The Scientist as a Responsible Member of Society:
A Personal Perspective on Research Integrity
Constantine G. Lyketsos, MD, MHS
Elizabeth Plank Althouse Professor, Johns Hopkins University
Chair of Psychiatry, Johns Hopkins Bayview
[email protected]
Presentation overview
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Definitions-why are we here?
Why am I giving this talk?
More on integrity
A few personal vignettes
WHILE MY FOCUS IS ON HUMAN
RESEARCH, THE KEY MESSAGES APPLY
TO ALL MEDICAL RESEARCH
Purpose of medical research
• Prevent, cure, or treat disease and
related human conditions
• Make the lives of our patients better
Johns Hopkins is a special place
For me, research on humans
necessitates a commitment to help
participants access the best possible
care at the same time
I am also their doctor
Definitions: research
…studious inquiry or examination; especially:
•investigation or experimentation aimed at the
discovery and interpretation of facts,
•revision of accepted theories or laws in the light of
new facts, or
•practical application of such new or revised
theories or laws
http://www.merriam-webster.com/dictionary/research?show=0&t=1316277023
Definitions: human subjects
research (CFR Title 45; Part 46)
(f) Human subject means a living
individual about whom an investigator
(whether professional or student)
conducting research obtains:
(1) data through intervention or interaction
with the individual, or
(2) identifiable private information.
http://ori.hhs.gov/education/products/mass_cphs/training_staff/RCReng/RCRCo
mmonRule.htm#46.102#46.102
DHHS-Office on Research Integrity
http://ori.hhs.gov/
“role and structure of
ORI…focus…on preventing
misconduct and promoting
research integrity through
expanded education programs”
http://ori.hhs.gov/about/ORI_Mission.shtml
Scientific misconduct
The violation of the
standard codes of scholarly
conduct and ethical
behavior in professional
scientific research
http://en.wikipedia.org/wiki/Scientific_misconduct
Research misconduct
Johns Hopkins Definition
… means fabrication, falsification, or plagiarism in
proposing, performing, or reviewing research, or in
reporting research results.
a) Fabrication is making up data or results and recording or reporting them.
b) Falsification is manipulating research materials, equipment, or processes, or changing or omitting
data or results such that the research is not accurately represented in research records or reports.
c) Plagiarism is the appropriation of another person's ideas, processes, results, or words without giving
appropriate credit.
d) Research misconduct does not include honest error or honest differences of opinion.
e) Research misconduct includes the destruction of, absence of, or accused person's failure to provide
research records accurately documenting the questioned research.
Forms of misconduct
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Falsification
Obfuscation
Fabrication
Supression
Plagiarism
Self-plagiarism
Ghost writing
http://en.wikipedia.org/wiki/Scientific_misconduct
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Bare assertions
Improper authorship
Misappropriation
Bibliometric inflation
• Violation of ethical
standards regarding
human and animal
experiments
Why research misconduct?
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Career advancement
Competitiveness
Laziness
Ability to get away with it
Why me?
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Investigator
Research mentor
Former IRB member and chair
Research misconduct investigator
•Son of George C. Lyketsos
George C. Lyketsos, MD, FRCPsych
11 January 1917- 20 August 2011
• Professor of Psychiatry, National
Kapodistrian Univeristy of Athens,
1974-1989
• Medical Director, Dromokaition
Mental Hospital, 1947-1985
• Lived through the transition to
modern psychiatry
Human subject researcher
in an era before regulation
Dromokaition Mental Hospital
• Bequest of major philanthropist 1887
• Where thousands of patients lived,
some for decades
• Where new therapies for mental
illness where introduced in Greece
• Where community placement of
most patients took place by the
1980s
• This was largely unregulated
research
The introduction of ECT to Greece:
from The Story of My Life (GCL, 1998)
The first patient finds himself
And then the time came for the great trial…of ECT in a patient. Thinking of those
days I am surprised by my confidence. I had no doubt things would go well. I chose
for the trial patient X who had been lost to the world…nobody had shown any
interest in him for many years…That morning in March 1946…(the staff) brought X.
He was catatonic…We laid him down on a sofa and placed the electrodes on his
temples which we had already rubbed with salted water… I pressed the button for
10ths of seconds. A jerk followed… I increased the intensity…I pressed the button
for a longer duration and after a few seconds the seizure happened. We became
scared as the patient turned blue. We fell onto him to provide artificial respiration.
