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Table 4.1

(continued)

SOURCE

OF BIAS SPECIFIC BIAS EXPLANATION PREVENTION

Pygmalion effect/

Rosenthal effect

When the same

interventionists are used for

different arms, their higher

expectations for one arm

positively inuence the

outcome of that arm

– Use different interven-

tionists for different

arms but insure similar

levels of expertise

Expectancy bias/

Optimistic

bias/“True

believer”

Principal investigator’s

strength of commitment to a

specic outcome or treatment

arm promotes preferences in

staff and participants

– Investigator adopts a

scientic mindset of

equipoise throughout all

aspects of trial

– Investigator limits trial

involvement to

supervising the

intervention

Early unblinding

to results

Knowledge of outcome

before completion of

follow-up changes

expectations for remaining

treatment and outcome

assessment

– Protocols for unblinding

to various outcomes are

pre-specied and

approved by a Data and

Safety Monitoring Board

– Interim results

evaluated by Data and

Safety Monitoring

Board only, presented

to them by an unblinded

biostatistician

Unintended

treatments

Inadvertent and differential

non-trial treatments

Non-specic

attention/

Hawthorne effect

Differential attention of any

type improves outcomes

– Use attention control

comparator

– Include attention as a

component of treatment

Placebo response Differential beliefs about

efcacy and/or contextual

factors in the treatment

setting promote placebo

response

– Use placebo control

– Include contextual

factors as components

of treatment

Interventionist

expertise

Differential expertise of

interventionists across arms

– Use highly experienced

interventionists for all

arms

– Manualize treatment

protocols

– Ongoing supervision

and delity checks of

interventionists

(continued)

4 Hypothesized Pathway andBias

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Table 4.1

(continued)

SOURCE

OF BIAS SPECIFIC BIAS EXPLANATION PREVENTION

Implementation/

Adherence

Different demands in trial

arms promote differential

ability to implement them

and/or willingness to adhere

to them

– Feasibility pilot studies

to assess and improve

adherence to respective

protocols

Dissimilar

treatments

Because treatments are not

identical, they trigger

differential reactivity to

them

Ascertainment

bias

Differences in patient contact

by trial arm inuence staff

awareness of events and

outcomes and participant

ability to recall them

– Use one standardized

approach for outcome

assessment in all

participants

– Separate reports of

outcomes obtained

during the course of

intervening from those

obtained using the

standardized trial

protocol

“Faking good”/

Reactive

self-reports/

Social desirability

Differential desire to please,

by arm, promotes spurious

self-reports

– Objective measures,

rather than self-reports,

whenever possible,

especially for the

primary outcome

Post-

randomization

selection bias

Differential dropout results in

post-randomization non-

equivalence between arms

– Encourage dropouts to

drop the intervention

but stay in the trial

– Minimize burden for

dropouts by obtaining

permission to assess

primary outcome only

– Budget travel to

participant location for

outcome assessment

– Provide generous

participant incentives to

complete nal outcome

assessment

– Intent-to-treat analyses

with conservative

assumptions for missing

data on the primary

endpoint

Overcoming These Challenges in a Behavioral Tria

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SELECTED EXPERIENCE

FROMBEHAVIORAL TRIALS

The Hypothesized Pathway inaSuccessful Behavioral Trial

The Diabetes Prevention Program was among the greatest successes reported to

date for a lifestyle program’s ability to improve a chronic disease outcome [

16, 31,

32]. The aim was to compare the benets of lifestyle, metformin, and placebo on

preventing the development of diabetes in patients who were insulin resistant.

Results showed that lifestyle was 30% better than the best drug available and 60%

better than a placebo pill.

This lifestyle treat-

ment was developed

progressively and sys-

tematically over

approximately

40years in an array to

studies done by a vari-

ety of investigators.

(See Chapter 3:

Behavioral Treatment

Development, Table

3.9.) This extensive

development resulted

in the ability to articu-

late a quantied

hypothesized pathway

by which the treatment

would translate into a reduction in diabetes incidence (Fig.4.5) [32]. It can be seen

that this pathway “sticks its neck out.” It portrays two components, each of which is

linked to a quantied implementation target and behavioral risk factor target.

Physical activity has a direct path to the primary outcome and an indirect path to it

through its ability to sustain weight loss over and above changes in dietary intake.

