS

Subjects The data illustrated are from the two groups of

patients participating in the CHART trials. Ten centres in the UK are taking part in the trials which are designed to compare conventional radiotherapy, given five days per week over six weeks, with the CHART regime (continuous, hyperfractionated, accelerated, radiotherapy), in which treatment is delivered three times daily on twelve consecutive days including the weekend. As these trials are still in progress, the infor- mation is combined for the two treatment cate- gories (those patients treated with conventional

Table 1 . Numbers of bronchus patients (Yo) with items missing on the HADS and RSCL

~~

RSCL

Psychological HADS

Anxiety Depression complaints

Pre-treatment C o m p 1 e t e 1 item missing 2 items missing

>2 items missing

3 Weeks C o m p 1 e t e 1 item missing 2 items missing

>2 items missing

4 Weeks Complete 1 item missing 2 items missing

> 2 items missing

6 Weeks Complete 1 item missing 2 items missing

>2 items missing

3 Months Complete 1 item missing 2 items missing

> 2 items missing

285 9 1 0

29 1 4 0 0

292 3 0 0

264 5 1 0

267 3 0 0

269 1 1 0

255 5 3 0

256 4 2 1

264 2 0 0

252 5 0 0

252 5 0 0

256 4 0 0

227 4 0 1

230 1 0 1

(99) (0.4)

233 2 0 0 (0.4) (0.4)

QUALITY OF LIFE QUESTIONNAIRES 217

radiotherapy and those treated with the CHART regime). Details of the patients’ characteristics are shown below:

Bronchus patients. Mean age 64.8 years (SD 9 years); 132 males (77Q/o), 40 females (23Vo); WHO performance status: 0 -65 (38%), 1 -107 (62%).

Head and Neck patients. Mean age 62.4 years (SD 10.4 years); 249 males (77%), 76 females (23Vo); WHO performance status: 0 -227 (70Vo), 1 -98 (30%).

Data assessment points The HADS and the RSCL were completed prior

to treatment, 3, 4 and 6 weeks after the start of the treatment and 3, 6, 12, 18, 24 and 30 months after the start of treatment. The data collection

points were selected to coincide with the collection of the clinical data and to assess patients when the side effects of treatment were most likely to be at a maximum. The numbers of patients with com- plete data, one item missing, two items missing and more than two items missing from the subscales of the two questionnaires are shown in Tables 1 and 2.

Imputing missing values Seven items comprise each of the two subscales

of the HADS and eight the psychological com- plaints subscale of the RSCL. Where one item from the subscale was omitted, the missing value was replaced with the mean of the other six scores for the HADS and the seven scores for the RSCL for each assessment. Calculations were based on

Table 2. Numbers of head and neck patients (Vo) with items missing on the HADS and RSCL

RSCL HADS

Psychological Anxiety Depression complaints

Pre-treatment Complete 504 (98) 51 1 (99) 507 (98) 1 item missing 9 (2) 3 (1) 8 (2) 2 items missing 1 (0.2) 0 1 (0.1)

> 2 items missing 0 0 0

3 Weeks Complete 483 (98) 480 (97) 484 (98) 1 item missing 9 (2) 1 1 (2) 8 (2) 2 items missing 0 1 (0.2) 2 (0.4)

>2 items missing 1 (0.2) 1 (0.2) 2 (0.4)

Complete 479 (98) 478 (98) 485 (99) I item missing 9 (2) 6 (1) 5 (1) 2 items missing 0 3 (0.6) 0

> 2 items missing 1 (0.2) 2 (0.4) 0

4 Weeks

6 Weeks Complete 46 1 (98) 46 1 (98) 464 (98) 1 item missing 7 (.I .5) 7 (1) 5 (1) 2 items missing 1 (0.2) 0 1 (0.2)

> 2 items missing 1 (0.2) 2 (0.4) 1 (0.2)

C o m p I e t e 438 (99) 439 (99) 438 (98) I item missing 5 (1) 4 (1) 5 (1) 2 items missing 0 0 2 (0.4)

3 Months

> 2 items missing 0 0 0

218 J . MORRIS AND D. COYLE

the mean of individual scores as recommended by Ware et al. (1993). Means of the population could also be substituted, as could means over all assess- ments for the item in question. Given the known fluctuations over time in quality of life scores as well as the variation in scores between individuals, these methods of imputing missing values were not pursued.

