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Weight loss as a predictor of cancer and serious disease in primary care: an ISAC-approved CPRD protocol for a retrospective cohort study using routinely collected primary care data from the UK

  • B. D. Nicholson1Email author,
  • P. Aveyard1,
  • F. D. R. Hobbs1,
  • M. Smith1,
  • A. Fuller1,
  • R. Perera1,
  • W. Hamilton2,
  • S. Stevens1 and
  • C. R. Bankhead1
Diagnostic and Prognostic Research20182:1

https://doi.org/10.1186/s41512-017-0019-9

Received: 26 October 2016

Accepted: 16 November 2017

Published: 10 January 2018

Abstract

Background

Unexpected weight loss is a symptom of serious disease in primary care, for example between 1 in 200 and 1 in 30 patients with unexpected weight loss go on to develop cancer. However, it remains unclear how and when general practitioners (GPs) should investigate unexpected weight loss. Without clarification, GPs may wait too long before referring (choosing to watch and wait and potentially missing a diagnosis) or not long enough (overburdening hospital services and exposing patients to the risks of investigation). The overall aim of this study is to provide the evidence necessary to allow GPs to more effectively manage patients with unexpected weight loss.

Methods

A retrospective cohort analysis of UK Clinical Practice Research Datalink (CPRD) data to: (1) describe how often in UK primary care the symptom of reported weight loss is coded, when weight is measured, and how GPs respond to a patient attending with unexpected weight loss; (2) identify the predictive value of recorded weight loss for cancer and serious disease in primary care, using cumulative incidence plots to compare outcomes between subgroups and Cox regression to explore and adjust for covariates. Preliminary work in CPRD estimates that weight loss as a symptom is recorded for approximately 148,000 eligible patients > 18 years and is distributed evenly across decades of age, providing adequate statistical power and precision in relation to cancer overall and common cancers individually. Further stratification by cancer stage will be attempted but may not be possible as not all practices within CPRD are eligible for cancer registry linkage, and staging information is often incomplete. The feasibility of using multiple imputation to address missing covariate values will be explored.

Discussion

This will be the largest reported retrospective cohort of primary care patients with weight measurements and unexpected weight loss codes used to understand the association between weight measurement, unexpected weight loss, and serious disease including cancer. Our findings will directly inform international guidelines for the management of unexpected weight loss in primary care populations.

Keywords

Weight lossEarly detection of cancerSerious diseasePrimary careCohort study

Background

A 2014 systematic review suggests that the positive predictive value (PPV) for cancer is 33% in patients with an unexpected 10% loss of weight from baseline over 6–12 months. The same review reported a wide range of differential diagnoses for patients with unexpected weight loss, including advanced heart failure, chronic obstructive pulmonary disease, renal disease, pancreatic insufficiency, malabsorption, and endocrine disease, with up to 25% of patients without a diagnosis to explain their weight loss after extended follow-up [1]. However, these data mainly come from hospital inpatient populations or patients referred to the outpatient clinic where the prevalence of cancer and serious disease is much higher than in primary care as GPs have already filtered out many cases of weight loss that are more likely to be attributable to another cause. Given the absence of appropriate clinical guidelines or standardised practice, clinicians have been reported to take a wide range of action in response to patients with unexpected weight loss, from doing nothing through to ordering “extensive blind investigations” because of the fear of underlying cancer [2].

On the basis of primary care research, NICE (2015) has since suggested that unexpected weight loss is a sign of seven cancers, citing evidence from 14 studies reporting positive predictive values (PPVs) of 0.4–3% [3]. The problem for GPs is how to interpret and implement the term weight loss in these cancer guidelines: NICE do not define the degree of weight loss, or the time period of loss, that should prompt referral. Most cited studies referred to in the NICE guidelines define weight loss on the basis of a coded entry in the GP record, often based on a report of weight loss (volunteered by, or elicited from, the patient) rather than measured weight change [46]. Only one study referred to by NICE quantified the degree of weight loss that predicts colorectal cancer in primary care reporting odds ratios of 1.2 (95% CI 0.99–1.5) for 5–9.9% and 2.5 (2.1–3) for ≥ 10% weight loss [7]. However, in this study, weight loss was defined by comparing the last recorded weight with the highest recorded weight in the preceding 2 years [7], as weight is not routinely recorded in primary care and is considered a common missing variable in primary care databases [8].

There is an evidence gap for a comprehensive study to describe the use of weight measurement and coding for unexpected weight loss in primary care and for a study that determines the association between unexpected weight loss and cancer and serious disease that may lead to a comprehensive recommendation for the investigation of unexpected weight loss in primary care.

Objective

The overall objective is to provide the evidence necessary to allow GPs to more effectively manage unexpected weight loss.

Aims and rationale

Aim 1.1

To describe how often and when weight is measured, and the symptom of unexpected weight loss recorded as a code, in adults aged > 18 years, in NHS primary care.

Aim 1.2

To describe what action is taken in response to unexpected weight loss, in adults aged > 18 years, in NHS primary care.

Weight measurements and weight loss codes will be categorised using a rule-based search strategy developed as part of this project to identify the clinical purpose and clinical condition related to each weight entry in the primary care record, and the investigations requested, medications prescribed, and referrals made in response to the symptom of weight loss.

Aim 2.1

To identify the predictive value of unexpected weight loss recorded as a symptom for cancer in primary care in adults aged > 18 years.

Aim 2.2

If the symptom of unexpected weight loss predicts cancer, to explore if it is (i) independent of other symptoms, signs, and test results and (ii) restricted to late-stage disease.

Aim 2.3

To ascertain the predictive value of unexpected weight loss recorded as a symptom for serious disease in primary care.

The evidence regarding the predictive value of unexpected weight loss for cancer in primary care, which underpins the 2015 NICE guideline, does not cover all cancer types or take cancer stage at diagnosis into account. We will identify the predictive value of unexpected weight loss in primary care across all cancer types, explore the incremental predictive value of symptom combinations, and examine the association with cancer stage at diagnosis using a matched open cohort study design. In cases where cancer is excluded, an understanding of which alternative diagnoses are related to unexpected weight loss will inform subsequent management decisions in primary care. We will therefore identify the disease groups for which unexpected weight loss is also predictive to develop clinical guidance for the investigation of unexpected weight loss in primary care.

Study type

Aim 1: Descriptive

The descriptive epidemiology of weight measurement and weight loss coding in NHS primary care.

Aims 2.1 and 2.3: Hypothesis testing

A cohort study of weight loss as a sign of cancer and serious disease in NHS primary care.

Aim 2.2: Exploratory

Exploratory analysis to investigate the influence of covariates on the relationship between weight loss and the occurrence of cancer and serious disease.

Study design

The design of the study is an open cohort study.

Sample size

In preparing this ISAC application, a preliminary search of 20 GP practices from 2000 to 2013 was conducted. Of 127,024 patients > 40 years with acceptable records, 80,562 (63.4%) had at least one weight measurement recorded during that period, 30,728 (24.1%) had two weight measurements within 6 months of each other, and 40,436 (31.8%) within 1 year; 3079 (2.4%) of patients had a Read code for weight loss but only half of these had an accompanying weight measurement.

Two thousand one hundred eighty-four patients with weight loss are required to detect a hazard ratio of 2 (a change in incidence of 1.5 to 3%) at 99% power (0.05% alpha) using a ratio of one case to five controls. It is anticipated that the study will therefore have sufficient power for stratification by cancer type, cancer stage, and using symptom combinations even though linkage to cancer registry may only be possible in approximately 60% of cancer cases [9].

