1.Know the difference between early detection vs. “usual” detection. 2.Whether you should use an...

1. Know the difference between early detection vs. “usual” detection.

2. Whether you should use an early detection test in your practice starts with “Is it effective?”

4. Two ways to sort out effectiveness (observational studies and RCTs).

5. Two kinds of RCTs (direct and indirect).

5. The impact of lead-time bias, length-time bias, and volunteerism on assessing effectiveness in observational studies.

6. Early detection tests can have serious negative effects.

7. Early detection is not a sure thing in terms of cost-effectiveness.

Screening and Case-Finding (Early Detection) - Some Take Home Ideas

What Would (Irene/Terri/Stan/Deric/Ruth/Merrill/Charlotte/Tisha/LisaAnn/Tamara) Do?All pregnant women should be screened for GDM [Grade C, Level 3]. CDA 2008 CPG

Although the benefits of universal screening for hypothyroidism in pregnancy may not bejustified by current evidence, we recommend case finding for thyroid disease by testing TSH [USPSTF Level B, fair evidence (GRADE 1| XXOO)]. Endocrine Society 2007

In adults, screening for CKD in diabetes should be done with a random ACR and serum creatinine [Grade D, Consensus]. Persons with T2D should be screened at diagnosis and then yearly [Grade D, Consensus]. CDA 2008 CPG

Adults with diabetes and persistent microalbuminuria should receive an ACE I or an ARB [Grade A, Level 1A]. CDA 2008 CPG

Women with GDM should strive to achieve glucose values of 3.8 – 5.2 mM (fasting/preprandial), 5.5 – 7.7 mM (1 hr PC), and 5.0 – 6.6 mM (2 hr PC) [not graded]. CDA 2008 CPG

Subclinical hypothyroidism has been associated with adverse outcomes for the mother and offspring. T4 treatment has been shown to improve obstetrical outcome but has not been proved to modify long-term neurological development in the offspring. However, given that the potential benefits outweigh the potential risks, the panel recommends T4 replacement in women with subclinical hypothyroidism. [For obstetrical outcome, USPSTF Level B, fair evidence (GRADE 1|XXOO). For neurological outcome, USPSTF Level I, poor evidence (GRADE OOOO)]. Endocrine Society 2007

Clinical Epidemiology: Screening and Case-Finding (Early Detection)

Use of tests to detect a problem in someone who is otherwise unaware it is present.

Screening: • Health Care System initiates the contact - public ads telling everyone > 40 yrs old to get tested for diabetes

Case-finding (“Opportunistic Screening”): • Person enters the Health Care System for one reason and test is done on the side - testing fasting blood glucose levels in patients with acute MIs

Problem Test

type 2 diabetes fasting plasma glucosegestational diabetes 50 gram glucose challengethyroid disease (women > 50 yrs) TSHcongenital hypothyroidism (neonates) TSHpostmenopausal osteoporosis DEXA scan diabetic retinopathy See an eye care professional atherosclerotic complications serum lipidsdiabetic renal failure urine A:C ratioCVA BP

reduced cognitive development TSH in pregnant women?prostate cancer PSA? colon cancer fecal occult blood/colonoscopy cervical cancer Pap smearbreast cancer mammography

Screening and Case-Finding are REAL Common

Mass Screening: • test recommended in all persons in a defined population • test ALL Ontario neonates for congenital hypothyroidism

Selective Screening: • test limited to a subgroup within a larger population• subgroup is usually at higher risk for problem of interest • test all Ontarians > 40 years old for diabetes (but not all

adult Ontarians)

Mass versus Selective Screening

“Mass” and “Selective” can be hard to tell apart (as can Screening and Case-finding for that matter…)

Clinicians (you) do most of the screening and case-finding:

• Major proponent of screening for Health Care Systems.• Most case-finding is done by clinicians (offices/hospitals).

Screening and Case-Finding (Early Detection)

Less important to know the difference between screening and case-finding (they’re both early detection tests).

More important to know the key differences between early detection tests and the other way we use diagnostic tests.

Doing a fasting plasma glucose for diabetes in:

• An asymptomatic 53 yr old man?

• A 53 yr old man complaining of fatigue?

What’s the difference between…

1. As far as the first guy’s concerned, there was nothing wrong. You then tell him he may have a serious problem.

Answers

2. Impact of false-positive and false-negative errors:

• Harder to justify (esp. false-positives) when the person is minding their own business and you tell them

something’s wrong. • “Labelling” effects.

