Monitoring in chronic disease: a rational approach
http://www.100md.com
《英国医生杂志》
1 University of Oxford, Department of Primary Health Care, Oxford OX3 7LF UK, 2 Screening and Test Evaluation Program, School of Public Health, University of Sydney, Camperdown, NSW 2006, Australia
Correspondence to: P Glasziou paul.glasziou@dphpc.ox.ac.uk
The objective and methods of monitoring change over the course of treatment. This course of monitoring can be usefully divided into the five phases listed in table 1.
The objectives for the five phases of monitoring
Figure 1 shows a control chart for these stages. At (a) we first note the abnormal measurement and begin a quick series of measurements before treatment to confirm the abnormal result; (b) then, if appropriate, initiate treatment and monitor at short intervals to check response and achieve control; (c) but once control is achieved, the intervals may be longer (d), although this may be supplemented by patients' self monitoring (small arrows) (e); but when one measurement is more than 3 standard deviations (SD) or two measurements are more than 2 standard deviations from target, we adjust therapy to re-establish control and shorten the re-check interval; and finally (f), if treatment becomes unnecessary, a period of monitoring after its cessation may be required. We now look at these phases in more detail.
Fig 1 The five phases of treatment monitoring
Pretreatment monitoring
Monitoring before treatment should establish the need for treatment and then a baseline to judge the response to treatment or changes in the patient's condition. Treatment should not start until sufficient measurements for a firm baseline have been obtained. This firm baseline confirms that the degree of abnormality is beyond the initiation threshold. Serial measurements often "normalise" before treatment for several reasons, such as training effects (for example, with a peak flow meter), accommodation to measurement (for example, with blood pressure measurement), and, perhaps most importantly, regression to the mean (the tendency of repeat tests to be closer to normal9). For example, in the first biennial check in the Framingham study, the average blood pressure fell by 3.4 mm Hg systolic and 2.4 mm Hg diastolic.10 Among 99 Dutch patients with apparently raised blood pressure, re-measurement resulted in average reductions of 9 mm Hg systolic and 4 mm Hg diastolic.11 The same study showed that two measurements were sufficient to establish the need for treatment in patients who were well above the initiation threshold. For borderline patients, even four measurements resulted in substantial misclassification.
Initial titration: response, control, and safety
After establishing the baseline, we should set a target and start titration to achieve that target. However, achieving the target is just one of several objectives of the initial titration phase, which should include checking the individual's response to treatment, detecting unacceptable adverse effects, and achieving the desired target range.
This initial monitoring checks adequate response to treatment—that is, whether it "works" as expected on the basis of clinical trials in other patients. Sometimes individual response to treatment can be predicted by other measurements, such as genetic testing (for example, the dose requirement on initiating warfarin treatment is strongly related to CYP2C9 gene variants12). Sometimes it can be predicted by pharmacokinetic studies—for example, in initiating tricyclic antidepressants, short term measurement of the drug concentration can characterise individual metabolism and guide the long term dose used.13 However, personalising treatment usually requires some pragmatic trial and error. We can therefore think of this phase as an "n = 1" trial.14 Ideally, the estimate of effect will be based on both the measurements in that patient and the known effect from trials.15
The initiation phase should also detect immediate or short term adverse effects.16 Measures of potential harm should hence be assessed and monitored. Almost half of the medicines in the electronic Medicines Compendium (www.medicines.org.uk) include a suggestion for some monitoring. Many drugs affect renal function, and regular monitoring of creatinine and electrolytes is widely recommended. A more specific example is treatment with clozapine, for which white cell counts are measured on a weekly basis for the first few months to detect agranulocytosis, which occurs in 0.8% of patients. However, the rationale for the timing of measurement is seldom explicit. The criteria for monitoring for adverse effects are similar to those for screening, including that the effect is serious, that a simple test is available, that earlier detection is predictive, and that change in treatment leads to a better outcome.17
Monitoring during treatment
Once the target is achieved, the objective of monitoring is to ensure that measurements stay within reasonable limits, called control limits. The control limits ensure that we detect real changes in the level of the target measure while minimising false positives resulting from variable measurements in the short term or errors in the technical measurement. The degree of short term variation can be estimated from population studies, subpopulations, or from the individual's own measurements. Because extreme measurements are unlikely to be due to variability of short term measurements, they may justify action to re-establish control. One approach suggested by statistical control theory is to consider that a shift from control has occurred if a single measurement is outside an upper and lower control limit of 3 standard deviations, or if two or three successive measurements are more than 2 standard deviations from the target.18 Figure 1 shows these two sets of action thresholds; one for action (SD 3) and one for re-measurement (SD 2), with action if the repeat result is also more than 2 standard deviations from target.