Preliminary work in Clinical Practice Research Datalink (CPRD) estimated that that unexpected weight loss is coded as a symptom for about approximately 148,000 patients > 18 years and is distributed evenly across decades of age providing adequate statistical power and precision for a comprehensive cohort study investigating cancer and serious disease in adults (> 18 years). For example, if 3% of patients with weight loss develop cancer the number of Events Per Variable will far exceed the minimum number required for robust statistical modelling.

Data linkage

NCDR Cancer Registry Data

Linkage to the cancer register is required as cancer is a major outcome variable in this cohort study. Cancer registry data will provide more accurate information on cancer site and stage than reliance on the primary care record.

Office of National Statistics (ONS) mortality data

Linkage is required to cross-validate cause of death for patients confirmed to have died of cancer using Cancer Registry Data linkage and to identify or confirm the cause of death in patients with and without serious disease as identified by the GP record.

Index of Multiple Deprivation (IMD) scores

They are required to provide a GP (and where possible patient) level proxy for socioeconomic status to be used when describing both the baseline characteristics in the descriptive analysis of Aim 1 and the cohort analysis of Aim 2. IMD score will also be used as a covariate in the multivariate cox regression analysis as part of Aim 2 (see below).

Study population

The study population is summarised in Fig. 1.
Fig. 1

Flowchart of study populations

Aim 1: Descriptive study

  • NHS patients > 18 years

  • Registered with a GP practice 1 January 2000–31 December 2011

  • Eligible for data linkage with Cancer registry and ONS data

Aim 2: Cohort analysis

Inclusions:
  • NHS patients > 18 years

  • Registered with a GP practice 1 January 2000–31 December 2011

  • Eligible for data linkage with Cancer registry and ONS data.

  • Patients with one of the unexpected weight loss codes (defined in Table 1)

Table 1

Weight measurement and unexpected weight loss codes

Unexpected weight loss codes

Medcode

Readcode

Readterm

126

22A6.00

O/E—underweight

654

1623

Weight decreasing

1581

162..00

Weight symptom

3647

R032.00

[D]Abnormal loss of weight

4663

1625

Abnormal weight loss

5812

1625.11

Abnormal weight loss—symptom

12,398

1D1A.00

Complaining of weight loss

12,530

R034800

[D]Underweight

14,764

162Z.00

Weight symptom NOS

22,005

2224

O/E—cachexic

24,068

R2y4.00

[D]Cachexia

32,914

22K3.00

Body Mass Index low K/M2

37,937

22A8.00

Weight loss from baseline weight

42,309

22A7.00

Baseline weight

53,801

R2y4z00

[D]Cachexia NOS

102,563

1627

Unintentional weight loss

Weight measurement codes

2

22A..00

O/E—weight

8105

22K..00

Body mass index

9015

22K4.00

Body mass index 25–29—overweight

13,278

22K5.00

Body mass index 30+—obesity

21,520

22AZ.00

O/E—weight NOS

22,556

22K7.00

Body mass index 40+—severely obese

24,496

22K6.00

Body mass index less than 20

28,937

22K2.00

Body mass index high K/M2

28,946

22K1.00

Body mass index normal K/M2

44,291

22K8.00

Body mass index 20–24—normal

101,047

22K9.00

Body mass index centile

105,791

22K9000

Baseline body mass index centile

105,800

22KB.00

Baseline body mass index

107,231

22KA.00

Target body mass index

Exclusions:
  • Patients with a diagnosis of cancer prior to the index symptom of weight loss.

Selection of comparison group(s) or controls

Aim 1: Descriptive study

-No comparison group is required.

Aim 2: Cohort analysis

  • A matched cohort of patients without weight loss—patients without a coded entry for weight loss will be matched for age and sex and selected from the population of patients registered with the same practice having consulted within ± 3 months of the index weight loss code.

  • Matching for age and sex will ensure there are sufficient patients without weight loss in each age and sex strata.

  • A 1:5 sampling ratio achieves the best balance between data cost and statistical power (see sample size).

Exposures, outcomes and covariates

Aim 1: Descriptive study

Outcome 1: Objective weight measurement—quantitative weight measurements.

Outcome 2: Weight loss code—Read Codes defined in Table 1.

Patients with objective weight measurements or the symptom of unexpected weight loss recorded using the following Medcodes and Read codes listed in Table 1.

Aim 2: Cohort analysis

Exposure—weight loss

Patients with the symptom of weight loss recorded using the unexpected weight loss Medcodes and Read Codes listed in Table 1. Weight loss codes will be independently categorised for clinical relavence by four co-investigators based on the results of the descriptive analysis, then consensus reached through discussion.   

Outcome—cancer

A library of over 1600 Read Codes and ICD-10 codes (grouped by site—see Table 2) developed by Hamilton and colleagues will be reviewed, updated using Read Code searches, and validated through consensus amongst co-investigators. All new cancer diagnoses in the 24 months following the weight loss code will be identified in CPRD and linked cancer registry data. To inform this analysis, data will also be extracted on cancer stage, grade, tumour size, and histology at diagnosis.
Table 2