Quickly, breathing returned and we took him to the ward where he fell asleep. Later
we visited him. He had awakened and was active… I asked him “How are you?”
and he ANSWERED “fine.” This gave us courage and we repeated the ECT after
two days. After that we were able to communicate enough to find out who his
relatives where who came to visit. He is the phenomenon and I think he still lives at
Dromokaition. In total he had ten ECT. It did not cure him, but he was able to live at
the level of social life of a developed psychiatric hospital.
Outcomes of ECT therapy
• Schizophrenia: N=75, 6-12 treatments
– 12 (16%) full remission (mostly catatonic)
– 17 (23%) partial remission
– 46 (61%) no change—mostly “demented”
• Affective disorder: N=25
– 18 (72%) full remission
– 6 (24%) partial remission
– 1 (1%) no change
Lyketsos GC, Arkalides N. The therapeutic method via electric shock at Dromokaition Therapeuterium. Results
of 100 cases. (Experience of over 4,000 treatments.) Kliniki 1 December 1946
Tidbits of the ECT story
• Built their own machines (“cost 10 gold
sovereigns to build and sold for 11”)
• Offered to most every patient
• Consent was obtained when families
available or patients could discuss (no
documentation)
About 30% of patients improved and left the
hospital within the next year
Other examples of Dromokaition research
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Observational studies
EEG research
Frontal leucotomies
Ancient Greek Drama therapy
Rehabilitation methods
None of our contemporary
processes followed
• Research happened
• Patients were helped
• Advances occurred
How is that possible?
INTEGRITY
Definitions: integrity
1. firm adherence to a code of especially
moral or artistic valuesINCORRUPTIBILITY
2. an unimpaired condition:
SOUNDNESS
3. the quality or state of being complete:
COMPLETENESS
http://www.merriam-webster.com/dictionary/integrity
But what is integrity really?
• An attitude
• A state of mind
• A commandment
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Must be cultivated and honed
Occurs in a context
A team sport: you are not alone
Modeling critical to its development
Measuring integrity
• Choice of research we conduct
– Why is the study important?
– Would you put your mother in your study?
• How we look after our participants
– How would you consent your sister/brother?
– How would you monitor your ill child?
• How we report our findings
Personal vignettes
• DIADS/CATIE/CITAD-placebo/vulnerable
• ADAPT-crisis in a prevention trial for AD
• DBS for AD-pushing the envelope
• Mrs. F-my patient in 3 studies
• Mrs. H-from participant to patient
35.5 million people have dementia today
The number of living cases doubles every 20 years
115.3 million people with dementia by 2050—NEW CASES
Alzheimer’s4/13/2015
Disease International
World Alzheimer’s Report, September 21, 2009
25
NPS are universal in dementia
Percentage
Five-year period prevalence of NPI sym ptom s (NPI>0)
100
90
80
70
60
50
40
30
20
10
0
5.3 years=36
NPI total
Aberrant Motor
Behavior
4.1 years=61
Irritability/Lability
3.0 years=106
Disinhibition
Steinberg et al, Int J Ger Psychiatry 2008
Anxiety
1.5 years=236
Elation/Euphoria
Apathy/Indifference
Depression/Dysphoria
Agitation/Aggression
Hallucinations
Delusions
baseline=408
NPS accelerate onset of severe dementia
including mild NPS
Rabins et al, Poster P-145, AAIC, Paris, July 2011
NPS are “bad” for patients & caregivers
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Greater ADL impairment1
Worse quality of life2
Earlier institutionalization3
Major source of caregiver burden4
$10,000/year additional care costs5
1Lyketsos
et al, 1997; 2Gonzales-Salvador et al, 1999; 3Steele et al, 1990;
4Lyketsos
et al, 1999; 5 Murman et al, 2002
Treating NPS is a high priority
• High utilization of treatments based on
findings in general psychiatry
– Antipsychotics, antidepressants, etc
• Little controlled research
• Safety concerns
• We undertook placebo controlled RCTs
The issues
• Placebo controls
• Vulnerable population
The CATIE-AD Study
Antipsychotics for agitation
Aripiprazole
Olanzapine
Quetiapine
Risperidone
Overall Effect
(SMD)= .20
DRAFT
AHRQ
Comparative
Effectiveness
Review
2011
Mortality in Dementia RCTs:
Pooled Analyses
Relative Risk
95% CI
Olanzapine
2.31
1.00-5.35
Risperidone
1.35
0.85-2.14
Aripiprazole
1.99
0.86-4.62
Quetiapine
1.35
0.85-2.14
OVERALL
1.65
1.19-2.29
Schneider L et al JAMA, 2005
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DIADS-2: sertraline for depression
10
5
Cornell score
15
Sertraline
Placebo
0
5
10
15
Week from enrollment
Rosenberg et al, Am J Geriatr Psychiatry, 2010
Weintraub et al, Am J Geriatr Psychiatry, 2010
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Seeking a paradigm shift: focus on 5 NPS
to accelerate treatment development
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Psychosis
Apathy
Agitation
Depression
Sleep
Approach
• Phenomenology
– Diagnostic criteria, prevalence, subtypes
• Assessment tools
– Define relevant endophenotypes, biomarkers
• Neurobiology
– What is known?
