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Bayesian Hierarchical Models for Detecting Safety Signals
in Clinical TrialsH. Amy Xia and Haijun Ma
Amgen, Inc.
MBSW 2009, Muncie, INMarch 20, 2009
Disclaimer: The views expressed in this presentation represent personal views and do not necessarily represent the views or practices of Amgen.
Outline• Introduction• A motivating example• Bayesian Hierarchical Models
– Meta analysis of Adverse Events data from multiple studies incorporating MedDRA structure
– Incorporate patient level data– Effective graphics
• Closing Remarks
Three-Tier System for Analyzing Adverse Events in Clinical Trials
• Tier 1: Pre-specified Detailed Analysis and Hypothesis Testing– Tier 1 AEs are events for which a hypothesis has
been defined• Tier 2: Signal Detection among Common Events
– Tier 2 AEs are those that are not pre-specified and “common”
• Tier 3: Descriptive Analysis of Infrequent AEs– Tier 3 AEs are those that are not pre-specified and
infrequent
Gould 2002 & Mehrotra 2004SPERT White Paper 2008
Multiplicity Issue in Detecting Signals Is Challenging
• Detection of safety signals from routinely collected, not pre-specified AE data in clinical trials is a critical task in drug development
• Multiplicity issue in such a setting is a challenging statistical problem – Without multiplicity considerations, there is a potential
for an excess of false positive signals – Traditional ways of adjusting for multiplicity such as
Bonferroni may lead to an excessive rate of false negatives
– The challenge is to develop a procedure for flagging safety signals which provides a proper balance between ‘no adjustment’ versus ‘too much adjustment’
Considerations Regarding Whether Flagging an Event
• Actual significance levels• Total number of types of AEs• Rates for those AEs not considered for flagging• Biologic relationships among various AEs
1st two are standard considerations in the frequentist approach. The 2nd two are not, but relevant in the Bayesian approach
-- Berry and Berry, 2004
Bayesian Work in Signal Detection
• Spontaneous adverse drug reaction reports– Gamma Poisson Shrinker (GPS) on FDA AERS
database (DuMouchel,1999)– Bayesian Confidence Propagation Neural Network
(BCPNN) on WHO database (Bate, et al. 1998)• Clinical trial safety (AE) data
– Bayesian hierarchical mixture modeling (Berry and Berry, 2004)
Meta Analysis• Glass (1976)
Meta-analysis refers to a statistical analysis that combines the results of some collection of related studies to arrive a single conclusion to the question at hand
• Meta-analysis based on – aggregate patient data (APD meta-analysis)– Individual patient data (IPD) meta-analysis
• Bayesian modeling is a natural choice to incorporate the complex hierarchical structure of the data
George Chi, H.M. James Hung, Robert O’Neill (FDA CDER)
“Safety assessment is one area where frequentist strategies have been less applicable. Perhaps Bayesian approaches in this area have more promise.”
(Pharmaceutical Report, 2002)
An Example• Data from four double-blind placebo-controlled studies
on drug X. Study populations are similar.• Sample sizes:
• After converting all AEs into same MedDRA version, reported AEs are coded to 464 PTs under 23 SOCs and 233 HLTs
Study Drug XN
Drug XSubj-yr
PlaceboN
PlaceboSubj-yr
Study A 57 28.25 55 19.02
Study B 486 104.75 166 34.93
Study C 390 85.44 193 40.97
Study D 312 68.78 306 65.91
N_0: sample size in placebo arm; N_1: sample size in treatment arm
n_0: # subject with AE in placebo arm; n_1: # subject with AE in treatment arm
rt_0: subject incidence in placebo arm; rt_1: subject incidence in treatment arm
SYSTEM ORGAN CLASS HIGH LEVEL TERM PREFERRED TERM STUDY n_0 n_1 N_0 N_1 rt_0 rt_1
INFECTIONS AND INFESTATIONSHERPES VIRAL INFECTIONS HERPES SIMPLEX 1 0 3 55 57 0.00 5.26
2 0 5 166 486 0.00 1.033 1 8 193 390 0.52 2.054 2 2 306 312 0.65 0.64
INFECTIONS AND INFESTATIONSUPPER RESPIRATORY TRACT INFECTIONS SINUSITIS 1 2 8 55 57 3.64 14.04
2 6 19 166 486 3.61 3.913 0 8 193 390 0.00 2.054 4 11 306 312 1.31 3.53
INFECTIONS AND INFESTATIONSUPPER RESPIRATORY TRACT INFECTIONS RHINITIS 1 0 0 55 57 0.00 0.00