Monitoring during treatment can be less frequent than during the initiation phase. The interval depends on the probability of being outside the control limits, which in turn depends on both random drift and systematic changes (progression or regression of disease).
The measurements intervals may be shorter than the decision interval. For example, monitoring measurements of blood pressure might be done daily by patients, but the decision made at a monthly consultation with the doctor. This is illustrated in figure 1, where multiple measures (3(b)—small arrows) occur between the decision points (3(a)—large arrows). Ideally a graphical presentation, such as a control chart, should be used to aid recording and deciding treatment changes.
Adjustment to re-establish control
When a clear drift beyond the control limits occurs, we should re-establish control. As in the initiation phase, a shorter measurement interval is generally warranted until control is re-established.
We have already cited several examples (for example, monitoring digoxin therapy) in which audits have shown that clinical decisions taken as a result of monitoring are suboptimal—sometimes tending to the conservative. A New Zealand study of digoxin monitoring showed that 53% of ordered measurements were inappropriately timed and that 5% of the ordered measurements led to inappropriate dose adjustments.19 Patients too find this difficult: a survey of diabetes educators showed that correct adjustment of insulin dosage is the single hardest skill to teach.20 This may be because of the lack of a planned and explicit response to test results or because the tests are seldom considered in context—they usually arrive as a single value, without reference to past values or a clear and useful statement about the variability of measurements. The appropriate degree of adjustment may be helped by nomograms or computer algorithms.
Cessation of treatment
Most therapies are not lifelong. Monitoring should inform stopping decisions. Again, such decisions are usually based on a threshold level—either a negative outcome (such as an adverse effect on renal function or frequency of epileptic seizures exceeding a threshold), or a positive outcome (such as pain relief) that falls below a minimum threshold. However, the precise thresholds chosen and the monitoring interval depend on the phase of treatment. Cessation of treatment mirrors the first phases of pre-treatment and initiating treatment. A decision to stop based on current risks and control is made, treatment is withdrawn (perhaps in stages), and, after a "washout" period, the patient is rechecked to ensure that treatment does not need to be restarted.
Monitoring strategy
Although monitoring is common in clinical practice, the principles of monitoring have not been well conceptualised, which in turn has led to suboptimal care. Chronic care could potentially be improved (and often at reduced costs) if for each chronic disease we determined whether and how monitoring was necessary, set explicit monitoring ranges and provided appropriate graphical representations that aided decision making, recognised the need for different optimal intervals for different phases, and understood better when and how to adjust treatment to avoid the increases in variability caused by overadjustment. Health professionals working in chronic care need to understanding these principles better, and systems needs to be improved, including use of appropriate decision aids that have been shown to improve monitoring care.28
Additional educational resources
For patients and clinicians
National electronic Library for Health (www.nelh.nhs.uk)—contains UK relevant guidelines on monitoring for many areas. A search on "monitoring" and choosing "evidence" provides the evidence base for a number of monitoring topics
The BTS/SIGN British Guideline for Asthma (www.brit-thoracic.org.uk/sign/index.htm)—few long term conditions have appropriate monitoring charts, but asthma is one of the better served. A printable peak flow diary is downloadable from the websites of the British Thoracic Society and Scottish Intercollegiate Guidelines Network (www.brit-thoracic.org.uk/sign/mainframe_download.html)
For researchers
Westgard QC (www.westgard.com)—a website for laboratory tests, which includes a database of within person variation for over 100 tests (see "Biologic Variation Database"), and the Westgard rules for detect readings beyond control limits
Summary points
Monitoring aims to establish the response to treatment, detect the need to adjust treatment, and detect adverse effects
Monitoring is not always necessary or beneficial and can lead to inappropriate changes
Control charts help distinguish natural variability from true change and reduce unnecessary adjustment
Monitoring for both benefit and harm is important, preferably with a single measurement
The interval between measurements varies between phases and is shorter after changes in treatment
We thank Andrew Farmer, Jeffrey Aronson, and Tom Fahey for detailed comments on various drafts, and Susan Jack who help with initial searches and problem formulation.
