Chronic diseases

1
Chronic diseases

• Chronic diseases have long and variable
  preclinical phases.
• The preclinical phase is that portion of the
  disease natural history during which the disease
  is potentially detectable, but unrecognized.

2
Chronic diseases

• One can conceive of complex functional
  relationships (sensitivity function) between time
  in preclinical phase and the sensitivity of a
  screening test for disease.

3

4
Chronic diseases

• Lead time is the interval between the time of
  disease detection through screening and the time
  of disease recognition in the absence of
  screening. The lead time produced by a screening
  program for a given individual depends on the
  time of screening, in relation to the preclinical
  phase, and on the sensitivity function of the
  screening test.

5
Chronic diseases

• The relative success of treatment for screen
  detected disease depends on the earliness of
  detection (or the amount of lead time produced by
  screening).

6


7
Chronic diseases

• Some chronic diseases have relatively short
  preclinical phases (on average), without much
  variability between diseased individuals. Some
  chronic diseases have very long preclinical
  phases (on average), with sizable variability
  between diseased individuals.

8
Chronic diseases

• The distribution of lead times produced by a
  screening program depends on durations of the
  preclinical phase, on the periodicity (or
  frequency) of screening, and on the sensitivity
  function of the screening test.

9
Chronic diseases

• Pseudodisease is a condition known only as a
  result of screening, a condition that would have
  remained unrecognized if not for screening.
  Pseudodisease is an instance of screen-detected
  disease with indefinitely long lead time.
  Pseudodisease includes screen-detected cases
  which would have regressed (even in the absence
  of treatment), screen-detected cases which would
  not have pro-gressed (even in the absence of
  treatment), and screen-detected cases with very
  long lead times, relative to remaining life
  expectancy.

10
Chronic diseases

• The success of secondary prevention depends on
  progressive disease existing in a preclinical
  phase, a screening test capable of detecting
  disease in the preclinical phase, and the
  production of lead times (coupled with
  treatments) sufficient to alter long term
  outcomes from disease.

11
Difficulties associated with inferences based on
prognosis

• Prognosis refers to outcomes among persons known
  to have disease, whether screen-detected or
  symptom-detected. Case-fatality is a measure of
  prognosis.

12
Difficulties associated with inferences based on
prognosis

• As a natural consequence of the earliness of
  detection, one would expect a successful
  screening program to improve the prognosis of
  screen-detected cases, relative to
  symptom-detected cases. One would also expect
  better prognosis among all cases, which come to
  attention among participants in a screening
  program, relative to all cases, which come to
  attention among non-participants of the program.
  Improved prognosis (reduced case-fatality) is a
  direct consequence of lead times produced through
  the act of screening for disease.

13
Difficulties associated with inferences based on
prognosis

• However, two important biases influence prognosis
  among screen-detected cases, even in the absence
  of any benefit from treatment.

14
Difficulties associated with inferences based on
prognosis

• Lead time bias -- Screen-detected cases
  experience lead time. Among screen-detected
  cases, lead time contributes to the duration at
  risk for poor outcome. Thus, even if screening
  does not change the time of death, screening will
  increase the proportion of screen-detected cases
  surviving beyond defined time intervals.

15
Difficulties associated with inferences based on
prognosis

• Length biased sampling -- Intermittent screening
  preferentially detects cases with a long
  preclinical phase that is, cases of less rapidly
  progressive disease. These persons would be
  expected to experience a relatively favorable
  outcome, even if allowed to progress to symptoms.

16
Difficulties associated with inferences based on
prognosis

• The effects of lead time bias and length biased
  sampling are difficult to separate from the
  effects of treatment. Therefore, prospective
  evaluations of the efficacy of screening must
  compare outcomes among all persons exposed to
  screening with outcomes among all persons not
  exposed to screening.

17
Prospective evaluation
18
Difficulties associated with inferences based on
prognosis

• Retrospective evaluations of the efficacy of
  screening must compare cases who experienced a
  preventable adverse disease outcome and controls
  who are at-risk for the adverse disease outcome.
  Remote history of screening during the
  preclinical phase constitutes the relevant
  exposure.

19
Retrospective evaluation
20
Effects of periodic screening

• Upon initiation of a new screening program, the
  prevalence of preclinical disease in the
  population depends on the incidence of
  preclinical disease and on the average duration
  of preclinical disease.
• The first round of screening preferentially
  removes prevalent cases of disease with
  relatively little time remaining in their
  preclinical phase.

21
Effects of periodic screening

• Subsequent rounds of screening have the potential
  of detecting new individuals (incident cases)
  entering their preclinical phase since the last
  round of screening.
• Depending on the periodicity of screening, in
  relation to the average duration of the
  preclinical phase, cases detected during
  subsequent rounds of screening include a high
  proportion of incident cases with relatively long
  lead times. Relative to cases detected at the
  first screening encounter, cases detected during
  later encounters may experience more benefit (on
  average) from early treatment of disease.

22
Estimating sensitivity in the absence of a gold
standard

• Sensitivity is the proportion detected by a
  screening test among all cases in the preclinical
  phase. (Sensitivity is the area under the
  sensitivity function, weighted according to the
  distribution of times remaining in the
  preclinical phase).
• The sensitivity of a screening test will depend
  on any factor which changes the distribution of
  times remaining in the preclinical phase (such
  as, age of screened group, previous screening
  history, self-referral status, level of awareness
  of disease in the population).

23
Estimating sensitivity in the absence of a gold
standard

• The calculation of sensitivity requires an
  ability to distinguish false negatives from true
  negatives. In practice, the application of the
  gold standard may require invasive or expensive
  diagnostic testing. It may be inappropriate or
  unacceptable to perform such testing among
  persons with negative screening test results.
  Moreover, even the so-called "gold standard" may
  fail among cases early in the preclinical phase.
  But, screening programs attempt to detect disease
  as early as possible in the preclinical phase.

24
Estimating sensitivity in the absence of a gold
standard

• Indirect calculation of sensitivity (detection
  method) ratio between screen-detected cases and
  screen-detected plus interval cases. This
  calculation may overestimate sensitivity.
• Indirect calculation of sensitivity (incidence
  method) 1 - ratio of interval disease incidence
  rate in a screened group and the disease
  incidence rate in a comparison group. May
  underestimate sensitivity.