2 0 0 166 486 0.00 0.003 1 4 193 390 0.52 1.034 0 0 306 312 0.00 0.00
SKIN AND SUBCUTANEOUS TISSUE DISORDERS URTICARIAS URTICARIA 1 0 1 55 57 0.00 1.75
2 1 1 166 486 0.60 0.213 0 4 193 390 0.00 1.034 1 4 306 312 0.33 1.28
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
PURPURA AND RELATED CONDITIONS ECCHYMOSIS 1 0 0 55 57 0.00 0.00
2 0 4 166 486 0.00 0.823 0 5 193 390 0.00 1.284 0 3 306 312 0.00 0.96
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
NON-SITE SPECIFIC INJURIES NEC EXCORIATION 1 0 0 55 57 0.00 0.00
2 0 7 166 486 0.00 1.443 0 0 193 390 0.00 0.004 0 1 306 312 0.00 0.32
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
NON-SITE SPECIFIC PROCEDURAL COMPLICATIONS PROCEDURAL PAIN 1 0 0 55 57 0.00 0.00
2 0 0 166 486 0.00 0.003 0 1 193 390 0.00 0.264 2 1 306 312 0.65 0.32
Proposed Bayesian Approach• Hierarchical mixture models for aggregated
binary responses was constructed based on the work by Berry & Berry(2004)– Explore impact of using different MedDRA hierarchy– Inclusion of study effects– Further extended to a hierarchical Poisson mixture
model, to account for different exposure/follow-up times between patients
• Individual patient level models are discussed• Implemented the above models with available
software– WinBUGS for model implementation– S-Plus graphics for inference
MedDRA
• MedDRA (the Medical Dictionary for Regulatory Activities Terminology) is a controlled vocabulary widely used as a medical coding scheme.
• MedDRA Definition (MSSO): – MedDRA is a clinically-validated international medical
terminology used by regulatory authorities and the regulated biopharmaceutical industry. The terminology is used through the entire regulatory process, from pre-marketing to post-marketing, and for data entry, retrieval, evaluation, and presentation.
https://eudract.emea.europa.eu/docs/medDRA/Introduction_To_MedDRA.ppt MSSO: Introduction to MedDRA
http://www.fda.gov/cder/present/dia-699/dia628/index.htmMedDRA and Pharmacovigilance - The Way Forward, 7/8/99
http://www.fda.gov/cder/present/dia-699/dia628/index.htmMedDRA and Pharmacovigilance - The Way Forward, 7/8/99
SOC = Respiratory, thoracic and mediastinal disorders
HLGT = Respiratory tract infections
HLT =Viral upper respiratorytract infections
HLT = Influenza viral infections
HLGT = Viral infectious disorders
SOC = Infections and infestations
PT = Influenza
Example of MedDRA Hierarchy
https://eudract.emea.europa.eu/docs/medDRA/Introduction_To_MedDRA.ppt MSSO: Introduction to MedDRA
Hierarchical Structure of MedDRA• Bayesian hierarchical models allow for explicitly
modeling AEs with the existing coding structure – AEs in the same SOC more likely to be similar within than
across SOCs. – Allow for this possibility, but does not impose it, depending on
the actual data– SOC tends to be too broad. HLT is more closely related to
medical concepts.• In fact, clinical and safety people would (informally)
consider the similarity of the AEs, say, within SOCs when they review AE tables – For example, if differences in several CV events were observed,
then each would be more likely to be causal than if differences came from medically unrelated areas (eg, skin, neurological, thrombosis, cancer)
• Bayesian hierarchical modeling allows a scientific, explicit, and more formal way to take it into consideration
Notations
• Study i=1,…I, SOC b=1,…B and PT j=1,…kb
• Data: For AEibj
– Treatment group: Yibj incident events observed in Nit patients with Tibj subjects’ exposure
– Control group: Xibj incident events observed in Nic patients with Cibj subjects’ exposure
Bayesian Meta Analysis Hierarchical Logistic Regression
ly.respective groups, control
and treatmentin the AEfor ratesevent are and where
,BinomialBinomial
ibjibjibj
ibj,icibjibj,itibj
ct
) c(N ~ ), X t(N ~ Y
)1()exp(~);1()exp(~
:prior 3 Stage
);,(~:prior 2 Stage
);,()1()0(~ :prior 1 Stage
:OR-logeffect ent for treatmPrior Mixture
),N( ~, ),N(~
)logit(t ,)logit(c
2bj
2bbbj
2bj,bjibj
bjibjibjibj ibj
pp
pp
ppb
bbbb
II
Beta
N
•Common treatment effect for same PT across studies
Bayesian Meta Analysis Hierarchical Logistic Regression (Cont.)
