Chemical Pathology Workshop I- Reference Intervals and Decision Values PDF 2024

Reference Intervals and Clinical Decision Values Professor CW Lam Chemical Pathology Department of Pathology The University of Hong Kong Learning Objectives State the concepts of ‘health’ and ‘reference interval’. Explain...

Reference Intervals and Clinical Decision Values Professor CW Lam Chemical Pathology Department of Pathology The University of Hong Kong Learning Objectives State the concepts of ‘health’ and ‘reference interval’. Explain how to interpret clinical laboratory results of patients using reference intervals and decision levels.  A Laboratory Report ----------------------------------------------------------------------------------------- Na 142 K 4.1 Chloride 106 Urea 8.2 Creatinine 108 What additional information is needed for interpreting this report? What are the missing items? Case 1 Lab No: 20CB1234XXX HKID No: A123xxxx Hospital: ?? Hospital Name: XXX, XXX Hosp No: HN123456xxx Unit/Ward/Bed: QMH/A&E/AE01 / DISCHARGED DOB: DD/MM/YYYY Request Loc: QMH/A&E/AE01 Sex/Age: M/20Y Requesting Dr: DR.____ Ref: Collect Date : 16/11/20 Collect Time : 12:06 Request No. : C1234xxx Ref. Range Units Remark : Decrease GC ----------------------------------------------------------------------------------------- Na 142 136 - 148 mmol/L K 4.1 3.6 - 5.0 mmol/L Chloride 106 100 - 110 mmol/L Urea 8.2 2.5 - 6.4 mmol/L Creatinine 108 67 - 109 umol/L Case 2 Lab No: 20CB1234XXX HKID No: A123xxxx Hospital: ?? Hospital Name: XXX, XXX Hosp No: HN123456xxx Unit/Ward/Bed: QMH/A&E/AE01 / DISCHARGED DOB: DD/MM/YYYY Request Loc: QMH/A&E/AE01 Sex/Age: F/20Y Requesting Dr: DR.____ Ref: Collect Date : 16/11/20 Collect Time : 12:06 Request No. : C1234xxx Ref. Range Units Remark : Decrease GC ----------------------------------------------------------------------------------------- Na 142 136 - 148 mmol/L K 4.1 3.6 - 5.0 mmol/L Chloride 106 100 - 110 mmol/L Urea 8.2 2.5 - 6.4 mmol/L Creatinine 108 H 49 - 82 umol/L Case 3 Lab No: 20CB1234XXX HKID No: A123xxxx Hospital: ?? Hospital Name: XXX, XXX Hosp No: HN123456xxx Unit/Ward/Bed: QMH/A&E/AE01 / DISCHARGED DOB: DD/MM/YYYY Request Loc: QMH/A&E/AE01 Sex/Age: F/20d Requesting Dr: DR.____ Ref: Collect Date : 16/11/20 Collect Time : 12:06 Request No. : C1234xxx Ref. Range Units Remark : Decrease GC ----------------------------------------------------------------------------------------- Na 142 136 - 148 mmol/L K 4.1 3.6 - 5.0 mmol/L Chloride 106 100 - 110 mmol/L Urea 8.2 2.5 - 6.4 mmol/L Creatinine 108 H 27 - 59 umol/L  Factors Influencing Result Interpretation (1) Pre-analytical factors: Patient factors: –Specimen obtained from the correct patient –Age and gender of the patient –Reproductive stage: pregnant, menstrual phase, menopausal status –Diet, drugs, smoking, posture, exercise –Drip arm? Sampling factors: –Quality of the specimen, e.g. haemolysis, prolonged storage –Time of specimen collection e.g. diurnal variation, menstrual phases –Specimen type (plasma, serum, whole blood, urine, CSF etc.) –Transport condition (Room temp, ice, light protected, preservative, pH, etc)  Factors Influencing Result Interpretation (2) Analytical factors: Correct test performed on the correct specimen Performance of the laboratory test e.g. accuracy, imprecision, sensitivity, specificity, predictive values, interference, etc.  Factors Influencing Result Interpretation (3) Post-analytical factors: Manual transcription / computer data uploading Appropriate reference interval provided Why the test was done? Screening/health check Newborn screening, colorectal cancer screening, etc. Diagnosis of disease AMI, DM, etc. Monitoring treatment efficacy Lipid profile after treatment, Therapeutic drug monitoring (TDM), etc. Follow up What is Reference Interval? Source: https://www.ifcc.org/media/476882/ejifcc2008vol19no2pp137-141.pdf Terminology (1) Reference population : a group consisting of all the reference individuals Reference sample group : an adequate number of persons selected to represent the reference population Reference individual : an individual selected from the reference population for testing using defined criteria age, sex, diet, conditions for specimen collection e.g. fasting or non- fasting, morning or afternoon, erect