Clinical prediction tools to identify patients at highest risk of myeloma in primary care: a retrospective open cohort study

Constantinos Koshiaris; Ann Van den Bruel; Brian D Nicholson; Sarah Lay-Flurrie; FD Richard Hobbs; Jason L Oke

doi:10.3399/BJGP.2020.0697

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Figure 1.
Calibration and discrimination of full blood count model.
AUC = area under curve.
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Figure 2.
Calibration and discrimination of all-test model.
AUC = area under curve.

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Multiple myeloma is a haematological cancer in which 50% of patients experience symptoms for at least 3 months before diagnosis and have multiple consultations in primary care before referral to secondary care. Symptoms on their own are not predictive enough to suggest referral and they have to be combined with abnormalities in blood tests. The authors of the present study developed two clinical prediction rules that combine patient characteristics, symptoms, and common blood tests to identify patients at high risk of having undiagnosed myeloma. The study found that the prediction rules were shown to have good discrimination, and have the potential to reduce the delays observed in the diagnosis of myeloma.

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Table 1.

Descriptive statistics for derivation dataset

Variable	Missing data (n = 835 404), n (%)^a	Non-myeloma (n= 834 909), n (%)^a	Myeloma (n= 495), n (%)^a
Demographics
Female	0 (0.0)	492 039 (58.9)	227 (45.9)
Mean age, years (SD)	0 (0.0)	63.7 (13.8)	70.9 (10.5)
Mean BMI (SD)	541 782 (64.9)	28.5 (6.2)	26.5 (4.6)

Symptoms
Back pain	0 (0.0)	78 291 (9.4)	94 (19.0)
Chest pain	0 (0.0)	53 256 (6.4)	56 (11.3)
Bone pain	0 (0.0)	12 933 (1.5)	12 (2.4)
Rib pain	0 (0.0)	3809 (0.5)	8 (1.6)
Joint pain	0 (0.0)	35 348 (4.2)	19 (3.8)
Shortness of breath	0 (0.0)	66 047 (7.9)	53 (10.7)
Chest infections	0 (0.0)	54 198 (6.5)	40 (8.1)
Fatigue	0 (0.0)	66 903 (8.0)	34 (6.9)
Nosebleeds	0 (0.0)	7022 (0.8)	14 (2.8)
Bruising	0 (0.0)	8682 (1.0)	5 (1.0)
Fracture	0 (0.0)	13 361 (1.6)	12 (2.4)
Weight loss	0 (0.0)	10 985 (1.3)	12 (2.4)
Nausea	0 (0.0)	25 126 (3.0)	21 (4.2)

Blood tests
2nd FBC test (index)
Mean haemoglobin (SD)	50 292 (6.0)	13.5 (1.6)	12.0 (1.9)
Mean white cell count (SD)	62 843 (7.5)	7.3 (5.2)	6.5 (3.6)
Mean platelets (SD)	67 222 (8.0)	265.4 (80.2)	247.4 (80.6)
Mean MCV (SD)	72 537 (8.7)	90.6 (5.9)	93.5 (6.1)

Difference in FBC parameters (2nd – 1st)
Mean haemoglobin diff (SD)	87 941 (10.5)	0.01 (1.0)	−0.25 (1.1)
Mean white cell count diff (SD)	101 091 (12.1)	−0.04 (5.3)	0.13 (2.3)
Mean platelets diff (SD)	107 485 (12.9)	−1.8 (54.9)	−2.9 (61.1)
Mean MCV diff (SD)	114 841 (13.7)	0.19 (3.1)	−0.06 (2.4)

Other tests
Mean calcium (SD)	634 969 (76.0)	2.3 (0.12)	2.4 (0.18)
Mean creatinine (SD)	453 831 (54.3)	89.3 (30.2)	99.9 (44.9)
Mean ESR (SD)	621 155 (74.4)	18.6 (19.5)	55.3 (41.7)
CRP, median (IQR)	679 841 (81.4)	5 (2 to 10)	5 (2.5 to 17)
Mean PV (SD)	798 298 (95.6)	1.71 (0.16)	1.96 (0.73)