• Treatment effect with additive study effects:
• A random treatment effect/multiplicative model:
),()1()0(~, ),N(~
),N( ~, ),N(~
)logit(t ,)logit(c
2bj
2bjbjibj
2bbbj
2bj,bjibj
ibjibjibjibj ibj
bbbb N
)01.0,0(~
),()1()0(~
),N( ~, ),N(~
)logit(t ,)logit(c
2bj
2bbbj
2bj,bjibj
ibjibjibjibj ibj
N
N
Study
i
bbbb
i
Bayesian Meta Analysis Hierarchical Logistic Regression (Cont.)
• Other priors– Stage 1 λbj ~N(μλb , σ2
λb );
– Stage 2 μλb~N(μλ0, σ2λ0 ); σ2
λb ~IG(αλ, βλ);
μθb ~N(μθ0, σ2θ0 ); σ2
θb ~IG(αθ, βθ)
- Stage 3 μλ0~N(μλ00 , σ2λ00 ); σ2
λ0 ~IG(αλ00, βλ00)
μθ0~N(μθ00 , σ2θ00 ); σ2
θ0 ~IG(αθ00, βθ00)
Hyperparameters μλ00, σ2λ00, αλ00, βλ00, μθ00, σ2
θ00,
αθ00, βθ00, αλ, βλ , αθ, βθ are fixed constants
Inference
• AEbj is flagged if – Pr( θbj > d*| Data) > p, where θbj is log-OR in
Binomial models and log-RR in Poisson models.
– d* and p are all prespecified constants.• Graphs are useful tools in deciphering
data and presenting results
Model Selection
• Deviance Information Criteria (DIC) was used to compare models with same data
• Limited sensitivity analyses were done to check the robustness of the models
• Different levels of MedDRA structures were used– SOC/PT, HLT/PT and SOC/HLT/PT
• Treatment effect with additive study effects model using SOC/PT structure was chosen
Bayesian Meta Analysis Hierarchical Log-linear Regression
• Poisson models – Adjust for different exposures in treatment and control– Assume constant hazard over time– Unless AEs are fairly common or follow up of studies are
quite unbalanced between treatment arms, usually are not very different from Binomial models
Yibj~Pois(tibj Tibj ); Xbj~Pois(cibj Cibj)where tibj and cibj are event rates, and Tibj and Cibj for AEibj are total exposure times in the treatment and control groups, respectively
log(cibj )=λibj; log(tibj )=λibj + θbj ,
Note that θbj =log(RRbj)
Fisher's Exact Test 2-sided P-values
Raw Risk Difference(%), Treatment - Placebo
- log
10 (F
ishe
r exa
ct p
-val
ue)
-0.01 0.0 0.01 0.02
0.0
0.5
1.0
1.5
2.0
2.5
ECCHYMOSIS
EXCORIATION
FATIGUE
HERPES SIMPLEX
SINUSITIS
GASTROINTESTINAL DISORDER...INFECTIONS AND INFESTATIO...SKIN AND SUBCUTANEOUS TIS...NEOPLASMS BENIGN, MALIGNA...GENERAL DISORDERS AND ADM...PSYCHIATRIC DISORDERSINJURY, POISONING AND PRO...RESPIRATORY, THORACIC AND...CARDIAC DISORDERSMUSCULOSKELETAL AND CONNE...REPRODUCTIVE SYSTEM AND B...RENAL AND URINARY DISORDE...EYE DISORDERSINVESTIGATIONSNERVOUS SYSTEM DISORDERSMETABOLISM AND NUTRITION ...IMMUNE SYSTEM DISORDERSEAR AND LABYRINTH DISORDE...SURGICAL AND MEDICAL PROC...VASCULAR DISORDERSENDOCRINE DISORDERSHEPATOBILIARY DISORDERSBLOOD AND LYMPHATIC SYSTE...