Results of the trial supported the hypothesis that this was the pathway by which the

treatment reduced the incidence of diabetes. At the conclusion of the 6-month life-

style treatment, 50% of participants met the goal of ≥7% loss of body weight, and

74% met the goal of ≥150minutes of physical activity/week [16]. By the end of the

average of 3.2years of follow-up, 38% continued to meet the body weight goal, and

58% continued to meet the physical activity goal [16]. Although the percentages of

people expected to meet the behavioral risk factor targets were not specied a priori,

the success of the trial suggests that the percentage of participants who achieved

Fig. 4.5 Hypothesized pathway in the Diabetes Prevention

Program

4 Hypothesized Pathway andBias

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each target was sufcient to reduce diabetes incidence. These percentages of suc-

cess can be embedded into future hypothesized pathways as clinically signicant

targets. Further support for the validity of the hypothesized model is provided by the

10-year follow-up of the program [33]. There were no differences in diabetes inci-

dence among the three randomized arms in the interval between the 3.2-year end of

treatment and the 10-year follow-up. This is tracked with posttreatment weight

regain over the same interval.

The Hypothesized Pathway Explains aNull Trial

The aim of the Women’s Health Initiative Dietary Modication Trial was to deter-

mine if a low-fat eating pattern would reduce risk of cardiovascular disease, colorec-

tal cancer, and breast cancer. A total of 48,385 women were randomized to a diet

intervention or a usual care comparison in a 40:60 ratio, respectively. This was a

null trial in which there was no benet of the dietary intervention on any of the three

primary clinical outcomes. This null result, in combination with the extraordinary

expenditure of resources expended in this trial, justied working back through the

hypothesized pathway to determine what happened.

The behavioral target of the intervention was a low-fat eating pattern, operational-

ized as ≤20% of intake from fat, 5 servings/day of vegetables and fruits, and 6 serv-

ings/day of grains. The results for the cardiovascular disease outcome are presented

in Table4.2 [34]. It can be seen that the diet improved but dietary goals were not met

at the end of the 6-year follow-up period.

A post hoc, per-protocol

investigation was aimed at

determining benet if partici-

pants had achieved dietary

goals. The treated group was

broken down into quartiles

based upon the dietary

changes achieved by 1 year.

Rates of cardiovascular dis-

ease at 6years were compared

in those who were in the lowest quartile in the treated arm relative to those in the

usual care comparator. Those who had an average intake of saturated fat <6.1%, had

an average intake of trans fat <1.1%, or ate ≥6.5 servings of vegetables and fruits/

day had a lower incidence of cardiovascular events than those randomized to usual

care (HR=0.81–0.88).

Although post hoc ndings are suggestive but not conclusive, they provide a valu-

able opportunity to consider reasonable next steps in a program of research after a

Table 4.2 Expected vs. observed dietary changes in the

Women’s Health Initiative Dietary Modication Trial

Goal Baseline 1year 6years

Percent energy

from fat

≤20% 37.8% 24.3% 28.8%

Vegetable/fruit

servings/day

5 3.6 5.1 4.9

Grains servings/

day

6 4.7 5.1 4.3

Selected Experience fromBehavioral Trials

https://t.me/medicina_free

null trial. Because a priori goals specied in the hypothesized pathway were not

met, this was a failure of the treatment, not the hypothesis. Post hoc analyses sug-

gested that the specic target for vegetable intake should be increased from 5 to 6.5

servings/day. They also suggested that the treatment be rened to target saturated

and trans fat rather than total fat. A rened hypothesized pathway, and a more tar-

geted intervention, may provide a conclusive test of the impact of diet on cardiovas-

cular disease. But before such a rigorous replication is undertaken, it would be wise

to conduct a small proof-of-concept study to determine if a rened and more tar-

geted intervention is strong enough to achieve the revised clinically signicant tar-

gets on vegetable, saturated fat, and trans fat intake.

Consequences ofMistaking aFailed Treatment foraFailed

Hypothesis

The Trials of Hypertension Prevention (TOHP) Collaborative Research Group tri-

als aimed to determine the best approach for preventing the development of hyper-

tension in persons with high normal diastolic blood pressure. In the rst of two

trials, the Phase I TOHP-I trial tested the feasibility and efcacy of seven nonphar-

macologic interventions on the primary endpoint of diastolic blood pressure [29].

These interventions included three lifestyle treatments (weight reduction, sodium

restriction, stress management) and four dietary supplements. All were compared

against a usual care control. The importance of TOHP-I was that only those inter-

ventions that were efcacious would go on to be tested in the larger Phase II

TOHP-II trial which examined the impact of the interventions on the incidence of

hypertension [35].