Blood tests (normal/abnormal)^b
FBC (index test)
Anaemia	50 292 (6.0)	120 247/784 649 (15.3)	269/463 (58.1)
Leukopenia	62 843 (7.5)	22 424/772 119 (2.9)	59/442 (13.3)
Low platelets	67 222 (8.0)	25 165/767 738 (3.3)	44/444 (9.9)
High MCV	72 537 (8.7)	52 385/762 443 (6.9)	85/424 (20.0)

Other tests^b
Abnormal calcium	634 969 (76.0)	4056/200 263 (2.0)	14/172 (8.1)
High creatinine	453 831 (54.3)	56 106/381 341 (14.7)	63/232 (27.2)
High ESR	621 155 (74.4)	89 735/214 088 (41.9)	129/161 (80.1)
High CRP	679 841 (81.4)	51 000/155 452 (32.8)	47/111 (42.3)
High PV	798 298 (95.6)	14 080/37 084 (38.0)	15/22 (68.2)

↵a Unless otherwise stated.
↵b Percentages reported for patients with complete data. Denominator displayed to indicate where missing data applies. BMI = body mass index. CRP = C-reactive protein. ESR = erythrocyte sedimentation rate. FBC = full blood count. IQR = interquartile range. MCV = mean corpuscular volume. PV = plasma viscosity. SD = standard deviation.

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Table 2.

Adjusted hazard ratios (95% CI) for the final models for myeloma

Variable	FBC model,^a	All-test model,^b
Variable	HR (95% CI)	HR (95% CI)
Demographics
Female	0.45 (0.37 to 0.54)	0.48 (0.39 to 0.58)
Age^c	FP (0.5, 0.5)	FP (0.5, 0.5)

Symptoms
Back pain	2.37 (1.89 to 2.98)	2.46 (1.96 to 3.10)
Chest pain	1.76 (1.33 to 2.33)	1.85 (1.39 to 2.45)
Rib pain	2.94 (1.46 to 5.99)	2.81 (1.38 to 5.72)
Nosebleeds	2.26 (1.32 to 3.85)	2.11 (1.23 to 3.61)

FBC
Haemoglobin^c	FP (3, 3)	FP (3, 3)
White cell count^c	FP (−2, −2)	FP (−2, −2)
Platelets^c	FP (−1, −0.5)	FP (−0.5, 0)
MCV^c	FP (3, 3)	FP (3, 3)

Other tests
ESR	NA	1.03 (1.03 to 10.33)
Calcium^c	NA	FP (−1)

↵a FBC model contains a single FBC.
↵b All-test model contains a single FBC, plus ESR and calcium.
↵c Numerals in parenthesis represent the transformations used. CI = confidence interval. ESR = erythrocyte sedimentation rate.
FBC = full blood count. FP = fractional polynomials. HR = hazard ratio. MCV = mean corpuscular volume. NA = not applicable.

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Table 3.

Comparison of different diagnostic approaches in the validation cohort (after performing imputation)^a

Variable	Pr, %^b	Sensitivity, % (95% CI)	Specificity, % (95% CI)	LR+ (95% CI)	LR– (95% CI)	PPV, % (95% CI)	NPV, % (95% CI)
Symptoms
Back pain	NA	21.5 (16.5 to 27.2)	91.2 (91.1 to 91.3)	2.4 (1.9 to 3.1)	0.86 (0.81 to 0.92)	0.13 (0.10 to 0.17)	99.95 (99.94 to 99.96)
Rib pain	NA	1.2 (0.3 to 3.6)	99.5 (99.5 to 99.5)	2.5 (0.8 to 7.7)	0.99 (0.99 to 1.0)	0.14 (0.01 to 0.29)	99.94 (99.94 to 99.95)
Chest pain	NA	9.1 (5.8 to 13.4)	93.6 (93.6 to 93.7)	1.4 (0.9 to 2.1)	0.97 (0.93 to 1.0)	0.08 (0.05 to 0.11)	99.95 (99.94 to 99.95)
Nosebleeds	NA	1.2 (0.3 to 3.6)	99.2 (99.2 to 99.2)	1.6 (0.5 to 4.9)	0.99 (0.98 to 1.0)	0.09 (0.01 to 0.18)	99.94 (99.94 to 99.95)