3. Magnifying effect on benefits and harms, including economic costs, as diagnostic tests are moved closer to the start of disease processes in more and more people.

Everyone > 40 yrs with type 2 DM

Everyone > 40 yrs

Everyone > 40 yrs with type 2 DM who don’t know they have it

Everyone > 40 yrs with type 2 DM who don’t know they have it and who have treatable or preventable structural complications (this is the group you really want to find)

Everyone MASS SCREENING

SELECTIVE SCREENING

Everyone > 40 yrs with a complaint that suggests they might have type 2 DM

Early Detection Seems Like a Good Idea(“ounce of prevention, pound of cure”)

Healthyperson

Onset ofbiological

disease

Early diagnosispossible

Usual clinical

diagnosis

Early death, poor quality

of life

FOB, Colonoscopy

Normal colon

epithelium

Neoplasia in situ

Asymptomaticcolon cancer

Rectal bleeding

Metastaticcolon cancer

x

Early Detection Seems Like a Good Idea(“ounce of prevention, pound of cure”)

Healthyperson

Onset ofbiological

disease

Early diagnosispossible

Usual clinical

diagnosis

Early death, poor quality

of life

Normal glucose

metabolism

Insulinresistance

Asymptomatichyperglycemia

Symptomatichyperglycemia

Microvascular,macrovascular,

neuropathic complications

Fasting plasmaglucose

x

Your options: • Trust experts (CDA, Canadian Task Force on Preventive Health Care, Canadian Hypertension Society, Endocrine Society, etc)

• DIY (find and critically appraise the primary evidence)

Should I undertake case-finding in my practice, or advocate screening on behalf

of the health care system?

Screening and case-finding are best thought of as interventions rather than diagnostic actions.

Ultimate goal of all interventions - net improvement in patients’ outcomes at a cost society can afford.

Should I undertake case-finding in my own practice or advocate screening on behalf


Should I undertake case-finding in my practice, or advocate screening on behalf


Ask THREE QUESTIONS:

1. Is the manouvre effective? (Does it cause benefit?)

2. Does the benefit exceed its negative effects? (What are the negative effects of the manouvre?)

3. Does the net benefit justify the manouvre’s economic costs? (Cost-effectiveness and all that)

“Is the manouvre effective?” means…

Earlier diagnosis (detecting asymptomatic colon CA via FOB and/or colonoscopy) and then treatment (remove polyp or colectomy) is more effective

(reduces the chance the person will die of metastatic colon CA) than waiting until usual

clinical diagnosis (melena).

“Is the manouvre effective?” means…

Earlier diagnosis (detecting asymptomatic hyperglycemia by a FPG) and then treating (lifestyle, metformin, LDL-C below 2.0 mM, BP below 130/80) is more

effective (reduces the chance the person develops overt structural complications) than waiting until usual clinical diagnosis (nocturia).

It’s the first question - if it isn’t effective, who cares.

Often, controversy about use of a screening test reflects uncertainty about effectiveness.

Observational studies:• “Ecological” studies (compare rates of cervical CA deaths between countries that adapted Pap smear vs. those that didn’t) • Case-control studies• Prospective cohort studies

Randomised trials: • Direct randomised trial• Indirect randomised trial

Is the manouvre effective?

Prospective cohort study of lipid screening:

• Test lipids in a group of volunteers

• Follow them to outcome of CAD (MI, cardiac death)

• Follow second group for CAD who haven’t had their lipids tested

• A lower rate of CAD in seen in the tested group

• Is this a real effect or due to bias?

Is the manouvre effective?

Observational studies tend to over-estimate the efficacy of screening and case-finding.

1. Lead-time bias: “You haven’t added any time without disease at the end – you just added more time with

disease at the start.”

3. Volunteerism: Persons submitting to early testing are more health conscious than persons who don’t (and therefore do better).

2. Length-time bias: Screening/case-finding detect diseasethat has a longer subclinical prodrome, and therefore a better prognosis.