TOHP-I results indicated that only the weight loss and sodium restriction groups

were effective at lowering diastolic blood pressure. Stress management was ineffec-

tive at both 6 and 18months suggesting a failure of the hypothesis that reduction in

stress was associated with a reduction in blood pressure. From the Abstract:

“Despite good compliance, stress management did not reduce diastolic blood pressure

signicantly (P>.05).”

However, a closer look raises the possibility that this was instead a failure of the

intervention aimed at managing stress. Although attendance at stress sessions was

86%, Table4.3 shows that at the 18-month end of treatment, the stress management

group experienced a signicant increase, and the usual care group a decrease, in the

frequency of hassles, the primary measure of stress (+1.9 vs. −0.5, respectively,

p < 0.05). This translated into no difference between arms on diastolic blood

pressure at 18months, although both were below the clinically signicant cutpoint

for hypertension of 80mmHg.

4 Hypothesized Pathway andBias

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In contrast, Table 4.3 shows that the weight outcome in TOHP-I followed the

expected pattern. Participants in the weight reduction intervention lost weight, and

the usual care controls gained weight (−3.8kg vs. +0.1kg, respectively, p<0.01).

This translated into a statistically signicant 2.6mmHg difference between arms on

diastolic blood pressure at 18months (p<0.01). Only the treated group achieved

the clinically signicant cutpoint for hypertension of <80mmHg.

Because the stress management intervention did not produce a statistically signi-

cant reduction in blood pressure in TOHP-I, it did not move forward to be evaluated

for its impact on incidence of hypertension in TOHP-II.However, the weight reduc-

tion treatment was evaluated in TOHP-II.It produced an average of 2.0kg of weight

loss and achieved a mean blood pressure of 81.5mmHg at 18months, both of which

were statistically different from usual care (p<0.001) due, to a certain extent, to the

large sample size. The primary endpoint, incidence of hypertension, was reduced by

22% at 18months (p = 0.05) and by 13% at 48months (p =0.06). This nding

resulted in the recommendation to include weight reduction in clinical practice

guidelines for patients with high normal blood pressure.

The failure to test the stress management intervention in TOHP-II was a missed

opportunity. This decision was made based upon the inability to distinguish between

a failure of the stress intervention and a failure of the hypothesis that reduction in

stress improves diastolic blood pressure. The “red ags” were the increase in stress

in the treated group and the decrease in stress in the usual care group. Whatever was

going on in these two arms, both arms decreased diastolic blood pressure from a

baseline of 82mmHg (above the cutpoint for hypertension of 80mmHg) to below

this cutpoint.

Table 4.3 Comparison of treatment effects in TOHP-I and TOHP-II at the 18-month

follow-up

TOHP- I TOHP-II

Behavioral

target:

∆ 0–18 months

Diastolic

blood pressure

target:

18months N

Behavioral

target:

∆ 0–18 months

Diastolic

blood pressure

target:

18months

Stress

management

Treated

Usual care

242

589

+1.9

∗a

−0.5

78.4 mmHg

78.9mmHg

—

Weight

reduction

Treated

Usual care

308

589

−3.8kg

∗∗

+0.1kg

77.5 mmHg

∗∗

80.1mmHg

595

596

−2.0kg

∗∗∗

+0.7kg

81.5 mmHg

∗∗∗

82.6mmHg

Frequency of Daily Hassles Scale

ns not signicant

∗

p<0.05

∗∗

p<0.01

∗∗∗

p<0.001

Selected Experience from Behavioral Trials

https://t.me/medicina_free

This is an excellent example of how critical it is to make the distinction between a

failure of the hypothesis and a failure of the treatment. The existence of a quantied

hypothesized pathway would have helped make this distinction. In the face of a

failed stress intervention, a reasonable next step would have been to increase its

strength in a renement study and replicate for the purpose of determining whether

or not it should be a candidate for further evaluation in TOHP-II.Because the stress

intervention was not evaluated in TOHP-II, it is unclear how it would have fared

alone, or in combination with the other lifestyle factors. Another trial is needed. The

clinical implication of this mistake is that experts in hypertension prevention inter-

pret the TOHP results to mean that preventive efforts should focus on weight, but

not on stress.

RECOMMENDATIONS

It is tempting to take the easy road in an academic career. It is, for example, com-

paratively easy to conduct a randomized trial guided by a complex conceptual

model, compare treated to controls on a wide variety of outcomes, show a statistically

signicant difference on one or more of these outcomes, judge the treatment to be

successful, get a publication needed to advance an academic career, and decide the

job is done. This is a reasonable strategy, supported by a culture that includes not

only investigators but also funders, institutions, and reviewers.