FBC (index test)
Anaemia (any type)	NA	55.6 (48.6 to 62.5)	83.6 (83.5 to 83.7)	3.4 (3.2 to 3.6)	0.53 (0.39 to 0.67)	0.18 (0.15 to 0.21)	99.97 (99.96 to 99.98)
Normocytic anaemia	NA	43.5 (37.0 to 50.0)	85.1 (84.9 to 85.2)	2.9 (2.7 to 3.2)	0.66 (0.54 to 0.77)	0.15 (0.13 to 0.19)	99.96 (99.95 to 99.97)
Macrocytic anaemia	NA	11.9 (8.1 to 15.8)	98.5 (98.4 to 98.6)	8.1 (6.3 to 9.8)	0.89 (0.84 to 0.95)	0.43 (0.26 to 0.61)	99.95 (99.94 to 99.96)
Low platelets	NA	8.3 (5.5 to 11.1)	96.5 (96.4 to 96.6)	2.4 (1.9 to 2.9)	0.95 (0.91 to 0.98)	0.13 (0.07 to 0.18)	99.95 (99.94 to 99.96)
Low WCC	NA	7.0 (4.5 to 9.6)	96.9 (96.9 to 97.0)	2.3 (1.7 to 2.9)	0.96 (0.93 to 0.99)	0.13 (0.06 to 0.19)	99.94 (99.94 to 99.95)
High MCV	NA	22.9 (17.5 to 28.4)	91.6 (91.5 to 91.7)	2.8 (2.3 to 3.2)	0.84 (0.76 to 0.92)	0.15 (0.10 to 0.19)	99.95 (99.94 to 99.96)

Other tests
Hypercalcemia	NA	5.7 (1.9 to 9.6)	98.3 (98.2 to 98.4)	3.4 (1.3 to 5.5)	0.96 (0.91 to 1.0)	0.19 (0.04 to 0.33)	99.95 (99.94 to 99.96)
High ESR	NA	80.3 (70.4 to 90.3)	54.8 (54.5 to 55.1)	1.7 (1.6 to 1.9)	0.35 (0.08 to 0.63)	0.10 (0.08 to 0.11)	99.98 (99.97 to 99.99)
High ESR or anaemia	NA	90.5 (81.4 to 99.5)	50.0 (49.8 to 50.3)	1.8 (1.7 to 1.9)	0.19 (0.13 to 0.28)	0.10 (0.08 to 0.12)	99.99 (99.98 to 99.99)
High ESR and anaemia	NA	45.5 (38.9 to 51.9)	88.4 (88.2 to 88.5)	3.9 (3.6 to 4.2)	0.62 (0.50 to 0.74)	0.20 (0.17 to 0.25)	99.96 (99.96 to 99.97)

FBC model
77th percentile^c	0.06	78.9 (73.2 to 83.9)	77.2 (77.1 to 77.3)	3.5 (3.2 to 3.7)	0.27 (0.21 to 0.35)	0.19 (0.16 to 0.22)	99.98 (99.97 to 99.98)
90th percentile	0.12	61.6 (55.1 to 67.7)	90.2 (90.1 to 90.3)	6.3 (5.7 to 6.9)	0.43 (0.36 to 0.50)	0.34 (0.29 to 0.40)	99.98 (99.97 to 99.98)
95th percentile	0.20	41.3 (35.1 to 47.8)	95.1 (95.0 to 95.2)	8.4 (7.3 to 9.8)	0.62 (0.55 to 0.69)	0.46 (0.37 to 0.55)	99.96 (99.96 to 99.97)
99th percentile	0.60	18.2 (13.5 to 23.6)	99.1 (99.1 to 99.1)	19.9 (15.2 to 26.1)	0.83 (0.78 to 0.88)	1.10 (0.80 to 1.40)	99.95 (99.95 to 99.96)
99.5th percentile	0.90	12.8 (8.9 to 17.7)	99.5 (99.5 to 99.6)	27.6 (19.8 to 38.4)	0.88 (0.84 to 0.92)	1.50 (1.00 to 2.10)	99.95 (99.95 to 99.96)
99.9th percentile	2.20	4.1 (2.0 to 7.5)	99.9 (99.9 to 99.9)	42.4 (23.5 to 82.9)	0.96 (0.94 to 0.99)	2.30 (1.10 to 4.10)	99.95 (99.94 to 99.95)