0 1 2 3
log Odds Ratio
GASTROENTERITIS VIRAL
INFLUENZA
BRONCHITIS
DIZZINESS
TENSION HEADACHE
BASAL CELL CARCINOMA
URTICARIA
EXCORIATION
HEADACHE
INJECTION SITE BRUISING
DYSPEPSIA
HERPES SIMPLEX
FATIGUE
SINUSITIS
ECCHYMOSIS
Peto's Method
0 1 2 3
log Odds Ratio
TENSION HEADACHE
UPPER RESPIRATORY TRACT INFECTION
PHARYNGITIS
URTICARIA
BRONCHITIS
DIZZINESS
NASOPHARYNGITIS
INFLUENZA
DYSPEPSIA
INJECTION SITE BRUISING
HEADACHE
ECCHYMOSIS
HERPES SIMPLEX
SINUSITIS
FATIGUE
M-H TA CC Method
log-OR posterior means
P(O
R >
1|D
ata)
-3 -2 -1 0 1 2
0.0
0.2
0.4
0.6
0.8
1.0
ECCHYMOSIS
BLOOD AND LYMPHATIC SYSTE...CARDIAC DISORDERSEAR AND LABYRINTH DISORDE...ENDOCRINE DISORDERSEYE DISORDERSGASTROINTESTINAL DISORDER...GENERAL DISORDERS AND ADM...HEPATOBILIARY DISORDERSIMMUNE SYSTEM DISORDERSINFECTIONS AND INFESTATIO...INJURY, POISONING AND PRO...INVESTIGATIONSMETABOLISM AND NUTRITION ...MUSCULOSKELETAL AND CONNE...NEOPLASMS BENIGN, MALIGNA...NERVOUS SYSTEM DISORDERSPSYCHIATRIC DISORDERSRENAL AND URINARY DISORDE...REPRODUCTIVE SYSTEM AND B...RESPIRATORY, THORACIC AND...SKIN AND SUBCUTANEOUS TIS...SURGICAL AND MEDICAL PROC...VASCULAR DISORDERS
log-OR posterior means
P(O
R >
1|D
ata)
-3 -2 -1 0 1 2
0.0
0.2
0.4
0.6
0.8
1.0
ECCHYMOSIS
BLOOD AND LYMPHATIC SYSTE...CARDIAC DISORDERSEAR AND LABYRINTH DISORDE...ENDOCRINE DISORDERSEYE DISORDERSGASTROINTESTINAL DISORDER...GENERAL DISORDERS AND ADM...HEPATOBILIARY DISORDERSIMMUNE SYSTEM DISORDERSINFECTIONS AND INFESTATIO...INJURY, POISONING AND PRO...INVESTIGATIONSMETABOLISM AND NUTRITION ...MUSCULOSKELETAL AND CONNE...NEOPLASMS BENIGN, MALIGNA...NERVOUS SYSTEM DISORDERSPSYCHIATRIC DISORDERSRENAL AND URINARY DISORDE...REPRODUCTIVE SYSTEM AND B...RESPIRATORY, THORACIC AND...SKIN AND SUBCUTANEOUS TIS...SURGICAL AND MEDICAL PROC...VASCULAR DISORDERS
log-OR posterior means
P(O
R >
1|D
ata)
-3 -2 -1 0 1 2
0.0
0.2
0.4
0.6
0.8
1.0
ARRHYTHMIA ARTERIOSCLEROSIS CORONARY ARTERY BUNDLE BRANCH BLOCK LEFT EAR DISCOMFORT TINNITUS VERTIGO VERTIGO POSITIONAL CATARACT CONJUNCTIVAL HAEMORRHAGE
CONJUNCTIVITIS DIPLOPIA
DRY EYE EYE INFLAMMATION EYE PRURITUS EYELID OEDEMA ABDOMINAL DISTENSION ABDOMINAL PAIN ABDOMINAL PAIN UPPER ABDOMINAL TENDERNESS DIARRHOEA DRY MOUTH
DYSPEPSIA
FLATULENCE FOOD POISONING GASTROINTESTINAL HYPERMOTILITY GASTROINTESTINAL INFLAMMATION GASTROOESOPHAGEAL REFLUX DISEASE GINGIVAL BLEEDING NAUSEA STOMACH DISCOMFORT TOOTH DISORDER TOOTHACHE
FATIGUE
INJECTION SITE BRUISING INJECTION SITE HAEMATOMA IRRITABILITY MALAISE
LIVER DISORDER HYPERSENSITIVITY
SEASONAL ALLERGY ABDOMINAL INFECTION ACUTE SINUSITIS APPENDICITIS BRONCHITIS BRONCHITIS CHRONIC
CANDIDIASIS CAT SCRATCH DISEASE CELLULITIS STAPHYLOCOCCAL CERVICITIS CONDYLOMA ACUMINATUM
CYSTITIS DIVERTICULITIS EAR INFECTION ERYSIPELAS EYELID INFECTION
FOLLICULITIS