The problem with this “easy road” is that this is not good science. The result could

have little to do with improving a chronic disease. It could be statistically, but not

clinically, signicant. It could be explained by simple design decisions such as the

choice of the control, the size of the sample, or the number of comparisons

conducted.

The “road not taken” is the harder

road. It is the one that aims to iden-

tify behavioral treatments that

improve chronic disease endpoints

for the purpose of maximizing

effective management. Should this

road be taken, the roadmap for the

trip is progressive treatment devel-

opment guided by a hypothesized

pathway. The pathway is created in the earliest stages of development and guides

the studies, designs, and milestones evaluated at each subsequent stage. As an

understanding of the treatment grows, the hypothesized pathway becomes simpler,

more targeted, and more precise, and treatment evaluation progresses toward bigger,

The Road Not Taken

“. . . Two roads diverged in the wood and I –

I took the one less traveled by,

And that has made all the difference.”

Robert Frost

(1874–1963)

4 Hypothesized Pathway andBias

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more rigorous, and more ambitious trials. The end game is an evidence-based

behavioral treatment that meets the rigorous standards of evidence established in

medical research.

For those who choose “the road not taken,” several recommendations are offered.

Stick Your Neck Out

Karl Popper, the great philosopher of science, has provided behavioral trialists with

two gifts that should be considered seriously. First, he encourages us to welcome

failure as an opportunity to rene, simplify, and progress. This mindset is consistent

with one of the key mantras of Silicon Valley: “Failure provides the seedbed for

innovation.” Second, Popper encourages humility. Any claims about the benets of

a treatment can be overturned in the next trial. Embracing failure and humility in

one’s science and career encourages the freedom to have intellectual curiosity.

“Stick your neck out” means guiding your research program with a quantied

hypothesized pathway. It means making bold hypotheses, seeing failure as an

opportunity for renement, persisting in the effort to understand, and progressing

toward simplication. In behavioral treatments for chronic diseases, the web of

causal factors is complex and progress can be slow. Those who are willing to “stick

your neck out” will be aligning the method to the complexity of the problem.

Advance Academically asaBehavioral Trialist

Aspiring behavioral trialists may believe they are faced with a dilemma. Either

advance one’s academic career or do good science. Academic advancement is based

upon products which most often take the form of external grants and publications.

Doing good science as a trialist is characterized by a process that features treatments

that fail and papers that have difculties getting published.

The contradictory goals of academic advancement and good science are beginning

to dissolve in the eld of behavioral treatments for chronic diseases with recent

evolutions in funding and publication practices. The National Institutes of Health

now offer a variety of funding mechanisms for early treatment development studies

and funding mechanisms that combine early feasibility studies with conrmatory

trials but make success in the former contingent for continued funding for the latter.

On the publication side, there has been an emergence of journals directed toward

early phase studies. Publishing potential is maximized if early studies are posi-

tioned within the context of a progressive program of research, rather than an end

Recommendations

https://t.me/medicina_free

unto themselves. Failures, guided by a priori hypothesized pathways, become

important topics for papers if they not only document the failure but articulate why

it is likely to have occurred and how it is a springboard to the next study guided by

a rened hypothesized pathway. Guidelines now exist for the publication of inter-

vention development studies [36].

Because behavioral treatment development is a slow process, it is wise to have other

lines of research with shorter timelines for publications. Fruitful second lines of

research can be developed through collaborations with investigators who are lead-

ing ongoing epidemiological studies or clinical trials. These investigators have a

responsibility to their funding agency to show productivity in exchange for the large

amount of resources they have been given to conduct such investigations. Afliating

with these investigators, learning how to work with their datasets, and writing

papers from them is mutually benecial. Beyond this, there are now many public

use datasets that exist for completed studies. These datasets can be accessed without

requiring collaboration with the principal investigator.

Become anExpert inBehavioral Clinical Trial Biases

Rigorous behavioral clinical trials require bridging disciplines and synthesizing

insights. The challenge in a behavioral trial is to preserve the randomization over

long periods of time, in the presence of treatment arms that often “look and feel”

very different from one another, and under conditions where investigators often

have a long-standing commitment to the treatment under investigation. Since the

treatment is behavioral, mastery of biases in experimental design is needed. Since

the outcome is a chronic disease or surrogate, mastery of biases in clinical trials

is needed.

Interdisciplinary sophistication in the range of potential biases that could occur in a

behavioral trial makes it clear that it is a mistake to assume that once randomization

is accomplished, the problems with bias are over. In fact, new challenges are now

beginning.

4 Hypothesized Pathway andBias

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References

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