Contributors: PG conceived the study, and all authors contributed to the ideas and writing. PG is guarantor.
Funding: PG and LI were in part funded by the Australian National Health and Medical Research Council for this work, as part of a programme grant 211205 on testing.
Competing interests: None declared.
References
Clague HW, Twum-Barima Y, Carruthers SG. An audit of requests for therapeutic drug monitoring of digoxin: problems and pitfalls. Ther Drug Monit 1983;5: 249-54.
Chen P, Tanasijevic MJ, Schoenenberger RA, Fiskio J, Kuperman GJ, Bates DW. A computer-based intervention for improving the appropriateness of antiepileptic drug level monitoring. Am J Clin Pathol 2003;119: 432-8.
Ryan PJ, Gilbert M, Rose PE. Computer control of anticoagulant dose for therapeutic management. BMJ 1989;299: 1207-8.
Gibson PG, Wlodarczyk J, Hensley MJ, Murree-Allen K, Olson LG, Saltos N. Using quality-control analysis of peak expiratory flow recordings to guide therapy for asthma. Ann Intern Med 1995;123: 488-92.
Jannuzzi G, Cian P, Fattore C, Gatti G, Bartoli A, Monaco F, Perucca E. A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy. Epilepsia 2000;41: 222-30.
Rachmani R, Levi Z, Slavachevski I, Avin M, Ravid M. Teaching patients to monitor their risk factors retards the progression of vascular complications in high-risk patients with Type 2 diabetes mellitus—a randomized prospective study. Diabet Med 2002;19: 385-92.
Robertson I, Phillips A, Mant D, Thorogood M, Fowler G, Fuller A, Yudkin P, Woods M. Motivational effect of cholesterol measurement in general practice health checks. Br J Gen Pract 1992;42: 469-72.
Yoos HL, Kitzman H, McMullen A, Henderson C, Sidora K Symptom monitoring in childhood asthma: a randomized clinical trial comparing peak expiratory flow rate with symptom monitoring. Ann Allerg Asthma Immunol 2002;88: 283-91
Bland JM, Altman DG. Regression towards the mean. BMJ 1994;308: 1499.
Dauber TR. The Framingham study: the epidemiology of atherosclerotic disease. Cambridge, MA: Harvard University Press, 1980.
Brueren MM, Petri H, van Weel C, van Ree JW. How many measurements are necessary in diagnosing mild to moderate hypertension? Fam Pract 1997;14: 130-5.
Peyvandi F, Spreafico M, Siboni SM, Moia M, Mannucci PM. CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulation therapy. Clin Pharmacol Ther 2004;75: 198-203.
Braithwaite RA, Dawling S, Montgomery SA. Prediction of steady-state plasma concentrations and individual dosage regimens of tricyclic antidepressants from a single test dose. Ther Drug Monit 1982;4: 27-31.
Guyatt GH, Keller JL, Jaeschke R, Rosenbloom D, Adachi JD, Newhouse MT. The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience. Ann Intern Med 1990;112: 293-9.
Irwig L, Glasziou P, Wilson A, Macaskill P. Estimating an individual's true cholesterol level and response to intervention. JAMA 1991;266: 1678-85.
Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 2003;327: 1222-5.
Pirmohamed M, Ferner RE. Monitoring drug treatment. BMJ 2003;327: 1179-81.
Boggs PB, Hayati FH, Washburne WF, Wheeler DA. Using statistical process control charts for the continual improvement of asthma care. J Qual Improve 1999:25: 163-81.
Sidwell A, Barcaly M, Begg E, Moore G. Digoxin therapeutic monitoring: an audit and review. N Z Med J 2003;116: U704.
Bonnet C, Gagnayre R, d'Ivernois JF.Learning difficulties of diabetic patients: a survey of educators. Patient Educ Couns 1998;35: 139-47.
Begg CB, Leung D. On the use of surrogate end points in randomized trials. J R Stat Soc A 2000;163: 15-28
Irwig L. This added to my multiple myopia. BMJ 2003;326: 1336.
Scottish Intercollegiate Guidelines Network. Lipids and the primary prevention of coronary heart disease. Edinburgh: SIGN, 1999. www.sign.ac.uk/guidelines/fulltext/40/index.html (accessed 5 Jan 2005).
Smith DH, Matzek KM, Kempthorne-Rawson J. Dose response and safety of telmisartan in patients with mild to moderate hypertension. J Clin Pharmacol 2000;40: 1380-90.
Lowy. A memorable patient: Home glucose monitoring, who started it? BMJ 1998;316: 1467.
Cappuccio FP, Kerry SM, Forbes L, Donald A. Blood pressure control by home monitoring: meta-analysis of randomised trials. BMJ 2004;329: 145-8.
Thoonen BP, Schermer TR, van Den Boom G, Molema J, Folgering H, Akkermans RP, et al. Self-management of asthma in general practice, asthma control and quality of life: a randomised controlled trial. Thorax 2003;58: 30-6
Schroeder K, Fahey T, Ebrahim S. How can we improve adherence to blood pressure-lowering medication in ambulatory care? Systematic review of randomized controlled trials. Arch Intern Med 2004;164: 722-32.(Paul Glasziou, professor1, Les Irwig, pr)
Correspondence to: P Glasziou paul.glasziou@dphpc.ox.ac.uk
The objective and methods of monitoring change over the course of treatment. This course of monitoring can be usefully divided into the five phases listed in table 1.
The objectives for the five phases of monitoring
Figure 1 shows a control chart for these stages. At (a) we first note the abnormal measurement and begin a quick series of measurements before treatment to confirm the abnormal result; (b) then, if appropriate, initiate treatment and monitor at short intervals to check response and achieve control; (c) but once control is achieved, the intervals may be longer (d), although this may be supplemented by patients' self monitoring (small arrows) (e); but when one measurement is more than 3 standard deviations (SD) or two measurements are more than 2 standard deviations from target, we adjust therapy to re-establish control and shorten the re-check interval; and finally (f), if treatment becomes unnecessary, a period of monitoring after its cessation may be required. We now look at these phases in more detail.
Fig 1 The five phases of treatment monitoring
Pretreatment monitoring
Monitoring before treatment should establish the need for treatment and then a baseline to judge the response to treatment or changes in the patient's condition. Treatment should not start until sufficient measurements for a firm baseline have been obtained. This firm baseline confirms that the degree of abnormality is beyond the initiation threshold. Serial measurements often "normalise" before treatment for several reasons, such as training effects (for example, with a peak flow meter), accommodation to measurement (for example, with blood pressure measurement), and, perhaps most importantly, regression to the mean (the tendency of repeat tests to be closer to normal9). For example, in the first biennial check in the Framingham study, the average blood pressure fell by 3.4 mm Hg systolic and 2.4 mm Hg diastolic.10 Among 99 Dutch patients with apparently raised blood pressure, re-measurement resulted in average reductions of 9 mm Hg systolic and 4 mm Hg diastolic.11 The same study showed that two measurements were sufficient to establish the need for treatment in patients who were well above the initiation threshold. For borderline patients, even four measurements resulted in substantial misclassification.