Calculations have been made for each of the items on the subscales in order to explore the differential effect on the percentage of patients moving between categories of ‘caseness’ for the HADS and the psychological complaints subscale of the RSCL.

RESULTS

The data were analysed using the SPSS package on a VAX mainframe. Data were from those patients who had completed the first five assess- ments (325 patients with cancer of the head and neck region and 172 patients with non-small cell cancer of the bronchus).

The main results are presented in terms of the numbers of patients moving between categories of

Table 3. Imputed values for bronchus patients

‘caseness’ for the HADS subscales and between ‘high’ (scores 2 11) and ‘low’ (scores < 11) scores on the psychological complaints subscale of the RSCL. Scores of 7 or less on the HADS represent non-cases and 11 or more represent cases. Scores between these cut-off points are borderline cases.

The results are shown in Table 3 for the bron- chus patients and Table 4 for the head and neck patients. The tables indicate the changes in cate- gories for each subscale (anxiety, depression, psychological complaints) according to which item value was imputed. Details of the item abbreviations for the HADS are listed in Appendix I. Results are shown using the data obtained from the first assessment; the results for the other four assessments are similar and can be obtained from the first author upon request. As shown in the tables, the extent of missing data is minimal and there is relatively little movement between categories when values are imputed for missing items. Rank ordering the items in terms of the percentage of patients moving between cate- gories indicated no pattern vis-u-vis the impact of individual items on category change. Further- more, there were no notable differences between patient groups, nor between assessments regarding percentages of patients who moved

Number of patients in each category: original derived Patients

moving Variable Non-case Non-case Border Border Border Case Case category replaced Non-case Border Non-case Border Case Border Case (%)

Anxiety TEN FRI WRY EAS BUTF RSTL PAN

Depression EN J LGH CHR SLW APPR LKF BTV

~

137 136 134 135 136 134 137

155 151 148 156 149 156 15 I

0 1 3 2 1 3 0

1 5 8 0 7 0 5

~~

0 4 2 1 1 2 0

2 1 1 3 0 1 0

~

16 13 14 16 16 15 17

9 8 8 8 9

10 11

1 0 1 0 0 0 0

0 2 2 0 2 0 0

1 4 3 0 0 2 2

3 0 0 2 0 2 0

17 14 15 18 18 16 16

2 5 5 3 5 3 3

2.3 5.1 5.1 1.7 1.1 4.0 1.1

3.4 4.6 0.6 2.9 5.1 1.7 2.9

QUALITY OF LIFE QUESTIONNAIRES 219

Table 3. Continued

Variable replaced

~~

Number in each category: original derived

Patients < I 1 211 < I 1 2 1 1 moving category < I 1 < I 1 2 1 1 211

Psychological complaints Irritability Worrying Depressed mood Despondent feelings about the future Anxious feelings Difficulty concentrating Nervousness Feeling tense

144 144 143 144 144 141 144 I43

21 22 28 24 23 21 22 26

0.6 3.4 0.6 2.3 2.9 2.3 3.4 1 .l

Table 4. Imputed values for head and neck patients

Number of patients in each category: original derived Patients

moving Variable Non-case Non-case Border Border Border Case Case category replaced Non-case Border Non-case Border Case Border Case (W)

Anxiety TEN 24 1 1 2 41 I 3 30 2.2 FRI 239 3 I5 35 0 1 26 1.7 WRY 238 4 1 42 1 10 23 6.8 EAS 24 1 1 1 49 0 6 21 2.5 BUTF 240 2 3 41 0 4 29 2.8 RSTL 24 I 1 9 41 0 4 29 4.3 PAN 236 6 4 42 4 4 29 5.5