Cancer codes

Cancer

Read code

Description

Medcode

ICD 10

Bladder

B490.00

Malignant neoplasm of trigone of urinary bladder

38,862

C670

B491.00

Malignant neoplasm of dome of urinary bladder

44,996

C671

B492.00

Malignant neoplasm of lateral wall of urinary bladder

35,963

C672

B493.00

Malignant neoplasm of anterior wall of urinary bladder

19,162

C673

B494.00

Malignant neoplasm of posterior wall of urinary bladder

42,012

C674

B495.00

Malignant neoplasm of bladder neck

41,571

C675

B496.00

Malignant neoplasm of ureteric orifice

28,241

C676

B497.00

Malignant neoplasm of urachus

42,023

C677

B49y000

Malignant neoplasm, overlapping lesion of bladder

47,801

C678

B49y.00

Malignant neoplasm of other site of urinary bladder

36,949

C679

B49z.00

Malignant neoplasm of urinary bladder NOS

31,102

C679

Breast

B335200

Malignant neoplasm of skin of breast

30,543

C445

B34..11

CA female breast

348

C50

B34..00

Malignant neoplasm of female breast

3968

C50

B340000

Malignant neoplasm of nipple of female breast

23,380

C500

B340.00

Malignant neoplasm of nipple and areola of female breast

26,853

C500

B340z00

Malignant neoplasm of nipple or areola of female breast nos

59,831

C500

B340100

Malignant neoplasm of areola of female breast

64,686

C500

B341.00

Malignant neoplasm of central part of female breast

31,546

C501

B342.00

Malignant neoplasm of upper-inner quadrant of female breast

29,826

C502

B343.00

Malignant neoplasm of lower-inner quadrant of female breast

45,222

C503

B344.00

Malignant neoplasm of upper-outer quadrant of female breast

23,399

C504

B345.00

Malignant neoplasm of lower-outer quadrant of female breast

42,070

C505

B346.00

Malignant neoplasm of axillary tail of female breast

20,685

C506

B34y000

Malignant neoplasm of ectopic site of female breast

95,057

C508

B34yz00

Malignant neoplasm of other site of female breast nos

38,475

C509

B34y.00

Malignant neoplasm of other site of female breast

56,715

C509

B34z.00

Malignant neoplasm of female breast nos

9470

C509

Cervix

B410z00

Malignant neoplasm of endocervix nos

50,285

C530

B410.00

Malignant neoplasm of endocervix

48,820

C530

B410000

Malignant neoplasm of endocervical canal

57,235

C530

B410100

Malignant neoplasm of endocervical gland

53,103

C530

B411.00

Malignant neoplasm of exocervix

50,297

C531

B412.00

Malignant neoplasm, overlapping lesion of cervix uteri

58,094

C538

B41y100

Malignant neoplasm of squamocolumnar junction of cervix

57,719

C538

B41y000

Malignant neoplasm of cervical stump

95,505

C538

B41yz00

Malignant neoplasm of other site of cervix nos

43,435

C539

B41z.00

Malignant neoplasm of cervix uteri nos

28,311

C539

B41y.00

Malignant neoplasm of other site of cervix

32,955

C539

Colorectal

B134.11

Carcinoma of caecum

22,163

C180

B134.00

Malignant neoplasm of caecum

3811

C180

B136.00

Malignant neoplasm of ascending colon

10,946

C182

B130.00

Malignant neoplasm of hepatic flexure of colon

9088

C183

B131.00

Malignant neoplasm of transverse colon

6935

C184

B137.00

Malignant neoplasm of splenic flexure of colon

18,619

C185

B132.00

Malignant neoplasm of descending colon

10,864

C186

B133.00

Malignant neoplasm of sigmoid colon

2815

C187

B138.00

Malignant neoplasm, overlapping lesion of colon

93,478

C188

B13y.00

Malignant neoplasm of other specified sites of colon

48,231

C189

B13z.11

Colonic cancer

9118

C189

B13z.00

Malignant neoplasm of colon nos

28,163

C189

B140.00

Malignant neoplasm of rectosigmoid junction

27,855

C19

B141.12

Rectal carcinoma

5901

C20

B141.11

Carcinoma of rectum

7219

C20

B141.00

Malignant neoplasm of rectum

1800

C20

B14y.00

Malig neop other site rectum, rectosigmoid junction and anus

55,659

C218

B14z.00

Malignant neoplasm rectum,rectosigmoid junction and anus nos

50,974

C218

B1z0.11

Cancer of bowel

11,628

C260

B18y200

Malignant neoplasm of mesorectum

30,165

C481

Larynx

B214.00

Malignant neoplasm, overlapping lesion of larynx

50,579

C328

B21z.00

Malignant neoplasm of larynx NOS

9237

C329

B21y.00

Malignant neoplasm of larynx, other specified site

26,813

C329

B210.00

Malignant neoplasm of glottis

318

C320

B215.00

Malignant neoplasm of epiglottis NOS

55,374

C321

B211.00

Malignant neoplasm of supraglottis

26,165

C321

B212.00

Malignant neoplasm of subglottis

22,441

C322

B213z00

Malignant neoplasm of laryngeal cartilage NOS

97,332

C323

B213000

Malignant neoplasm of arytenoid cartilage

63,460

C323

B213.00

Malignant neoplasm of laryngeal cartilage

43,111

C323

B213100

Malignant neoplasm of cricoid cartilage

37,805

C323

Thyroid

B213300

Malignant neoplasm of thyroid cartilage

47,862

C323

B53..00

Malignant neoplasm of thyroid gland

5637

C73

Sarcoma

B150200

Primary angiosarcoma of liver

68,410

C223

B1z1100

Fibrosarcoma of spleen

72,224

C261

B30z000

Osteosarcoma

19,437

C419

B339.00

Dermatofibrosarcoma protuberans

24,375

C449

B33z000

Kaposi’s sarcoma of skin

27,931

C460

B05z000

Kaposi’s sarcoma of palate

37,549

C462

B6z0.00

Kaposi’s sarcoma of lymph nodes

50,290

C463

B592X00

Kaposi’s sarcoma of multiple organs

65,466

C468

Byu5300

[X]kaposi’s sarcoma, unspecified

93,665

C469

B59zX00

Kaposi’s sarcoma, unspecified

49,525

C469

B600000

Reticulosarcoma of unspecified site

60,242

C833

B600100

Reticulosarcoma of lymph nodes of head, face, and neck

71,031

C833

B600700

Reticulosarcoma of spleen

95,058

C833

B600300

Reticulosarcoma of intra-abdominal lymph nodes

70,374

C833

B600.00

Reticulosarcoma

1481

C839

B601000

Lymphosarcoma of unspecified site

71,625

C850

B601200

Lymphosarcoma of intrathoracic lymph nodes

62,380

C850

B601.00

Lymphosarcoma

27,416

C850

B601100

Lymphosarcoma of lymph nodes of head, face and neck

71,238

C850

B601z00

Lymphosarcoma nos

63,723

C850

B601300

Lymphosarcoma of intra-abdominal lymph nodes

64,670

C850

B653.00

Myeloid sarcoma

70,724

C923

B653100

Granulocytic sarcoma

39,629

C923

B67y000

Lymphosarcoma cell leukaemia

72,197

C947

B304200

Malignant neoplasm of humerus

61,741

C400

B304000

Malignant neoplasm of scapula

49,054

C400

B304300

Malignant neoplasm of radius

92,371

C400

B304.00

Malignant neoplasm of scapula and long bones of upper arm

71,810

C400

B304z00

Malignant neoplasm of scapula and long bones of upper arm NOS

65,880

C400

B304400

Malignant neoplasm of ulna

64,848

C400

B305.00

Malignant neoplasm of hand bones