All-test model
84th percentile^c	0.06	82.6 (77.3 to 87.2)	83.9 (83.8 to 84.0)	5.1 (4.8 to 5.4)	0.21 (0.16 to 0.27)	0.28 (0.24 to 0.32)	99.98 (99.98 to 99.99)
90th percentile	0.09	71.9 (65.8 to 77.5)	90.3 (90.2 to 90.4)	7.4 (6.9 to 8.0)	0.31 (0.25 to 0.38)	0.40 (0.34 to 0.47)	99.98 (99.97 to 99.98)
95th percentile	0.15	62.4 (56.8 to 68.5)	95.1 (95.0 to 95.1)	12.9 (11.7 to 14.2)	0.40 (0.34 to 0.47)	0.70 (0.59 to 0.81)	99.98 (99.97 to 99.98)
99th percentile	0.45	34.3 (28.3 to 40.6)	99.0 (99.0to 99.1)	35.1 (29.4 to 41.9)	0.66 (0.61 to 0.73)	1.9 (1.5 to 2.3)	99.96 (99.96 to 99.97)
99.5th percentile	0.70	24.0 (18.7 to 29.9)	99.5 (99.5 to 99.5)	48.9 (38.9 to 61.4)	0.76 (0.71 to 0.82)	2.6 (2.0 to 3.3)	99.96 (99.95 to 99.96)
99.9th percentile	1.90	7.8 (4.8 to 12.0)	99.9 (99.9 to 99.9)	80.5 (51.8 to 125.0)	0.92 (0.89 to 0.96)	4.2 (2.5 to 6.4)	99.95 (99.94 to 99.95)

↵a Results presented are based on multiple imputation as described in the methods section.
↵b Pr = corresponding probability (%) of the selected risk score percentile.
↵c These percentile values were selected to match the background prevalence in the whole cohort. ESR = erythrocyte sedimentation rate. FBC = full blood count. LR– = negative likelihood ratio. LR+ = positive likelihood ratio. MCV = mean corpuscular volume. NA = not applicable. NPV = negative predictive value. PPV = positive predictive value. WCC = white cell count.

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Table 4.

Performance of the different diagnostic approaches in a population of 100 000 tested individuals based on the validation cohort measures

Variable	Per 100 000 patients (60 myeloma cases), n				Ratio of false alarms to cancers diagnosed	Ratio of true negatives to cancers missed

	Cancers diagnosed	False alarms	Cancers missed	Correctly spared investigations
Symptoms
Back pain	13	8995	47	90 945	692 to 1	1935 to 1
Chest pain	5	5996	55	93 944	1199 to 1	1708 to 1
Rib pain	1	500	59	99 440	500 to 1	1685 to 1
Nosebleeds	1	800	59	99 140	800 to 1	1680 to 1

FBC (index test)
Anaemia (any type)	34	16 990	26	82 950	500 to 1	3190 to 1
Low platelets	5	2998	55	96 942	600 to 1	1763 to 1
Low WCC	4	2999	56	96 941	750 to 1	1731 to 1
High MCV	14	7995	46	91 945	571 to 1	1998 to 1

Other tests
Hypercalcemia^a	4	1999	56	97 941	500 to 1	1748 to 1
High ESR^a	48	44 973	12	54 967	936 to 1	4581 to 1
High ESR or anaemia^a	54	49 970	6	49 970	925 to 1	8328 to 1
High ESR and anaemia^a	27	11 993	33	87 947	444 to 1	2665 to 1

FBC model
Prevalence	48	22 986	12	76 954	479 to 1	6412 to 1
90th percentile	37	9994	23	89 946	270 to 1	3910 to 1
95th percentile	25	4997	35	94 943	200 to 1	2712 to 1
99th percentile	11	999	49	98 941	91 to 1	2019 to 1

All-test model^a
Prevalence	50	16 090	10	83 850	322 to 1	8385 to 1
90th percentile	43	9994	17	89 946	232 to 1	5290 to 1
95th percentile	37	4997	23	94 943	135 to 1	4127 to 1
99th percentile	20	999	40	98 941	25 to 1	2473 to 1

↵a Corresponds to the performance measures if ESR and calcium were to be ordered for all patients in the sample. ESR = erythrocyte sedimentation rate. FBC = full blood count.
MCV = mean corpuscular volume. WCC = white cell count.

Supplementary Data

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