FUNGAL INFECTION FURUNCLE GASTROENTERITIS VIRAL
GENITAL INFECTION FEMALE GINGIVAL INFECTION
HERPES SIMPLEX
HERPES VIRUS INFECTION INFECTED INSECT BITE INFECTED SEBACEOUS CYST INFECTIOUS MONONUCLEOSIS INFLUENZA LABYRINTHITIS LARYNGITIS LOWER RESPIRATORY TRACT INFECTION MASTITIS NASOPHARYNGITIS ONYCHOMYCOSIS
ORAL PUSTULE OTITIS EXTERNA OTITIS MEDIA
PHARYNGITIS
PNEUMONIA POSTOPERATIVE WOUND INFECTION PULPITIS DENTAL PUNCTURE SITE INFECTION RASH PUSTULAR RHINITIS SIALOADENITIS
SINUSITIS
SKIN INFECTION SUBCUTANEOUS ABSCESS TINEA CRURIS TINEA INFECTION TINEA VERSICOLOUR TONSILLITIS TOOTH ABSCESS TOOTH INFECTION VAGINAL CANDIDIASIS
VAGINAL INFECTION VIRAL INFECTION VIRAL UPPER RESPIRATORY TRACT INFECTION
ANIMAL BITE CONTUSION
EXCORIATION FALL FOOT FRACTURE HAND FRACTURE HEAT STROKE POST-TRAUMATIC PAIN ROAD TRAFFIC ACCIDENT SCAPULA FRACTURE TENDON INJURY THERMAL BURN TOOTH FRACTURE TOOTH INJURY WOUND
BLOOD CHOLESTEROL INCREASED
BLOOD GLUCOSE INCREASED
BLOOD PRESSURE INCREASED
BODY TEMPERATURE INCREASED WEIGHT DECREASED WEIGHT INCREASED HYPERCHOLESTEROLAEMIA BACK PAIN INTERVERTEBRAL DISC DEGENERATION JOINT EFFUSION MYALGIA SHOULDER PAIN TENDONITIS
BASAL CELL CARCINOMA
FIBROUS HISTIOCYTOMA LIPOMA PROSTATE CANCER SEBORRHOEIC KERATOSIS SKIN PAPILLOMA
SQUAMOUS CELL CARCINOMA OF SKIN BURNING SENSATION
CAROTID ARTERY STENOSIS CARPAL TUNNEL SYNDROME CEREBROVASCULAR ACCIDENT CEREBROVASCULAR INSUFFICIENCY DISTURBANCE IN ATTENTION
DIZZINESS
DIZZINESS POSTURAL DYSGEUSIA FACIAL PALSY HEADACHE HYPERSOMNIA HYPERTONIA HYPOAESTHESIA LETHARGY MEMORY IMPAIRMENT MIGRAINE NERVE COMPRESSION NEURALGIA PARAESTHESIA RESTLESS LEGS SYNDROME SCIATICA SENSORY DISTURBANCE
SINUS HEADACHE SOMNOLENCE SYNCOPE SYNCOPE VASOVAGAL
TENSION HEADACHE
AGITATION ALCOHOLISM
ANXIETY
ATTENTION DEFICIT/HYPERACTIVITY DISORDER BIPOLAR I DISORDER DEPRESSION DYSPHORIA
INSOMNIA LIBIDO DECREASED NERVOUSNESS PREMATURE EJACULATION STRESS CALCULUS BLADDER HAEMATURIA NEPHROLITHIASIS POLLAKIURIA STRESS INCONTINENCE TRIGONITIS URINARY INCONTINENCE URINARY RETENTION BENIGN PROSTATIC HYPERPLASIA CERVICAL DYSPLASIA
ERECTILE DYSFUNCTION OVARIAN CYST RUPTURED VAGINAL LACERATION VULVOVAGINAL DRYNESS ALLERGIC COUGH DYSPHONIA DYSPNOEA DYSPNOEA EXERTIONAL EPISTAXIS HYPERVENTILATION
NASAL CONGESTION RHINITIS ALLERGIC RHINORRHOEA
RHONCHI SINUS CONGESTION SLEEP APNOEA SYNDROME SNEEZING SNORING
THROAT IRRITATION ACNE ACTINIC KERATOSIS
DERMAL CYST
DERMATITIS CONTACT
ECCHYMOSIS
ECZEMA GUTTATE PSORIASIS INGROWING NAIL INTERTRIGO NIGHT SWEATS ONYCHOMADESIS SKIN HAEMORRHAGE SKIN LESION
URTICARIA
ENDODONTIC PROCEDURE FLUSHING
HOT FLUSH HYPERTENSION LYMPHOEDEMA