73,530

C401

B305.12

Malignant neoplasm of metacarpal bones

72,464

C401

B305C00

Malignant neoplasm of fifth metacarpal bone

94,427

C401

B305z00

Malignant neoplasm of hand bones NOS

73,556

C401

B305100

Malignant neoplasm of carpal bone—lunate

69,104

C401

B305000

Malignant neoplasm of carpal bone—scaphoid

57,988

C401

B305D00

Malignant neoplasm of phalanges of hand

86,812

C401

B307z00

Malignant neoplasm of long bones of leg NOS

62,630

C402

B307.00

Malignant neoplasm of long bones of leg

68,055

C402

B307200

Malignant neoplasm of tibia

40,814

C402

B307100

Malignant neoplasm of fibula

50,402

C402

B307000

Malignant neoplasm of femur

56,513

C402

B308300

Malignant neoplasm of medial cuneiform

34,878

C403

B308800

Malignant neoplasm of first metatarsal bone

69,927

C403

B308B00

Malignant neoplasm of fourth metatarsal bone

92,382

C403

B308100

Malignant neoplasm of talus

95,182

C403

B308D00

Malignant neoplasm of phalanges of foot

58,949

C403

B308200

Malignant neoplasm of calcaneum

72,212

C403

B30X.00

Malignant neoplasm/bones + articular cartilage/limb, unspecified

43,614

C409

Byu3100

[X]Malignant neoplasm/bones + articular cartilage/limb, unspecified

73,296

C409

B300600

Malignant neoplasm of parietal bone

54,747

C410

B300400

Malignant neoplasm of occipital bone

55,953

C410

B300z00

Malignant neoplasm of bones of skull and face NOS

69,146

C410

B300300

Malignant neoplasm of nasal bone

95,458

C410

B300900

Malignant neoplasm of zygomatic bone

50,299

C410

B300C00

Malignant neoplasm of vomer

44,452

C410

B300500

Malignant neoplasm of orbital bone

50,298

C410

B300700

Malignant neoplasm of sphenoid bone

55,595

C410

B300200

Malignant neoplasm of malar bone

59,520

C410

B300B00

Malignant neoplasm of turbinate

96,445

C410

B300000

Malignant neoplasm of ethmoid bone

53,594

C410

B300100

Malignant neoplasm of frontal bone

53,599

C410

B300800

Malignant neoplasm of temporal bone

62,104

C410

B300.00

Malignant neoplasm of bones of skull and face

59,036

C410

B300A00

Malignant neoplasm of maxilla

17,475

C410

B301.00

Malignant neoplasm of mandible

33,833

C411

B302100

Malignant neoplasm of thoracic vertebra

32,372

C412

B302.00

Malignant neoplasm of vertebral column

16,704

C412

B302000

Malignant neoplasm of cervical vertebra

46,939

C412

B302200

Malignant neoplasm of lumbar vertebra

54,691

C412

B302z00

Malignant neoplasm of vertebral column NOS

49,701

C412

B303000

Malignant neoplasm of rib

37,842

C413

B303.00

Malignant neoplasm of ribs, sternum and clavicle

27,528

C413

B303100

Malignant neoplasm of sternum

49,491

C413

B303z00

Malignant neoplasm of rib, sternum and clavicle NOS

51,237

C413

B303500

Malignant neoplasm of xiphoid process

54,493

C413

B303300

Malignant neoplasm of costal cartilage

60,403

C413

B303200

Malignant neoplasm of clavicle

66,639

C413

B306.00

Malignant neoplasm of pelvic bones, sacrum and coccyx

54,631

C414

B306100

Malignant neoplasm of ischium

59,223

C414

B306400

Malignant neoplasm of coccygeal vertebra

66,908

C414

B306z00

Malignant neoplasm of pelvis, sacrum or coccyx NOS

38,938

C414

B306300

Malignant neoplasm of sacral vertebra

40,966

C414

B306200

Malignant neoplasm of pubis

51,921

C414

B306000

Malignant neoplasm of ilium

44,609

C414

Byu3200

[X]Malignant neoplasm/overlap lesion/bone + articular cartilage

63,300

C418

B30W.00

Malignant neoplasm/overlap lesion/bone + articular cartilage

67,451

C418

B303400

Malignant neoplasm of costo-vertebral joint

67,763

C418

B30z.00

Malignant neoplasm of bone and articular cartilage NOS

16,075

C419

Byu3300

[X]Malignant neoplasm/bone + articular cartilage, unspecified

43,151

C419

B310z00

Malig neop connective and soft tissue head, face, neck NOS

73,718

C490

B310100

Malignant neoplasm of soft tissue of face

40,014

C490

B310000

Malignant neoplasm of soft tissue of head

59,382

C490

B310300

Malignant neoplasm of cartilage of ear

60,035

C490

B310.00

Malignant neoplasm of connective and soft tissue head, face and neck

43,475

C490

B310200

Malignant neoplasm of soft tissue of neck

48,517

C490

B310400

Malignant neoplasm of tarsus of eyelid

49,463

C490

B311500

Malignant neoplasm of connective and soft tissue of thumb

63,988

C491

B311200

Malignant neoplasm of connective and soft tissue of fore-arm

57,482

C491

B311100

Malignant neoplasm of connective and soft tissue, upper arm

64,345

C491

B311000

Malignant neoplasm of connective and soft tissue of shoulder

50,222

C491

B311400

Malignant neoplasm of connective and soft tissue of finger

91,586

C491

B311300

Malignant neoplasm of connective and soft tissue of hand

19,321

C491

B311.00

Malignant neoplasm connective and soft tissue upper limb/shoulder

53,989

C491

B312300

Malignant neoplasm of connective and soft tissue of lower leg

30,542

C492

B312400

Malignant neoplasm of connective and soft tissue of foot

54,222

C492

B312.00

Malignant neoplasm of connective and soft tissue of hip and leg

66,088

C492

B312z00

Malignant neoplasm connective and soft tissue hip and leg NOS

90,546

C492

B312200

Malignant neoplasm connective and soft tissue of popliteal space

54,965

C492

B312100

Malignant neoplasm of connective and soft tissue thigh and upper leg

44,805

C492

B313100

Malignant neoplasm of diaphragm

54,186

C493

B313.00

Malignant neoplasm of connective and soft tissue of thorax

22,290

C493

B313000

Malignant neoplasm of connective and soft tissue of axilla

29,160

C493

B313200

Malignant neoplasm of great vessels

72,522

C493

B314.00

Malignant neoplasm of connective and soft tissue of abdomen

45,071

C494

B314z00

Malignant neoplasm of connective and soft tissue of abdomen NOS

60,247

C494

B314000

Malignant neoplasm of connective and soft tissue of abdominal wall

66,488

C494

B315z00

Malignant neoplasm of connective and soft tissue of pelvis NOS

58,836

C495

B315000

Malignant neoplasm of connective and soft tissue of buttock

70,463

C495

B315200

Malignant neoplasm of connective and soft tissue of perineum

59,152

C495

B315.00

Malignant neoplasm of connective and soft tissue of pelvis

51,965

C495

B315100

Malignant neoplasm of connective and soft tissue of inguinal region

67,324

C495

Byu5800

[X]Mal neoplasm/connective + soft tissue of trunk, unspecified

91,896

C496

B314100

Malig neoplasm of connective and soft tissues of lumb spine

94,272

C496

B316.00