or supine Reference value : a value obtained by observation or measurement of a particular type of quantity on a reference individual in the reference sample group e.g. serum sodium concentration  Terminology (2) Reference distribution : the distribution of reference values Reference limit : a value derived from the reference distribution and used for descriptive purposes, e.g. lower and upper reference limits Reference interval : an interval, between, and including, the upper and lower reference limits, which are values derived from the distribution of results obtained from a sample of the reference population, e.g. serum sodium 135 - 145 mmol/L sometimes only one reference limit is important, e.g. serum bilirubin < 23 μmol/L Reference: Recommendation for the review of biological reference intervals in medical laboratories. Clin Chem Lab Med. 2016;54:1893-1900.  Reference 1) Parametric: Interval: CALCULATION for those data with or assume a Gaussian distribution ~68% within +/- 1SD ~95% within +/- 2SD ~99% within +/- 3SD Reference Interval: mean + 2 SD 2) Non-parametric: No assumption on pattern of distribution Reference Interval: 2.5 and 97.5 percentile Reference interval represents the central 95% of reference individuals Case 4 Lab No: xxxxxxx HKID No: xxxxxxx Hospital: Hospital A Name: xxxx, Hosp No: xxxxxxxxxxxxx Unit/Ward/Bed: XXX/XXX/XXX DOB: DD/MM/YYYY Request Loc: XXX/XXX/XXX Sex/Age: M/65Y Requesting Dr: Dr. A Collect Date : 18/11/20 Collect Time : 11:15 Request No. : xxxxxxx Ref. Range Units Remark : ERECTILE DYSFUNCTI ON ----------------------------------------------------------------------------------------- Testosterone 15 See Below nmol/L Footnotes: Testosterone - Reference Interval : Late Prepubertal 0.35 - 0.7 Adult 10 - 35 Case 5 Lab No: xxxxxxx HKID No: xxxxxxx Hospital: Hospital A Name: xxxx, Hosp No: xxxxxxxxxxxxx Unit/Ward/Bed: XXX/XXX/XXX DOB: DD/MM/YYYY Request Loc: XXX/XXX/XXX Sex/Age: M/6Y Requesting Dr: Dr. A Collect Date : 18/11/20 Collect Time : 11:15 Request No. : xxxxxxx Ref. Range Units Remark : PRECOCIOUS PUBERTY ----------------------------------------------------------------------------------------- Testosterone 15 See Below nmol/L Footnotes: Testosterone - Reference Range : Late Prepubertal 0.35 - 0.7 Adult 10 - 35 Case 6 Lab No: xxxxxxx HKID No: xxxxxxx Hospital: Hospital A Name: xxxx, Hosp No: xxxxxxxxxxxxx Unit/Ward/Bed: XXX/XXX/XXX DOB: DD/MM/YYYY Request Loc: XXX/XXX/XXX Sex/Age: F/65Y Requesting Dr: Dr. A Collect Date : 18/11/20 Collect Time : 11:15 Request No. : xxxxxxx Ref. Range Units Remark : HIRSUTISM ----------------------------------------------------------------------------------------- Testosterone 15 See Below nmol/L Footnotes: Testosterone - Reference Interval : Follicular phase 0.7 – 2.8 Luteal phase 0.7 – 2.8 Postmenopausal 0.28 – 1.20 Partitioning of Reference Intervals The aim is to reduce the variation between subjects so that the reference intervals become more sensitive Necessity for partitioning is assessed by statistical means Factors for Partitioning of Reference Intervals Age Preterm / full-term babies Pubertal stage Non-pregnant / gestational stages / menopausal / menstrual phase Gender Ethnicity Diurnal rhythm Posture Erect / supine Ambulatory / recumbent Diet Fasting / post-prandial etc Some Examples of Blood Analytes Requiring Partitioning of Reference Intervals Age Alkaline phosphatase, creatinine, growth hormone Gender Testosterone, oestrogen Ethnicity Creatinine Diurnal rhythm Cortisol Posture Renin, aldosterone Diet Glucose, lipid profile Case 7a Lab No: XXXXXXXX HKID No: XXXXXXXX Hospital: Hospital A Name: XXX, Hosp No: XXXXXXXXXXX Unit/Ward/Bed: XXX/XXX/XXX DOB: dd/mm/yyyy Request Loc: XXX/XXX/XXX Sex/Age: M/60Y Requesting Dr: DR. A Ref: Collect Date : 18/10/20 Collect Time : 22:00 Request No. : xxxxxxx Ref. Range Units Remark : Bone pain ----------------------------------------------------------------------------------------- Total Protein 74 68 - 84 g/L Albumin 44 39 - 50 g/L Globulin 30 24 - 37 g/L Total Bili 9 4 - 23 umol/L ALP 50 42 - 110 U/L ALT 16 8 - 58 U/L AST 19 15 - 38 U/L Case 7b: Is it normal or abnormal? Lab No: XXXXXXXX HKID No: XXXXXXXX Hospital: Hospital A Name: XXX, Hosp No: XXXXXXXXXXX Unit/Ward/Bed: XXX/XXX/XXX DOB: dd/mm/yyyy