Lead-time Bias: Survival After Cancer DetectionPer

Cen

t S

urv

ival

Years of Followup

100%

90%

80%

70%

60%

50%

1 2 3

Usual clinical diagnosis

Screened group

Length-time Bias

usual clinical diagnosis

biological onset of disease

screen test positive

death

Screening Test

The Volunteer Effect: An RCT of Mammography (HIP Study)

Deaths per 10,000 Women per Year

Breast CancerAll Other Causes CVD

Control women

Mammography group

40-49 50-59 60-69

2.4 5.0 5.0

2.5 2.3 3.4

54 25

54 24

Deaths per 10,000 Women per Year

All Causes

CVD

Control women

Mammography group VolunteeredRefused

54 25

42 1777 38

Sackett et al. Clinical Epidemiology, 1991 (based on Shapiro, Cancer, 1971)

Effectiveness of the early detection test is so convincing,

and/or the apparent benefit easily exceeds the risks, that a randomised trial of the test is deemed

unethical. • Test all newborns for congenital hypothyroidism

• Pap smears for cervical cancer

• Oral glucose tolerance testing for GDM in pregnant women

Sometimes observational studies are all we need (or will ever get)

Copyright ©2000 CMA Media Inc. or its licensors

Direct Versus Indirect Randomized Trials of Screening

Guidelines to Assess Therapy Articles Apply

1. Are the results valid? Were patients randomised? Was randomisation concealed? Were patients analysed in the groups to which they were

randomised? Were treatment and control groups similar re: known prognostic

factors? Were patients aware of group allocation? Were clinicians aware of group allocation? Were outcome assessors aware of group allocation? Was follow-up complete?

1. What are the results? How large was the treatment effect? How precise was the estimate of the treatment effect?

• How can I apply the results to patient care? Were the study patients similar to my patients? Were all clinically important outcomes considered? Are the likely treatment benefits worth the potential harm and

costs?

Enrollment and Outcomes

Crowther, C. et al. N Engl J Med 2005;352:2477-2486

Crowther et al. NEJM 2005; 352:2477

Effect of Treatment of Gestational Diabetes on Pregnancy Outcome

Baseline Characteristics of the Women




Primary Clinical Outcomes among the Infants and Their Mothers




Secondary Outcomes among the Infants




Lazarus JH et al. N Engl J Med 2012;366:493-501

Antenatal Thyroid Screening and Childhood Cognitive Function

Lazarus et al. NEJM 2012; 366:493.

Characteristics of Women with Positive Screening Results and Their Children Who Completed Psychological Testing



Standardized Full-Scale Child IQ and Scores on the Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function Preschool

Version (Brief-P) by Study Group.



Relative Risk of an IQ Score below Specified Cutoff Scores in the Screening Group as Compared with the Control Group, According to the

Intention-to-Treat Analysis



Relative Risk of an IQ Score below Specified Cutoff Scores in the Screening Group as Compared with the Control Group, According to the

On-Treatment Analysis



Does the test’s benefit exceed

its negative effects?

Direct adverse effects of the test sequence itself.

• depends upon the particular activity

• tend to escalate from the initial test to confirmatory tests

• colonoscopy for a positive FOB: - 2% risk for perforation

- remote risk for death

• venipuncture for a lipid profile - trivial risk

• DEXA scan for osteoporosis - no known direct risk

Early Detection Can Have Negative Effects (I)

Early Detection Can Have Negative Effects (II)

• Children told they had a heart murmur (which proved to be completely benign) were less physically active years later

• Reduced insurability in someone with diabetes and microalbuminuria

• Cancer anxiety following a positive mammogram

Positive Test Turns an Asymptomatic Person into a Patient

”Labelling Effects”

(negative behavioural and economic effects of a positive test)

Early Detection Can Have Negative Effects (III)

• False-positives: - needlessly expose person to labelling effects - needlessly treated for a problem they never had

• False-negatives: failing to treat someone with the problem

• Impact of errors depends on frequency (lower is better, obviously) and specific consequences of each

The impact of false-negative and false-positive tests(no diagnostic test sequence is perfect).

• The ethical point - false-positives and negatives “worse” in early detection vs. usual diagnostic encounter (someone with a perceived problem comes to us seeking relief).

EXTRA SLIDES

Problem Test (?)

type 1 diabetes pancreatic autoantibodies

hemachromatosis serum ferritin

atherosclorosis plasma homocysteine, hs-CRP

diseases with a genetic basis DNA typing (everything ?!)

Screening and Case-Finding are Likely to Become More Common

Focus:chronic disease

Targets:asymptomatic early phase (urine ACR) of disease (DM-ESRF)risk factors (BP) for the disease (CVA)

Outcomes:impaired quality of life due to clinically important sequelae of disease and its treatmentspremature mortality

Screening and Case-Finding

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