Malig neop of connective and soft tissue trunk unspecified

57,471

C496

B31z.00

Malignant neoplasm of connective and soft tissue, site NOS

15,182

C499

Byu5900

[X]Malignant neoplasm/connective + soft tissue, unspecified

91,457

C499

B31y.00

Malignant neoplasm connective and soft tissue other specified site

65,233

C499

Kidney

B4A0.00

Malignant neoplasm of kidney parenchyma

1599

C64

B4A..11

Renal malignant neoplasm

18,712

C64

B4A..00

Malignant neoplasm of kidney and other unspecified urinary organs

13,559

C64

B4A0000

Hypernephroma

7978

C64

B4A1000

Malignant neoplasm of renal calyces

27,540

C65

B4A1z00

Malignant neoplasm of renal pelvis NOS

54,184

C65

B4A1.00

Malignant neoplasm of renal pelvis

12,389

C65

B4Az.00

Malignant neoplasm of kidney or urinary organs NOS

29,462

C689

Lung

B221100

Malignant neoplasm of hilus of lung

33,444

C340

B221.00

Malignant neoplasm of main bronchus

12,870

C340

B221z00

Malignant neoplasm of main bronchus NOS

21,698

C340

B221000

Malignant neoplasm of carina of bronchus

17,391

C340

B222.11

Pancoast’s syndrome

20,170

C341

B222.00

Malignant neoplasm of upper lobe, bronchus or lung

10,358

C341

B222000

Malignant neoplasm of upper lobe bronchus

31,700

C341

B222100

Malignant neoplasm of upper lobe of lung

25,886

C341

B222z00

Malignant neoplasm of upper lobe, bronchus or lung NOS

44,169

C341

B223100

Malignant neoplasm of middle lobe of lung

39,923

C342

B223z00

Malignant neoplasm of middle lobe, bronchus or lung NOS

54,134

C342

B223.00

Malignant neoplasm of middle lobe, bronchus or lung

31,268

C342

B223000

Malignant neoplasm of middle lobe bronchus

41,523

C342

B224z00

Malignant neoplasm of lower lobe, bronchus or lung NOS

42,566

C343

B224100

Malignant neoplasm of lower lobe of lung

12,582

C343

B224000

Malignant neoplasm of lower lobe bronchus

18,678

C343

B224.00

Malignant neoplasm of lower lobe, bronchus or lung

31,188

C343

B225.00

Malignant neoplasm of overlapping lesion of bronchus and lung

36,371

C348

B22z.00

Malignant neoplasm of bronchus or lung NOS

3903

C349

Byu2000

[X]malignant neoplasm of bronchus or lung, unspecified

40,595

C349

B22z.11

Lung cancer

2587

C349

B22y.00

Malignant neoplasm of other sites of bronchus or lung

38,961

C349

B26..00

Malignant neoplasm, overlap lesion of resp and intrathor orgs

66,646

C398

B2zy.00

Malignant neoplasm of other site of respiratory tract

29,283

C399

Hodgkins lymphoma

B613.00

Hodgkin’s disease, lymphocytic-histiocytic predominance

38,939

C810

B613600

Hodgkin’s, lymphocytic-histiocytic pred intrapelvic nodes

95,338

C810

B613z00

Hodgkin’s, lymphocytic-histiocytic predominance nos

29,876

C810

B613300

Hodgkin’s, lymphocytic-histiocytic pred intra-abdominal node

73,532

C810

B613000

Hodgkin’s, lymphocytic-histiocytic predominance unspec site

71,142

C810

B613200

Hodgkin’s, lymphocytic-histiocytic pred intrathoracic nodes

92,245

C810

B613100

Hodgkin’s, lymphocytic-histiocytic pred of head, face, neck

68,330

C810

B613500

Hodgkin’s, lymphocytic-histiocytic pred inguinal and leg

93,951

C810

B614400

Hodgkin’s nodular sclerosis of lymph nodes of axilla and arm

65,483

C811

B614300

Hodgkin’s nodular sclerosis of intra-abdominal lymph nodes

61,149

C811

B614.00

Hodgkin’s disease, nodular sclerosis

29,178

C811

B614100

Hodgkin’s nodular sclerosis of head, face and neck

55,303

C811

B614z00

Hodgkin’s disease, nodular sclerosis NOS

63,054

C811

B614200

Hodgkin’s nodular sclerosis of intrathoracic lymph nodes

67,506

C811

B614000

Hodgkin’s disease, nodular sclerosis of unspecified site

57,225

C811

B614800

Hodgkin’s nodular sclerosis of lymph nodes of multiple sites

19,140

C811

B615200

Hodgkin’s mixed cellularity of intrathoracic lymph nodes

58,684

C812

B615z00

Hodgkin’s disease, mixed cellularity NOS

94,005

C812

B615.00

Hodgkin’s disease, mixed cellularity

49,605

C812

B615100

Hodgkin’s mixed cellularity of lymph nodes head, face, neck

94,407

C812

B615000

Hodgkin’s disease, mixed cellularity of unspecified site

97,863

C812

B616.00

Hodgkin’s disease, lymphocytic depletion

67,703

C813

B616400

Hodgkin’s lymphocytic depletion lymph nodes axilla and arm

63,625

C813

B616000

Hodgkin’s lymphocytic depletion of unspecified site

95,049

C813

ByuD000

[X]other Hodgkin’s disease

43,415

C817

B610.00

Hodgkin’s paragranuloma

65,489

C817

B611.00

Hodgkin’s granuloma

44,196

C817

B61z100

Hodgkin’s disease NOS of lymph nodes of head, face and neck

59,778

C819

B61..00

Hodgkin’s disease

2462

C819

B61zz00

Hodgkin’s disease NOS

42,461

C819

B61z800

Hodgkin’s disease NOS of lymph nodes of multiple sites

97,746

C819

B61z200

Hodgkin’s disease NOS of intrathoracic lymph nodes

59,755

C819

B61z.00

Hodgkin’s disease NOS

53,397

C819

B61z000

Hodgkin’s disease NOS, unspecified site

61,662

C819

B61z400

Hodgkin’s disease NOS of lymph nodes of axilla and arm

91,900

C819

B61z700

Hodgkin’s disease NOS of spleen

94,279

C819

B612.00

Hodgkin’s sarcoma

64,036

C817

B612400

Hodgkin’s sarcoma of lymph nodes of axilla and upper limb

68,039

C817

Non-Hodgkins lymphoma

B627000

Follicular non-Hodgkin’s small cleaved cell lymphoma

28,639

C820

B627100

Follicular non-Hodgkin’s mixed sml cleavd & lge cell lymphoma

70,842

C821

B627200

Follicular non-Hodgkin’s large cell lymphoma

49,262

C822

B627B00

Other types of follicular non-Hodgkin’s lymphoma

31,576

C827

ByuD100

[X]other types of follicular non-Hodgkin’s lymphoma

67,518

C827

B620500

Nodular lymphoma of lymph nodes of inguinal region and leg

94,995

C829

B627C11

Follicular lymphoma NOS

17,182

C829

B620000

Nodular lymphoma of unspecified site

66,327

C829

B620100

Nodular lymphoma of lymph nodes of head, face and neck

45,264

C829

B620z00

Nodular lymphoma NOS

65,701

C829

B620.00

Nodular lymphoma (brill - symmers disease)

5179

C829

B620300

Nodular lymphoma of intra-abdominal lymph nodes

92,068

C829

B627C00

Follicular non-Hodgkin’s lymphoma

21,549

C829

B620800

Nodular lymphoma of lymph nodes of multiple sites

58,082

C829

B627300

Diffuse non-Hodgkin’s small cell (diffuse) lymphoma

50,668

C830

B627500

Diffuse non-Hodgkin mixed small & large cell (diffuse) lymphoma

50,695

C832

B627600

Diffuse non-Hodgkin’s immunoblastic (diffuse) lymphoma

53,551

C834

B627700

Diffuse non-Hodgkin’s lymphoblastic (diffuse) lymphoma

17,460

C835

B627800

Diffuse non-Hodgkin’s lymphoma undifferentiated (diffuse)