Request Loc: XXX/XXX/XXX Sex/Age: M/60Y Requesting Dr: DR. A Ref: Collect Date : 18/10/20 18/11/20 Collect Time : 22:00 10:00 Request No. : xxxxxxx xxxxxxx Ref. Range Units Remark : Bone pain Bone pain ----------------------------------------------------------------------------------------- Total Protein 74 75 68 - 84 g/L Albumin 44 49 39 - 50 g/L Globulin 30 26 24 - 37 g/L Total Bili 9 9 4 - 23 umol/L ALP 50 105 42 - 110 U/L ALT 16 16 8 - 58 U/L AST 19 20 15 - 38 U/L  Intra- vs Inter-individual Variation Sodium Alkaline Phosphatase Reference: Intra-individual variation of some serum constituents and its relevance to population-based reference ranges. Clin Chem. 1977;23:842-50.  Intra-individual Variation vs Inter-individual Variation Intra-individual Variation Inter-individual Variation Change in the concentration Variation between different of a substance inside the individuals body due to physiological For analytes with narrow responses to internal and intra-individual variation, external rhythms and stimuli population-based reference “Biological variation” intervals will be less sensitive e.g. change in plasma cortisol to changes than the concentration throughout individual’s own record of the day, change in hormone test measurements during levels in the menstrual cycle the recent past  Clinical Decision Limits While reference interval can remain quite stable over time, clinical decision limits may change with time with new scientific evidence The dividing lines between the ‘normal’ and the ‘diseased’ or between ‘those who need not be investigated further’ and ‘those who do’ Can be quite distinct from the reference limits for the test Useful for integrating test results to algorithms for diagnosis and clinical management Reference: “Are my Laboratory Results Normal?” Considerations to be Made Concerning Reference Intervals and Decision Limits. EJIFCC. 2008; 19: 106–114. Clinical Decision Limits Bayesian approach: Requires the knowledge of : Definition of the disease Pathogenesis of the disease Clinical (diagnostic) sensitivity of the test Clinical (diagnostic) specificity of the test Prevalence of the disease Clinical costs for misclassification Only a few analytes had the clinical decision limits defined using this approach e.g. cardiac troponin I Lab No: xxxxxxxx HKID No: xxxxxxxx Hospital: Hospital A Name: xxxx, Hosp No: xxxxxxxxxxx Unit/Ward/Bed: xxx/xxx/xxx DOB: dd/mm/yyyy Request Loc: xxx/xxx/xxx Sex/Age: M/80Y Requesting Dr: DR. A Ref: Collect Date : 18/11/20 Collect Time : 11:00 Request No. : xxxxxxxx Ref. Range Units Remark : chest pain ----------------------------------------------------------------------------------------- Troponin T 5.5 See Below ng/L ----------------------------------------------------------------------------------------- Reference Interval Comments Troponin T - Troponin T - result must be interpreted with clinical/imaging/ECG findings. Slightly raised conc. can be seen in heart failure, cardiomyopathies, renal failure, sepsis, diabetes, etc. Reported 99 percentile = 14 ng/L. Optimal cutoff for AMI = 100 ng/L. Clinical Decision Limits Epidemiological approach: Based on population studies and national or international consensus / guidelines The precise choice of the number is arbitrary (often based on easiness to remember) but the rationale is based on outcome studies that demonstrated a different level of survival or a different incidence of complications for patients with concentrations below or above the limit e.g. cholesterol, glucose Clinical decision limits for dyslipidemia Clinical Decision Limits Physiopathological approach: Involves the use of “critical values” which are results representing a pathophysiological state which is life- threatening These limits are somewhat arbitrary being based on clinical experience, usually without the support of any statistical mean e.g. potassium 6.5 mmol/L with life-threatening cardiac arrhythmias or cardiac arrest Reference: “Are my Laboratory Results Normal?” Considerations to be Made Concerning Reference Intervals and Decision Limits. EJIFCC. 2008; 19: 106–114.  Take-home message Tools for clinical interpretation of laboratory results include Reference intervals & intraindividual and interindividual variations Clinical Decisions Limits