BLOOD AND LYMPHATIC SYSTE...CARDIAC DISORDERSEAR AND LABYRINTH DISORDE...ENDOCRINE DISORDERSEYE DISORDERSGASTROINTESTINAL DISORDER...GENERAL DISORDERS AND ADM...HEPATOBILIARY DISORDERSIMMUNE SYSTEM DISORDERSINFECTIONS AND INFESTATIO...INJURY, POISONING AND PRO...INVESTIGATIONSMETABOLISM AND NUTRITION ...MUSCULOSKELETAL AND CONNE...NEOPLASMS BENIGN, MALIGNA...NERVOUS SYSTEM DISORDERSPSYCHIATRIC DISORDERSRENAL AND URINARY DISORDE...REPRODUCTIVE SYSTEM AND B...RESPIRATORY, THORACIC AND...SKIN AND SUBCUTANEOUS TIS...SURGICAL AND MEDICAL PROC...VASCULAR DISORDERS
log-OR posterior means
P(O
R >
1|D
ata)
-3 -2 -1 0 1 2
0.0
0.2
0.4
0.6
0.8
1.0
ARRHYTHMIA ARTERIOSCLEROSIS CORONARY ARTERY BUNDLE BRANCH BLOCK LEFT EAR DISCOMFORT TINNITUS VERTIGO VERTIGO POSITIONAL CATARACT CONJUNCTIVAL HAEMORRHAGE
CONJUNCTIVITIS DIPLOPIA
DRY EYE EYE INFLAMMATION EYE PRURITUS EYELID OEDEMA ABDOMINAL DISTENSION ABDOMINAL PAIN ABDOMINAL PAIN UPPER ABDOMINAL TENDERNESS DIARRHOEA DRY MOUTH
DYSPEPSIA
FLATULENCE FOOD POISONING GASTROINTESTINAL HYPERMOTILITY GASTROINTESTINAL INFLAMMATION GASTROOESOPHAGEAL REFLUX DISEASE GINGIVAL BLEEDING NAUSEA STOMACH DISCOMFORT TOOTH DISORDER TOOTHACHE
FATIGUE
INJECTION SITE BRUISING INJECTION SITE HAEMATOMA IRRITABILITY MALAISE
LIVER DISORDER HYPERSENSITIVITY
SEASONAL ALLERGY ABDOMINAL INFECTION ACUTE SINUSITIS APPENDICITIS BRONCHITIS BRONCHITIS CHRONIC
CANDIDIASIS CAT SCRATCH DISEASE CELLULITIS STAPHYLOCOCCAL CERVICITIS CONDYLOMA ACUMINATUM
CYSTITIS DIVERTICULITIS EAR INFECTION ERYSIPELAS EYELID INFECTION
FOLLICULITIS
FUNGAL INFECTION FURUNCLE GASTROENTERITIS VIRAL
GENITAL INFECTION FEMALE GINGIVAL INFECTION
HERPES SIMPLEX
HERPES VIRUS INFECTION INFECTED INSECT BITE INFECTED SEBACEOUS CYST INFECTIOUS MONONUCLEOSIS INFLUENZA LABYRINTHITIS LARYNGITIS LOWER RESPIRATORY TRACT INFECTION MASTITIS NASOPHARYNGITIS ONYCHOMYCOSIS
ORAL PUSTULE OTITIS EXTERNA OTITIS MEDIA
PHARYNGITIS
PNEUMONIA POSTOPERATIVE WOUND INFECTION PULPITIS DENTAL PUNCTURE SITE INFECTION RASH PUSTULAR RHINITIS SIALOADENITIS
SINUSITIS
SKIN INFECTION SUBCUTANEOUS ABSCESS TINEA CRURIS TINEA INFECTION TINEA VERSICOLOUR TONSILLITIS TOOTH ABSCESS TOOTH INFECTION VAGINAL CANDIDIASIS
VAGINAL INFECTION VIRAL INFECTION VIRAL UPPER RESPIRATORY TRACT INFECTION
ANIMAL BITE CONTUSION
EXCORIATION FALL FOOT FRACTURE HAND FRACTURE HEAT STROKE POST-TRAUMATIC PAIN ROAD TRAFFIC ACCIDENT SCAPULA FRACTURE TENDON INJURY THERMAL BURN TOOTH FRACTURE TOOTH INJURY WOUND
BLOOD CHOLESTEROL INCREASED
BLOOD GLUCOSE INCREASED
BLOOD PRESSURE INCREASED
BODY TEMPERATURE INCREASED WEIGHT DECREASED WEIGHT INCREASED HYPERCHOLESTEROLAEMIA BACK PAIN INTERVERTEBRAL DISC DEGENERATION JOINT EFFUSION MYALGIA SHOULDER PAIN TENDONITIS
BASAL CELL CARCINOMA
FIBROUS HISTIOCYTOMA LIPOMA PROSTATE CANCER SEBORRHOEIC KERATOSIS SKIN PAPILLOMA
SQUAMOUS CELL CARCINOMA OF SKIN BURNING SENSATION
CAROTID ARTERY STENOSIS CARPAL TUNNEL SYNDROME CEREBROVASCULAR ACCIDENT CEREBROVASCULAR INSUFFICIENCY DISTURBANCE IN ATTENTION