ENJ 299 0 5 11 0 2 8 2.2 LGH 295 4 0 14 2 0 10 1.8 CHR 2% 3 0 16 0 0 10 0.9 SLW 298 1 6 10 0 1 9 2.5 APPR 293 6 1 12 3 1 9 3.4 LKF 297 2 2 13 1 2 8 2.2 BTV 290 9 0 14 2 1 9 3.1

Depression

Number in each category: original derived

Variable replaced

Patients < I 1 211 < I 1 211 moving category < I 1 < I 1 211 2 11 V O )

Psychological complaints Irritability Worrying Depressed mood Despondent feelings about the future Anxious feelings Difficulty concentrating Nervousness Feeling tense

280 280 219 219 280 213 211 219

39 34 41 41 41 42 36 41

1.8 3.4 1.5 4.5 1.2 3.1 3.7 1.5

220 J . MORRIS AND D. COYLE

Table5. Mean subscale scores for head and neck patients with (+) and without (-) mean item substitution (n = 325)

Pre-treatment 3 Weeks 4 Weeks 6 Weeks 3 Months

- + - f - + - + - Variable replaced + Anxiety

TEN FRI WRY EAS BUTF RSTL PAN

Depression EN J LGH CHR SLW APPR LKF BTV

Psychological complaints

Irritability Worrying Depressed mood Despondent feelings

about the future Anxious feelings Difficulty

concentrating Nervousness Feeling tense

4.81 4.79 4.82 4.89 5.02 4.66 5.10

2.58 2.95 2.90 2.25 2.92 2.74 2.96

5.87 5.44 5.91 5.80

5.68 6.12

5.77 5.74

4.87 4.00 4.12 4.17 3.93 4.38 3.15 4.30

3.88 4.52 4.44 3.56 4.50 4.21 4.41

2.76

5.19

5.13 5.14 5.27 5.31

5.21 5.41

5.46 5.36

4.10 3.84 3.99 4.01 3.75 4.2 3.6 4.07

3.79 4.21 4.21 3.37 4.33 4.01 4.18

4.23

5.30

5.09 5.07 5.24 5.29

5.20 5.34

5.41 5.31

3.92 3.60 3.11 3.77 3.56 4.02 3.50 3.88

3.59 3.98 3.91 3.12 4.01 3.74 3.96

4.02

5.24

4.69 4.74 4.90 4.92

4.86 4.98

5.03 4.91

3.73 3.59 3.55 3.57 3.66 3.50 3.78 3.35 3.70

3.76 3.13 3.03 3.35 3.30 2.52 3.31 3.10 3.28

4.88 4.38

4.36 4.21 4.43 4.36

4.33 4.50

4.50 4.38

between categories when missing item values were imputed.

Summary statistics for subscales of the HADS and the RSCL are often presented using mean scores. Table 5 illustrates the mean scores of the three subscales with and without mean item substitution using the data from the head and neck patients (results were similar for the bron- chus patients). The standard deviations were large for each of the values, approximate to or larger than the mean in the majority of cases (full details available upon request). Comparisons between mean subscale scores with and without mean item substitution revealed minimal differences. For all three subscales, differences between means were less than 0.4 except for the variable ‘I feel as if I am slowed down’ on the depression subscale

of the HADS where the differences were less than 0.7.

DISCUSSION

With the increasing use of quality of life assess- ments in cancer clinical trials, it is essential that there is agreement as to how best to handle missing information. This paper has addressed one aspect-items missing from the subscales of two widely used questionnaires. It is notable that there is a developing interest among statisticians vis-ci-vis the analysis of quality of life data (R. Stephens, personal communication; Fayers and Jones, 1983; Zwinderman, 1992) and this is to be welcomed. However, until a consensus is reached

QUALITY OF LIFE QUESTIONNAIRES 22 1

about the appropriate statistical model to use, users of quality of life instruments need to agree a method of imputing values for questionnaire items where the information is missing.

As indicated earlier, Ware et a/. (1993) recom- mended using person-specific average scores for missing data for the subscales of the SF-36 when at least half of the items were completed for each subscale. The SF-36 consists of eight subscales with the number of items in each ranging from two (social functioning, bodily pain) to ten (physical functioning). Given this recommen- dation, we feel it acceptable to adopt a similar approach using the seven-item subscales of the HADS, and the eight-item psychological com- plaints subscale of the RSCL.