Initial titration: response, control, and safety
After establishing the baseline, we should set a target and start titration to achieve that target. However, achieving the target is just one of several objectives of the initial titration phase, which should include checking the individual's response to treatment, detecting unacceptable adverse effects, and achieving the desired target range.
This initial monitoring checks adequate response to treatment—that is, whether it "works" as expected on the basis of clinical trials in other patients. Sometimes individual response to treatment can be predicted by other measurements, such as genetic testing (for example, the dose requirement on initiating warfarin treatment is strongly related to CYP2C9 gene variants12). Sometimes it can be predicted by pharmacokinetic studies—for example, in initiating tricyclic antidepressants, short term measurement of the drug concentration can characterise individual metabolism and guide the long term dose used.13 However, personalising treatment usually requires some pragmatic trial and error. We can therefore think of this phase as an "n = 1" trial.14 Ideally, the estimate of effect will be based on both the measurements in that patient and the known effect from trials.15
The initiation phase should also detect immediate or short term adverse effects.16 Measures of potential harm should hence be assessed and monitored. Almost half of the medicines in the electronic Medicines Compendium (www.medicines.org.uk) include a suggestion for some monitoring. Many drugs affect renal function, and regular monitoring of creatinine and electrolytes is widely recommended. A more specific example is treatment with clozapine, for which white cell counts are measured on a weekly basis for the first few months to detect agranulocytosis, which occurs in 0.8% of patients. However, the rationale for the timing of measurement is seldom explicit. The criteria for monitoring for adverse effects are similar to those for screening, including that the effect is serious, that a simple test is available, that earlier detection is predictive, and that change in treatment leads to a better outcome.17
Monitoring during treatment
Once the target is achieved, the objective of monitoring is to ensure that measurements stay within reasonable limits, called control limits. The control limits ensure that we detect real changes in the level of the target measure while minimising false positives resulting from variable measurements in the short term or errors in the technical measurement. The degree of short term variation can be estimated from population studies, subpopulations, or from the individual's own measurements. Because extreme measurements are unlikely to be due to variability of short term measurements, they may justify action to re-establish control. One approach suggested by statistical control theory is to consider that a shift from control has occurred if a single measurement is outside an upper and lower control limit of 3 standard deviations, or if two or three successive measurements are more than 2 standard deviations from the target.18 Figure 1 shows these two sets of action thresholds; one for action (SD 3) and one for re-measurement (SD 2), with action if the repeat result is also more than 2 standard deviations from target.
Monitoring during treatment can be less frequent than during the initiation phase. The interval depends on the probability of being outside the control limits, which in turn depends on both random drift and systematic changes (progression or regression of disease).
The measurements intervals may be shorter than the decision interval. For example, monitoring measurements of blood pressure might be done daily by patients, but the decision made at a monthly consultation with the doctor. This is illustrated in figure 1, where multiple measures (3(b)—small arrows) occur between the decision points (3(a)—large arrows). Ideally a graphical presentation, such as a control chart, should be used to aid recording and deciding treatment changes.
Adjustment to re-establish control
When a clear drift beyond the control limits occurs, we should re-establish control. As in the initiation phase, a shorter measurement interval is generally warranted until control is re-established.
We have already cited several examples (for example, monitoring digoxin therapy) in which audits have shown that clinical decisions taken as a result of monitoring are suboptimal—sometimes tending to the conservative. A New Zealand study of digoxin monitoring showed that 53% of ordered measurements were inappropriately timed and that 5% of the ordered measurements led to inappropriate dose adjustments.19 Patients too find this difficult: a survey of diabetes educators showed that correct adjustment of insulin dosage is the single hardest skill to teach.20 This may be because of the lack of a planned and explicit response to test results or because the tests are seldom considered in context—they usually arrive as a single value, without reference to past values or a clear and useful statement about the variability of measurements. The appropriate degree of adjustment may be helped by nomograms or computer algorithms.