– Useful to guide interventions?
• Interventions
– Pharmacologic and nonpharmacologic-efficacy?
– Change progression?
Neurobiology of Psychosis in AD
Proposed schematic
Sweet et al., AAIC Plenary, Paris, 2011
APPswe/PS1 Δ E9 mouse model
Liu, Savonenko, Price, Lee et al. J Neurosci. 2008;28(51):13805-14.
Increased Beta Amyloid Deposition (RED) and Decreased
Serotonin Transporter Availability (BLUE) in MCI vs. Controls
Smith, GS, Marano, C., Workman, CI, Zhou, Y, Savonenko, A., Wong, DF, Lyketsos CG. Unpublished data, 2010
Prophylactic treatment with paroxetine ameliorates behavioral deficits and
retards the development of amyloid and tau pathologies in 3xTgAD mice
Nelson RL, Guo Z, Halagappa VM, Pearson M, Gray AJ, Matsuoka Y, Brown M, Martin B, Iyun T, Maudsley S,
Clark RF, Mattson MP. Exp Neurol. 2007;205(1):166-76
Citalopram for agitation in AD:
Multi-center trial (R01AG031348)
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200 patients with AD and agitation
9-week RCT: citalopram 30mg v placebo
Psychosocial intervention for all
First patient randomized Aug 2009
Can NSAIDs prevent AD?
• At least 22 studies and one meta-analysis1
including case-control, case-cohort, and
prospective (incidence) studies
• 7 case-control studies of OA or RA with
summary odds ratio (OR) 0.56 (0.44 - 0.77)
• 2 population (“case – cohort”) studies of RA
with summary OR 0.19 (0.09 - 0.41)
1McGeer
PL, Schulzer M, McGeer EG. Neurology 1996;47:425-432.
Alzheimer Disease Anti-inflammatory
Prevention Trial (ADAPT)
• Primary prevention RCT with two outcomes:
– Incident Alzheimer Disease (AD)
– Cognitive Decline
• Treatments vs. placebo
– Conventional NSAID (naproxen 225 BID)
– Selective COX-2 inhibitor (celecoxib 200 BID)
• Six sites: Baltimore, Boston, Phoenix,
Rochester, Seattle, Tampa/Sarasota
• N=2422 aged 70+ with history of AD-like
dementia in 1o relative: 437 at JHU
ADAPT in crisis
• Dec 2004—adenomatous polyps prevention trials suggest
increased risk of cardiovascular events with celecoxib (OR~2.5)
• Two similar trials stopped Dec 17
• ADAPT DSMB met week before and recommended continuation
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WHAT TO DO IN ADAPT?
Took the risk seriously especially in prevention trial
Considered re-consent and continuation, esp naproxen arm
Logistics got in the way: media effects on participants, concerns
about IRB review process, FDA hold on celecoxib trials
• ENROLLMENT AND TREATMENTS STOPPED
• FOLLOWUP CONTINUED
Did we make the right decision?
• Stopped a trial mid-stream out of safety
concerns, largely for pragmatic reasons
• Delayed an experiment that may have
identified a preventive therapy for AD
• We may never know
Patient to research participant
Mrs. RF
• Married, artist in her 80s; healthy
• Closely connected with husband-agent
• First seen as outpatient for depression
• Did well on antidepressants
• Developed AD dementia
• Requested research participation
• ADRC, GSI RCT, apathy Rx RCT
Research participant to patient
Mrs. EH
• ADAPT participant—her mother had AD
• During ADAPT followup diagnosed MCI
• Asked to become my patient
• Continues in ADAPT
• Several complex clinical issues
The issues
• My own patient in my own research
• Triage of what’s the right study
• Communication, disclosure, oversight
The next plunge
Final words: threats to integrity
Excessive focus on process
• Uses up resources and energy
• Gives the wrong signal that the process
assures integrity
Research Integrity
• An attitude
• A state of mind
• A commandment
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Must be cultivated and honed
Occurs in a context
A team sport: you are not alone
Modeling critical to its development
Johns Hopkins is a special place
For me, research on humans
necessitates a commitment to help
participants access the best possible
care at the same time
I am also their doctor
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Presentation overview - Johns Hopkins Medicine