Alternative methods (arithmetic rather than statistical techniques) include using the average over time for a particular item value, or the most recent value. We chose not to use these methods for the following reasons, although others may elect to test the relative merits of the different approaches: - - (a) Using the average value over time can

present problems if the same item is omitted on several occasions. Furthermore, indi- vidual variability over time in quality of life profiles as a consequence of both the course of the disease and the treatment may render the use of such average scores inappropriate. We found extreme variability in individual subscale scores over the data collection period and chose not to pursue this method. Use of the most recent value could also present problems if the same item is omitted on several occasions. Similarly, with the known variation in individual scores across time, the most recent value may not be a useful measure.

The approach outlined in this paper: use of the average of completed items obtained at the same assessment which are part of the same construct as the missing item, shouId minimize the above problems.

In this study, we tested imputing values when only one item was missing from each of the subscales. This decision was made for pragmatic reasons, as relatively few patients had more than one item missing. Sensitivity analyses could be undertaken by others with similarly large data sets to examine the extent to which patients ‘move’

between categories and the differences between mean scores where values are imputed for more than one missing item.

Two issues are worth noting in this study. First, missing data were minimal which may limit the extent to which the method suggested can be applied to other data sets where large amounts of data are missing. The CHART studies were adequately funded for the collection of quality of life information and it is argued that it is this which led to high completion rates. Communi- cation with others involved in clinical trials indicated more extensive amounts of missing data when funds were not available for the collection of quality of life information, but this component of a trial seen as an ‘add on’ to the clinical trial.

Second, using the mean scores of completed items in subscales as a substitute for missing values did not cause notable shifts between cate- gories of caseness for the HADS, nor between high and low scores of the psychological com- plaints subscale of the RSCL. Furthermore, the differences in mean scores were minimal, only exceeding 0.4 for one variable of the depression subscale of the HADS. This suggests that imputing missing values in the way outlined does not cause serious distortion of patient data. It could be argued that this is a function of the method used in this study, and we would welcome seeing results from other data sets where different methods have been employed.

Finally, it would be helpful if authors could include in reports the extent to which data are missing and what methods were used to overcome the difficulties associated with analysing data col- lected over time. In this way, it will be possible to assess the magnitude of the problem and reach a consensus about a solution.

ACKNOWLEDGEMENTS

We would like to thank the Medical Research Council and the Department of Health for funding the CHART trials. Further information about the clinical aspects of the trials can be obtained from the trial co-ordinators: Bronchus trial-Dr Michelle Saunders; Head and Neck Trial-Professor Stanley Dische. Both can be contacted at the Marie Curie Research Wing for Oncology, Regional Centre for Radiotherapy and Oncology, Mount Vernon Hospital, Northwood, Middlesex, HA6 2RN, UK.

222 J . MORRIS AND D. COYLE

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Aaronson, N., Ahmedzai, S., Bergman. B.. Bullinger, M., Cull, A,, Duez, N. et al. (1993) The European Organization for Research and Treatment of Cancer QLQ-C30 a quality-of-life instrument for use in international clinical trials in oncology. J. Natl Cancer Inst. 85, 365-316.

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67, 361-370.

APPENDIX I: DETAILS OF HADS ITEMS LISTED IN TABLES 3 ’ 4 AND 5

Anxiety

TEN I feel tense or ‘wound up’ FRI I get a sort of frightened feeling as if

something awful is about to happen WRY Worrying thoughts go through my

mind EAS I can sit at ease and feel relaxed BUTF I get a sort of frightened feeling like

‘butterflies’ in the stomach RSTL I feel restless as if I have to be on the

move PAN I get sudden feelings of panic.

Depression ENJ I still enjoy the things I used to enjoy LGH I can laugh and see the funny side of

things CHR I feel cheerful SLW I feel as if I am slowed down APPR I have lost interest in my appearance LKF I look forward with enjoyment to

things BTV I can enjoy a good book or radio or

TV programme.