Cessation of treatment
Most therapies are not lifelong. Monitoring should inform stopping decisions. Again, such decisions are usually based on a threshold level—either a negative outcome (such as an adverse effect on renal function or frequency of epileptic seizures exceeding a threshold), or a positive outcome (such as pain relief) that falls below a minimum threshold. However, the precise thresholds chosen and the monitoring interval depend on the phase of treatment. Cessation of treatment mirrors the first phases of pre-treatment and initiating treatment. A decision to stop based on current risks and control is made, treatment is withdrawn (perhaps in stages), and, after a "washout" period, the patient is rechecked to ensure that treatment does not need to be restarted.
Monitoring strategy
Although monitoring is common in clinical practice, the principles of monitoring have not been well conceptualised, which in turn has led to suboptimal care. Chronic care could potentially be improved (and often at reduced costs) if for each chronic disease we determined whether and how monitoring was necessary, set explicit monitoring ranges and provided appropriate graphical representations that aided decision making, recognised the need for different optimal intervals for different phases, and understood better when and how to adjust treatment to avoid the increases in variability caused by overadjustment. Health professionals working in chronic care need to understanding these principles better, and systems needs to be improved, including use of appropriate decision aids that have been shown to improve monitoring care.28
Additional educational resources
For patients and clinicians
National electronic Library for Health (www.nelh.nhs.uk)—contains UK relevant guidelines on monitoring for many areas. A search on "monitoring" and choosing "evidence" provides the evidence base for a number of monitoring topics
The BTS/SIGN British Guideline for Asthma (www.brit-thoracic.org.uk/sign/index.htm)—few long term conditions have appropriate monitoring charts, but asthma is one of the better served. A printable peak flow diary is downloadable from the websites of the British Thoracic Society and Scottish Intercollegiate Guidelines Network (www.brit-thoracic.org.uk/sign/mainframe_download.html)
For researchers
Westgard QC (www.westgard.com)—a website for laboratory tests, which includes a database of within person variation for over 100 tests (see "Biologic Variation Database"), and the Westgard rules for detect readings beyond control limits
Summary points
Monitoring aims to establish the response to treatment, detect the need to adjust treatment, and detect adverse effects
Monitoring is not always necessary or beneficial and can lead to inappropriate changes
Control charts help distinguish natural variability from true change and reduce unnecessary adjustment
Monitoring for both benefit and harm is important, preferably with a single measurement
The interval between measurements varies between phases and is shorter after changes in treatment
We thank Andrew Farmer, Jeffrey Aronson, and Tom Fahey for detailed comments on various drafts, and Susan Jack who help with initial searches and problem formulation.
Contributors: PG conceived the study, and all authors contributed to the ideas and writing. PG is guarantor.
Funding: PG and LI were in part funded by the Australian National Health and Medical Research Council for this work, as part of a programme grant 211205 on testing.
Competing interests: None declared.
References
Clague HW, Twum-Barima Y, Carruthers SG. An audit of requests for therapeutic drug monitoring of digoxin: problems and pitfalls. Ther Drug Monit 1983;5: 249-54.
Chen P, Tanasijevic MJ, Schoenenberger RA, Fiskio J, Kuperman GJ, Bates DW. A computer-based intervention for improving the appropriateness of antiepileptic drug level monitoring. Am J Clin Pathol 2003;119: 432-8.
Ryan PJ, Gilbert M, Rose PE. Computer control of anticoagulant dose for therapeutic management. BMJ 1989;299: 1207-8.
Gibson PG, Wlodarczyk J, Hensley MJ, Murree-Allen K, Olson LG, Saltos N. Using quality-control analysis of peak expiratory flow recordings to guide therapy for asthma. Ann Intern Med 1995;123: 488-92.
Jannuzzi G, Cian P, Fattore C, Gatti G, Bartoli A, Monaco F, Perucca E. A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy. Epilepsia 2000;41: 222-30.