DIZZINESS
DIZZINESS POSTURAL DYSGEUSIA FACIAL PALSY HEADACHE HYPERSOMNIA HYPERTONIA HYPOAESTHESIA LETHARGY MEMORY IMPAIRMENT MIGRAINE NERVE COMPRESSION NEURALGIA PARAESTHESIA RESTLESS LEGS SYNDROME SCIATICA SENSORY DISTURBANCE
SINUS HEADACHE SOMNOLENCE SYNCOPE SYNCOPE VASOVAGAL
TENSION HEADACHE
AGITATION ALCOHOLISM
ANXIETY
ATTENTION DEFICIT/HYPERACTIVITY DISORDER BIPOLAR I DISORDER DEPRESSION DYSPHORIA
INSOMNIA LIBIDO DECREASED NERVOUSNESS PREMATURE EJACULATION STRESS CALCULUS BLADDER HAEMATURIA NEPHROLITHIASIS POLLAKIURIA STRESS INCONTINENCE TRIGONITIS URINARY INCONTINENCE URINARY RETENTION BENIGN PROSTATIC HYPERPLASIA CERVICAL DYSPLASIA
ERECTILE DYSFUNCTION OVARIAN CYST RUPTURED VAGINAL LACERATION VULVOVAGINAL DRYNESS ALLERGIC COUGH DYSPHONIA DYSPNOEA DYSPNOEA EXERTIONAL EPISTAXIS HYPERVENTILATION
NASAL CONGESTION RHINITIS ALLERGIC RHINORRHOEA
RHONCHI SINUS CONGESTION SLEEP APNOEA SYNDROME SNEEZING SNORING
THROAT IRRITATION ACNE ACTINIC KERATOSIS
DERMAL CYST
DERMATITIS CONTACT
ECCHYMOSIS
ECZEMA GUTTATE PSORIASIS INGROWING NAIL INTERTRIGO NIGHT SWEATS ONYCHOMADESIS SKIN HAEMORRHAGE SKIN LESION
URTICARIA
ENDODONTIC PROCEDURE FLUSHING
HOT FLUSH HYPERTENSION LYMPHOEDEMA
BLOOD AND LYMPHATIC SYSTE...CARDIAC DISORDERSEAR AND LABYRINTH DISORDE...ENDOCRINE DISORDERSEYE DISORDERSGASTROINTESTINAL DISORDER...GENERAL DISORDERS AND ADM...HEPATOBILIARY DISORDERSIMMUNE SYSTEM DISORDERSINFECTIONS AND INFESTATIO...INJURY, POISONING AND PRO...INVESTIGATIONSMETABOLISM AND NUTRITION ...MUSCULOSKELETAL AND CONNE...NEOPLASMS BENIGN, MALIGNA...NERVOUS SYSTEM DISORDERSPSYCHIATRIC DISORDERSRENAL AND URINARY DISORDE...REPRODUCTIVE SYSTEM AND B...RESPIRATORY, THORACIC AND...SKIN AND SUBCUTANEOUS TIS...SURGICAL AND MEDICAL PROC...VASCULAR DISORDERS
log-OR posterior means
P(O
R >
1|D
ata)
-3 -2 -1 0 1 2
0.0
0.2
0.4
0.6
0.8
1.0
ARRHYTHMIA ARTERIOSCLEROSIS CORONARY ARTERY BUNDLE BRANCH BLOCK LEFT EAR DISCOMFORT TINNITUS VERTIGO VERTIGO POSITIONAL CATARACT CONJUNCTIVAL HAEMORRHAGE
CONJUNCTIVITIS DIPLOPIA
DRY EYE EYE INFLAMMATION EYE PRURITUS EYELID OEDEMA ABDOMINAL DISTENSION ABDOMINAL PAIN ABDOMINAL PAIN UPPER ABDOMINAL TENDERNESS DIARRHOEA DRY MOUTH
DYSPEPSIA
FLATULENCE FOOD POISONING GASTROINTESTINAL HYPERMOTILITY GASTROINTESTINAL INFLAMMATION GASTROOESOPHAGEAL REFLUX DISEASE GINGIVAL BLEEDING NAUSEA STOMACH DISCOMFORT TOOTH DISORDER TOOTHACHE
FATIGUE
INJECTION SITE BRUISING INJECTION SITE HAEMATOMA IRRITABILITY MALAISE
LIVER DISORDER HYPERSENSITIVITY
SEASONAL ALLERGY ABDOMINAL INFECTION ACUTE SINUSITIS APPENDICITIS BRONCHITIS BRONCHITIS CHRONIC
CANDIDIASIS CAT SCRATCH DISEASE CELLULITIS STAPHYLOCOCCAL CERVICITIS CONDYLOMA ACUMINATUM
CYSTITIS DIVERTICULITIS EAR INFECTION ERYSIPELAS EYELID INFECTION