65,180

C836

B602300

Burkitt’s lymphoma of intra-abdominal lymph nodes

97,577

C837

B602z00

Burkitt’s lymphoma NOS

71,304

C837

B602.00

Burkitt’s lymphoma

21,402

C837

B602500

Burkitt’s lymphoma of lymph nodes of inguinal region and leg

92,380

C837

B602100

Burkitt’s lymphoma of lymph nodes of head, face and neck

59,115

C837

B627D00

Diffuse non-Hodgkin’s centroblastic lymphoma

70,509

C838

ByuDC00

[X]Diffuse non-Hodgkin’s lymphoma, unspecified

64,515

C839

B627X00

Diffuse non-Hodgkin’s lymphoma, unspecified

39,798

C839

B622.00

Sezary’s disease

35,014

C841

B62x000

T-zone lymphoma

90,201

C842

B62x100

Lymphoepithelioid lymphoma

57,737

C843

B62x200

Peripheral t-cell lymphoma

12,464

C844

B62xX00

Oth and unspecif peripheral and cutaneous t cell lymphomas

44,318

C845

B627W00

Unspecified b-cell non-Hodgkin’s lymphoma

31,794

C851

ByuDE00

[X]unspecified b-cell non-Hodgkin’s lymphoma

63,375

C851

ByuD300

[X]Other specified types of non-Hodgkin’s lymphoma

64,336

C857

B62y100

Malignant lymphoma NOS of lymph nodes of head, face and neck

50,696

C859

B62y500

Malignant lymphoma NOS of lymph node inguinal region and leg

63,105

C859

B62y400

Malignant lymphoma NOS of lymph nodes of axilla and arm

34,089

C859

B62y000

Malignant lymphoma NOS of unspecified site

57,427

C859

B62y700

Malignant lymphoma NOS of spleen

60,092

C859

ByuDF11

[X]Non-Hodgkin’s lymphoma NOS

7940

C859

B62y600

Malignant lymphoma NOS of intrapelvic lymph nodes

71,262

C859

B62y200

Malignant lymphoma NOS of intrathoracic lymph nodes

72,725

C859

B62yz00

Malignant lymphoma NOS

15,027

C859

ByuDF00

[X]Non-Hodgkin’s lymphoma, unspecified type

8649

C859

B62y.00

Malignant lymphoma NOS

12,335

C859

B62y300

Malignant lymphoma NOS of intra-abdominal lymph nodes

42,579

C859

B62x600

True histiocytic lymphoma

95,630

C963

B6z..00

Malignant neoplasm lymphatic or haematopoietic tissue NOS

49,301

C969

B62y800

Malignant lymphoma NOS of lymph nodes of multiple sites

15,504

C969

B621000

Mycosis fungoides of unspecified site

95,949

C840

B621500

Mycosis fungoides of lymph nodes of inguinal region and leg

72,714

C840

B621.00

Mycosis fungoides

12,006

C840

B621800

Mycosis fungoides of lymph nodes of multiple sites

95,012

C840

B621400

Mycosis fungoides of lymph nodes of axilla and upper limb

96,379

C840

B621300

Mycosis fungoides of intra-abdominal lymph nodes

91,674

C840

B621z00

Mycosis fungoides NOS

38,005

C840

B62x400

Malignant reticulosis

62,437

C857

Melanoma

B320.00

Malignant melanoma of lip

70,637

C430

B321.00

Malignant melanoma of eyelid including canthus

54,632

C431

B322000

Malignant melanoma of auricle (ear)

59,061

C432

B322.00

Malignant melanoma of ear and external auricular canal

57,260

C432

B322z00

Malignant melanoma of ear and external auricular canal NOS

73,744

C432

B323100

Malignant melanoma of chin

71,136

C433

B323200

Malignant melanoma of eyebrow

47,094

C433

B323500

Malignant melanoma of temple

58,958

C433

B323z00

Malignant melanoma of face NOS

67,806

C433

Byu4000

[X]malignant melanoma of other + unspecified parts of face

56,925

C433

B323.00

Malignant melanoma of other and unspecified parts of face

47,252

C433

B323300

Malignant melanoma of forehead

68,133

C433

B323400

Malignant melanoma of external surface of nose

45,139

C433

B323000

Malignant melanoma of external surface of cheek

41,278

C433

B324000

Malignant melanoma of scalp

55,881

C434

B324.00

Malignant melanoma of scalp and neck

65,625

C434

B324100

Malignant melanoma of neck

45,306

C434

B325700

Malignant melanoma of back

43,463

C435

B325800

Malignant melanoma of chest wall

51,209

C435

B325600

Malignant melanoma of umbilicus

43,715

C435

B325100

Malignant melanoma of breast

32,768

C435

B325300

Malignant melanoma of groin

34,259

C435

B325200

Malignant melanoma of buttock

53,629

C435

B325500

Malignant melanoma of perineum

95,629

C435

B325.00

Malignant melanoma of trunk (excluding scrotum)