Rachmani R, Levi Z, Slavachevski I, Avin M, Ravid M. Teaching patients to monitor their risk factors retards the progression of vascular complications in high-risk patients with Type 2 diabetes mellitus—a randomized prospective study. Diabet Med 2002;19: 385-92.
Robertson I, Phillips A, Mant D, Thorogood M, Fowler G, Fuller A, Yudkin P, Woods M. Motivational effect of cholesterol measurement in general practice health checks. Br J Gen Pract 1992;42: 469-72.
Yoos HL, Kitzman H, McMullen A, Henderson C, Sidora K Symptom monitoring in childhood asthma: a randomized clinical trial comparing peak expiratory flow rate with symptom monitoring. Ann Allerg Asthma Immunol 2002;88: 283-91
Bland JM, Altman DG. Regression towards the mean. BMJ 1994;308: 1499.
Dauber TR. The Framingham study: the epidemiology of atherosclerotic disease. Cambridge, MA: Harvard University Press, 1980.
Brueren MM, Petri H, van Weel C, van Ree JW. How many measurements are necessary in diagnosing mild to moderate hypertension? Fam Pract 1997;14: 130-5.
Peyvandi F, Spreafico M, Siboni SM, Moia M, Mannucci PM. CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulation therapy. Clin Pharmacol Ther 2004;75: 198-203.
Braithwaite RA, Dawling S, Montgomery SA. Prediction of steady-state plasma concentrations and individual dosage regimens of tricyclic antidepressants from a single test dose. Ther Drug Monit 1982;4: 27-31.
Guyatt GH, Keller JL, Jaeschke R, Rosenbloom D, Adachi JD, Newhouse MT. The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience. Ann Intern Med 1990;112: 293-9.
Irwig L, Glasziou P, Wilson A, Macaskill P. Estimating an individual's true cholesterol level and response to intervention. JAMA 1991;266: 1678-85.
Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 2003;327: 1222-5.
Pirmohamed M, Ferner RE. Monitoring drug treatment. BMJ 2003;327: 1179-81.
Boggs PB, Hayati FH, Washburne WF, Wheeler DA. Using statistical process control charts for the continual improvement of asthma care. J Qual Improve 1999:25: 163-81.
Sidwell A, Barcaly M, Begg E, Moore G. Digoxin therapeutic monitoring: an audit and review. N Z Med J 2003;116: U704.
Bonnet C, Gagnayre R, d'Ivernois JF.Learning difficulties of diabetic patients: a survey of educators. Patient Educ Couns 1998;35: 139-47.
Begg CB, Leung D. On the use of surrogate end points in randomized trials. J R Stat Soc A 2000;163: 15-28
Irwig L. This added to my multiple myopia. BMJ 2003;326: 1336.
Scottish Intercollegiate Guidelines Network. Lipids and the primary prevention of coronary heart disease. Edinburgh: SIGN, 1999. www.sign.ac.uk/guidelines/fulltext/40/index.html (accessed 5 Jan 2005).
Smith DH, Matzek KM, Kempthorne-Rawson J. Dose response and safety of telmisartan in patients with mild to moderate hypertension. J Clin Pharmacol 2000;40: 1380-90.
Lowy. A memorable patient: Home glucose monitoring, who started it? BMJ 1998;316: 1467.
Cappuccio FP, Kerry SM, Forbes L, Donald A. Blood pressure control by home monitoring: meta-analysis of randomised trials. BMJ 2004;329: 145-8.
Thoonen BP, Schermer TR, van Den Boom G, Molema J, Folgering H, Akkermans RP, et al. Self-management of asthma in general practice, asthma control and quality of life: a randomised controlled trial. Thorax 2003;58: 30-6
Schroeder K, Fahey T, Ebrahim S. How can we improve adherence to blood pressure-lowering medication in ambulatory care? Systematic review of randomized controlled trials. Arch Intern Med 2004;164: 722-32.(Paul Glasziou, professor1, Les Irwig, pr)