38,689

C435

B325z00

Malignant melanoma of trunk, excluding scrotum, NOS

45,760

C435

B325000

Malignant melanoma of axilla

49,814

C435

B326200

Malignant melanoma of fore-arm

45,755

C436

B326400

Malignant melanoma of finger

25,602

C436

B326300

Malignant melanoma of hand

62,475

C436

B326000

Malignant melanoma of shoulder

50,505

C436

B326500

Malignant melanoma of thumb

63,997

C436

B326z00

Malignant melanoma of upper limb or shoulder NOS

55,292

C436

B326100

Malignant melanoma of upper arm

54,685

C436

B326.00

Malignant melanoma of upper limb and shoulder

65,164

C436

B327500

Malignant melanoma of ankle

42,714

C437

B327700

Malignant melanoma of foot

41,490

C437

B327000

Malignant melanoma of hip

73,536

C437

B327100

Malignant melanoma of thigh

51,873

C437

B327800

Malignant melanoma of toe

36,899

C437

B327200

Malignant melanoma of knee

54,305

C437

B327.00

Malignant melanoma of lower limb and hip

46,255

C437

B327600

Malignant melanoma of heel

61,246

C437

B327300

Malignant melanoma of popliteal fossa area

39,878

C437

B327z00

Malignant melanoma of lower limb or hip NOS

64,327

C437

B327900

Malignant melanoma of great toe

53,369

C437

B327400

Malignant melanoma of lower leg

37,872

C437

B32y000

Overlapping malignant melanoma of skin

96,585

C438

B32z.00

Malignant melanoma of skin NOS

28,556

C439

Byu4100

[X]malignant melanoma of skin, unspecified

19,444

C439

B32..00

Malignant melanoma of skin

865

C439

B32y.00

Malignant melanoma of other specified skin site

42,153

C439

Myeloma

B63z.00

Immunoproliferative neoplasm or myeloma NOS

43,450

C889

B630.12

Myelomatosis

15,211

C900

B630.00

Multiple myeloma

4944

C900

B630300

Lambda light chain myeloma

46,042

C900

B631.00

Plasma cell leukaemia

39,187

C901

B630100

Solitary myeloma

19,028

C902

B630200

Plasmacytoma NOS

21,329

C902

B630000

Malignant plasma cell neoplasm, extramedullary plasmacytoma

22,158

C902

Oesophagus

B100.00

Malignant neoplasm of cervical oesophagus

61,695

C150

B101.00

Malignant neoplasm of thoracic oesophagus

41,362

C151

B102.00

Malignant neoplasm of abdominal oesophagus

63,470

C152

B103.00

Malignant neoplasm of upper third of oesophagus

50,789

C153

B104.00

Malignant neoplasm of middle third of oesophagus

54,171

C154

B105.00

Malignant neoplasm of lower third of oesophagus

42,416

C155

B106.00

Malignant neoplasm, overlapping lesion of oesophagus

67,497

C158

B10y.00

Malignant neoplasm of other specified part of oesophagus

53,591

C159

B10z.00

Malignant neoplasm of oesophagus NOS

30,700

C159

B10z.11

Oesophageal cancer

4865

C159

B110111

Malignant neoplasm of gastro-oesophageal junction

94,278

C160

Ovary

B440.00

Malignant neoplasm of ovary

7805

C56

B440.11

Cancer of ovary

1986

C56

B44..00

Malignant neoplasm of ovary and other uterine adnexa

19,141

C578

Pancreas

B162.00

Malignant neoplasm of ampulla of vater

10,949

C241

B170.00

Malignant neoplasm of head of pancreas

8771

C250

B171.00

Malignant neoplasm of body of pancreas

40,810

C251

B172.00

Malignant neoplasm of tail of pancreas

39,870

C252

B173.00

Malignant neoplasm of pancreatic duct

35,535

C253

B174.00

Malignant neoplasm of islets of langerhans

35,795

C254

B17y.00

Malignant neoplasm of other specified sites of pancreas

48,537

C257

B17yz00

Malignant neoplasm of specified site of pancreas NOS

95,783

C257

B175.00

Malignant neoplasm, overlapping lesion of pancreas

97,875

C258

B17y000

Malignant neoplasm of ectopic pancreatic tissue

96,635

C259

B17z.00

Malignant neoplasm of pancreas NOS

34,388

C259

Prostate

B46..00

Malignant neoplasm of prostate

780

C61

Stomach

B110100

Malignant neoplasm of cardio-oesophageal junction of stomach

22,894

C160

B110z00

Malignant neoplasm of cardia of stomach NOS

37,859

C160

B110.00

Malignant neoplasm of cardia of stomach

32,022

C160

B113.00

Malignant neoplasm of fundus of stomach

32,362

C161

B114.00

Malignant neoplasm of body of stomach

43,572

C162

B112.00

Malignant neoplasm of pyloric antrum of stomach

19,318

C163

B111z00

Malignant neoplasm of pylorus of stomach NOS

59,092

C164

B111100

Malignant neoplasm of pyloric canal of stomach

41,215

C164

B111000

Malignant neoplasm of prepylorus of stomach

48,237

C164

B111.00

Malignant neoplasm of pylorus of stomach

21,620

C164

B115.00

Malignant neoplasm of lesser curve of stomach unspecified

42,193

C165

B116.00

Malignant neoplasm of greater curve of stomach unspecified

55,434

C166

B11y000

Malignant neoplasm of anterior wall of stomach nec

65,312

C168

B11y100

Malignant neoplasm of posterior wall of stomach nec

96,802

C168

B117.00

Malignant neoplasm, overlapping lesion of stomach

51,690

C168

B11yz00

Malignant neoplasm of other specified site of stomach NOS

65,372

C169

B11y.00

Malignant neoplasm of other specified site of stomach

55,019

C169

B11z.00

Malignant neoplasm of stomach NOS

14,800

C169

Testis

B470200

Seminoma of undescended testis

7740

C620

B470.00

Malignant neoplasm of undescended testis

64,602

C620

B470300

Teratoma of undescended testis

36,325

C620

B470z00

Malignant neoplasm of undescended testis NOS

96,429

C620

B471z00

Malignant neoplasm of descended testis NOS

91,509

C621

B471000

Seminoma of descended testis

21,786

C621

B471100

Teratoma of descended testis

9476

C621

B471.00

Malignant neoplasm of descended testis

19,475

C621

B47z.00

Malignant neoplasm of testis NOS

38,510

C629

B47z.11

Seminoma of testis

2961

C629

B47z.12

Teratoma of testis

15,989

C629

B48y100

Malignant neoplasm of tunica vaginalis

47,668

C637

Uterus

B431000

Malignant neoplasm of lower uterine segment

59,097

C540

B431z00

Malignant neoplasm of isthmus of uterine body NOS

70,729

C540

B431.00

Malignant neoplasm of isthmus of uterine body

43,940

C540

B430211

Malignant neoplasm of endometrium

49,400

C541

B430200

Malignant neoplasm of endometrium of corpus uteri

2890

C541

B430300

Malignant neoplasm of myometrium of corpus uteri

45,793

C542

B430100

Malignant neoplasm of fundus of corpus uteri

68,155

C543

B432.00

Malignant neoplasm of overlapping lesion of corpus uteri

16,967

C548

B43z.00

Malignant neoplasm of body of uterus NOS

33,617

C549

B43y.00

Malignant neoplasm of other site of uterine body

31,608

C549

B430000

Malignant neoplasm of cornu of corpus uteri

72,723

C549

B430z00

Malignant neoplasm of corpus uteri NOS

45,490

C549

B43..00

Malignant neoplasm of body of uterus

7046

C549

B40..00

Malignant neoplasm of uterus, part unspecified

2744

C55

Vulval

B451.00

Malignant neoplasm of labia majora

43,761

C510

B453.00

Malignant neoplasm of clitoris

53,910

C512

B45y000

Malignant neoplasm of overlapping lesion of vulva

27,617

C518

B454.00

Malignant neoplasm of vulva unspecified

4554

C519

B454.11

Primary vulval cancer

11,991

C519

B451z00

Malignant neoplasm of labia majora NOS

59,362

C510

B451000

Malignant neoplasm of greater vestibular (Bartholin’s) gland

47,899

C510

B452.00

Malignant neoplasm of labia minora

58,061

C511

Vaginal

B450.00

Malignant neoplasm of vagina

37,328

C52

B450100

Malignant neoplasm of vaginal vault

10,698

C52

B450z00

Malignant neoplasm of vagina NOS

60,772

C52

Outcome—serious disease

A library of candidate Read Codes for the most common serious diseases related to unexpected weight loss will be developed by combining two approaches: (i) review of the most frequent diagnostic codes entered in the clinical record within the period surrounding the unexpected weight loss code (descriptive study analysis section); (ii) review of the literature on causes of unexpected weight loss [1, 2]. A list of these candidate conditions will be reviewed independently by four co-investigators until consensus is reached on up to 20 serious diseases to be identified in the 24 months following the weight loss code.

Covariates

Data will also be extracted to explore the effect of the following factors which could independently impact the recording of weight and the occurrence of cancer:
  1. 1.

    Personal characteristics—age, gender, ethnicity, smoking history, alcohol intake, family history of cancer, and IMD score recorded before the date of the weight loss code (index date).

     
  2. 2.

    Co-morbidity—recorded before the index date (no time limit) or implied from the prescribing record at the index date.

     
  3. 3.

    Other cancer symptoms and signs—using Read Codes for symptoms shown to have an independent association with cancer as described by NICE [3]. These will be sought for 3 months before to 2 years after the index date.

     
  4. 4.

    Results of basic cancer investigations used routinely in primary care: CxR, FBC, LFTs (inc. alkaline phosphatase), calcium, PSA, CA125, and inflammatory markers. These will be sought for 3 months before to 2 years after the index date.

     

Data/statistical analysis

Aim 1: Descriptive study

To describe how often and when weight is recorded, we will request preliminary CPRD searches to identify all: (1) Read coded entries for weight loss and (2) quantitative weight measurements.

A subset of patients with weight measurements and unexpected weight loss codes will be used to develop a rule-based search strategy to categorise: (1) the clinical purpose (e.g. prevention, monitoring, diagnosis); (2) the related clinical condition (e.g. diabetes, heart failure, cancer). The GPs’ subsequent actions will be described in terms of (1) investigations requested, (2) medications prescribed, and (3) referrals made. The search strategy will then be applied to the entire cohort of weight measurements and weight loss codes.

The most effective method to identify the reason for the weight entry and the subsequent action will be investigated. For example, codelists will be developed to capture the clinical purpose of the consultation associated with each weight measurement or weight loss code: health check codes will be used to identify prevention activity; chronic disease review codes will be used to identify monitoring. For associated clinical conditions, symptom and diagnostic codes entered at the same time as each weight measurement or weight loss code will be ascertained and frequency ranked for the entire descriptive study population. Initially, searches will be performed on the day of the weight entry, then a sensitivity analysis will be performed increasing the time window to ± 1 day of the weight entry, then 1 week, 1 month, and so on. This strategy will be repeated to identify investigation and referral codes following entry of the weight loss code.

Aim 2: Cohort analysis

Cumulative incidence plots

Cumulative incidence plots will be used to describe the probability of cancer or serious disease over time for those with and without weight loss. These will be assessed in aggregate and stratified by disease type, cancer stage, grade, tumour size, histology, and covariates.

Differences between those with and without weight loss will be assessed using the log-rank test.

Multivariate Cox regression

Cox regression will be used to estimate the adjusted hazard ratios (HR) for cancer or serious disease associated with weight loss recorded as a symptom.

The impact of choosing to restrict the follow-up period on the predictive value of weight loss will be explored by limiting the analysis by time period (0–6, 6–12, 12–18, and 18–24 months) and by including weight loss as a time dependent variable.

Age at index date, sex, ethnicity, IMD score, co-morbidity, smoking, and alcohol intake will be included, and the predictive value of other symptoms and investigations will be explored for (1) all cancers in aggregate, (2) cancer type, (3) by cancer stage, (4) by tumour size, (5) by grade of cancer and (6) serious disease type.

Performance of diagnostic strategies

To allow clinical guidance to be developed on how to rule-in or rule-out cancer or serious disease in adult patients (> 18 years) with unexpected weight loss, diagnostic accuracy measures will be calculated for investigative strategies including those described in the literature including the subgroups of (1) gender and (2) age-group.

Plan for addressing confounding

Aim 1: Descriptive study

Not required.

Aim 2: Cohort analysis

Patients who have conditions which might explain the weight loss (e.g. co-morbidities at the time of entry to the cohort or planned dieting) will be included and the impact of their inclusion assessed in multivariate and sensitivity analyses.

Patients with coded weight loss will be matched with patients without a weight loss code based on GP practice to account for systematic biases in coding between practices.

Age at index date, sex, IMD score, co-morbidity, smoking, and alcohol intake will be adjusted for in the multivariate modelling.

Plan for addressing missing data

Aim 1: Descriptive study

Weight is cited as a missing variable in CPRD as GPs do not routinely measure weight in NHS primary care [8]. This descriptive analysis will add to our understanding of how often and when weight is recorded.

We will also describe the completeness of personal characteristics (as defined above) in relation to weight measurements and weight loss codes.

Aim 2: Cohort analysis

As measurements appear to be too infrequent to allow us to identify weight loss from serial weight measurement data, the cohort design will make best use of the coded weight loss information available in CPRD. For this reason, we do not intend to impute missing weight measurement values in the primary analysis, although the feasibility of using multiple imputation to address missing covariate values will be explored [10].

Discussion

Within this section, we expand on the protocol as submitted to ISAC to elucidate decisions made about study design and to report developments made since commencing the study. We have incorporated and expanded upon the “Limitations of the study design, data sources and analytical methods” section of the original ISAC protocol.

Reliance on weight loss coding

It appears from our preliminary searches that weight measurement is infrequent for the majority of patients in primary care, most likely initiated by a concern for underlying disease or existing chronic disease management. This is consistent with studies that acknowledge weight measurement as a source of missing data in NHS primary care records [8]. Consequently, the detection of weight loss from serial weight measurements cannot be relied on as a method of defining weight loss. Our descriptive analysis is designed to identify whether a group of patients exists who undergo weight measurements more frequently, in which a future analysis involving serial weight measurements may be feasible. However, any subgroup is unlikely to be representative of the NHS primary care population. We have therefore chosen to focus on weight loss coding.

As with previous primary care studies using routinely collected data, an assumption will be made that the absence of a symptom code represents the absence of the symptom [5, 11]. This assumption has two major limitations: firstly, a coded entry is reliant on the patient visiting the GP and reporting the symptom; and secondly, that the GP chooses to enter the code in the record. Lack of the former would lead to an underestimation of the associated HR, and for the latter, selective recording of symptoms only deemed severe by the GP could lead to overestimated HRs. The latter is likely to differ by GP but cluster by GP practice, as GPs within the same practice are likely to have more similar approaches to coding. One method to address these limitations would be to analyse free-text entries to identify reported but uncoded symptoms, but at present CPRD does not allow requests for free-text entries and we will cite this as a weakness of our study [12]. We decided to adjust for age and sex in multivariate analysis as the association between weight loss and cancer is not established for these variables.

Sample size for cohort analysis

Progress since the initial ISAC application has established that there are 148,000 patients eligible patients aged > 18 years with an unexpected weight loss code as described in Appendix 1 (preliminary pilot work had suggested there was at least 30,000). This will therefore be the largest primary care CPRD cohort study using unexpected weight loss coding as the exposure variable. We originally calculated that only 2184 patients with weight loss are required to detect a hazard ratio of 2 at 99% power (0.05% alpha) using an enrolment ratio of 1:5. That is, a change in a cancer risk from a PPV of 1.5% in patients without weight loss to 3% in patients with weight loss. An alternative approach to estimating sample size is the number of Events Per Varaible in multivariate modelling. If 3% of patients with weight loss develop cancer the number of Events Per Variable will far exceed the minimum number of ten required for robust multivariate modelling. It is anticipated that the study will therefore have sufficient power for stratification by cancer type.

We aim to understand the association between weight loss and cancer in as much detail as the data permits. However, we accept it may not be possible to stratify for cancer stage or for other covariates with sufficient numbers remaining in each stratum. Cancer stage information is unsatisfactory in CPRD, which is why we have requested data linkage to the cancer registry (which will also be incomplete, but less so). Lifestyle covariates are non-essential for our main aim (to determine the predictive value of weight loss for cancer), and we will only perform analysis on sub-strata when numbers permit. Multiple imputation will be explored for these (and all other relevant missing) variables.

Investigation and referral outcomes

There remains uncertainty over the completeness of investigation and referral data until the descriptive analysis has been conducted. Data for laboratory investigations are likely to be more complete than data on radiological and endoscopic investigations, as laboratory investigations are commonly transmitted directly into the electronic health record from the laboratory whereas results for the other tests are not. Further linkage to the Diagnostic Imaging Dataset (for radiology activity) and Hospital Event Statistics (for endoscopy activity) may be necessary if these data are judged to be incomplete following the descriptive analysis, which would allow a formal comparison of data completeness to be conducted between these datasets and CPRD.

Implications

A second cohort study using American primary care data is also in set-up to assess whether there is greater value in defining weight loss using serial weight measurements rather than a reliance on patient reported weight loss and a GP entered code. In particular, this study aims to establish whether weight loss detected using change in serial weight measurements leads to less advanced disease at diagnosis.

Together, these studies will provide the largest reported retrospective cohorts of primary care patients with unexpected weight loss used to understand the association between unexpected weight loss and serious disease including cancer. We hope our findings will directly inform international guidelines for the management of unexpected weight loss in primary care populations.

Abbreviations

BMI: 

Body mass index

CPRD: 

Clinical Practice Research Datalink

IMD: 

Index of Multiple Deprivation

ISAC: 

Independent Scientific Advisory Group (to the CPRD)

Medcode: 

The CPRD unique code for the medical term selected by the GP

NCDR: 

National Cancer Data Repository

NICE: 

National Institute for Health and Care Excellence

Read code: 

The standard clinical terminology system used in general practice in the UK

Declarations

Acknowledgements

We thank Professor David Mant for his insight and expertise that greatly assisted the development of this protocol.

Funding

BDN is funded by NIHR DRF-2015-08-185. The NIHR peer-reviewed this protocol at an earlier stage as part of the application for funding. This article presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Availability of data and materials

Not applicable.

Authors’ contributions

BDN prepared the first draft of the protocol. All authors reviewed and edited the protocol. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not Applicable.

Consent for publication

Not Applicable.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Nuffield Department of Primary Care Health Sciences, Radcliffe Observatory Quarter, University of Oxford, Oxford, UK
(2)
University of Exeter, Medical School, Exeter, UK

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© The Author(s) 2018

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