FOLLICULITIS
FUNGAL INFECTION FURUNCLE GASTROENTERITIS VIRAL
GENITAL INFECTION FEMALE GINGIVAL INFECTION
HERPES SIMPLEX
HERPES VIRUS INFECTION INFECTED INSECT BITE INFECTED SEBACEOUS CYST INFECTIOUS MONONUCLEOSIS INFLUENZA LABYRINTHITIS LARYNGITIS LOWER RESPIRATORY TRACT INFECTION MASTITIS NASOPHARYNGITIS ONYCHOMYCOSIS
ORAL PUSTULE OTITIS EXTERNA OTITIS MEDIA
PHARYNGITIS
PNEUMONIA POSTOPERATIVE WOUND INFECTION PULPITIS DENTAL PUNCTURE SITE INFECTION RASH PUSTULAR RHINITIS SIALOADENITIS
SINUSITIS
SKIN INFECTION SUBCUTANEOUS ABSCESS TINEA CRURIS TINEA INFECTION TINEA VERSICOLOUR TONSILLITIS TOOTH ABSCESS TOOTH INFECTION VAGINAL CANDIDIASIS
VAGINAL INFECTION VIRAL INFECTION VIRAL UPPER RESPIRATORY TRACT INFECTION
ANIMAL BITE CONTUSION
EXCORIATION FALL FOOT FRACTURE HAND FRACTURE HEAT STROKE POST-TRAUMATIC PAIN ROAD TRAFFIC ACCIDENT SCAPULA FRACTURE TENDON INJURY THERMAL BURN TOOTH FRACTURE TOOTH INJURY WOUND
BLOOD CHOLESTEROL INCREASED
BLOOD GLUCOSE INCREASED
BLOOD PRESSURE INCREASED
BODY TEMPERATURE INCREASED WEIGHT DECREASED WEIGHT INCREASED HYPERCHOLESTEROLAEMIA BACK PAIN INTERVERTEBRAL DISC DEGENERATION JOINT EFFUSION MYALGIA SHOULDER PAIN TENDONITIS
BASAL CELL CARCINOMA
FIBROUS HISTIOCYTOMA LIPOMA PROSTATE CANCER SEBORRHOEIC KERATOSIS SKIN PAPILLOMA
SQUAMOUS CELL CARCINOMA OF SKIN BURNING SENSATION
CAROTID ARTERY STENOSIS CARPAL TUNNEL SYNDROME CEREBROVASCULAR ACCIDENT CEREBROVASCULAR INSUFFICIENCY DISTURBANCE IN ATTENTION
DIZZINESS
DIZZINESS POSTURAL DYSGEUSIA FACIAL PALSY HEADACHE HYPERSOMNIA HYPERTONIA HYPOAESTHESIA LETHARGY MEMORY IMPAIRMENT MIGRAINE NERVE COMPRESSION NEURALGIA PARAESTHESIA RESTLESS LEGS SYNDROME SCIATICA SENSORY DISTURBANCE
SINUS HEADACHE SOMNOLENCE SYNCOPE SYNCOPE VASOVAGAL
TENSION HEADACHE
AGITATION ALCOHOLISM
ANXIETY
ATTENTION DEFICIT/HYPERACTIVITY DISORDER BIPOLAR I DISORDER DEPRESSION DYSPHORIA
INSOMNIA LIBIDO DECREASED NERVOUSNESS PREMATURE EJACULATION STRESS CALCULUS BLADDER HAEMATURIA NEPHROLITHIASIS POLLAKIURIA STRESS INCONTINENCE TRIGONITIS URINARY INCONTINENCE URINARY RETENTION BENIGN PROSTATIC HYPERPLASIA CERVICAL DYSPLASIA
ERECTILE DYSFUNCTION OVARIAN CYST RUPTURED VAGINAL LACERATION VULVOVAGINAL DRYNESS ALLERGIC COUGH DYSPHONIA DYSPNOEA DYSPNOEA EXERTIONAL EPISTAXIS HYPERVENTILATION
NASAL CONGESTION RHINITIS ALLERGIC RHINORRHOEA
RHONCHI SINUS CONGESTION SLEEP APNOEA SYNDROME SNEEZING SNORING
THROAT IRRITATION ACNE ACTINIC KERATOSIS
DERMAL CYST
DERMATITIS CONTACT
ECCHYMOSIS
ECZEMA GUTTATE PSORIASIS INGROWING NAIL INTERTRIGO NIGHT SWEATS ONYCHOMADESIS SKIN HAEMORRHAGE SKIN LESION
URTICARIA
ENDODONTIC PROCEDURE FLUSHING
HOT FLUSH HYPERTENSION LYMPHOEDEMA
BLOOD AND LYMPHATIC SYSTE...CARDIAC DISORDERSEAR AND LABYRINTH DISORDE...ENDOCRINE DISORDERSEYE DISORDERSGASTROINTESTINAL DISORDER...GENERAL DISORDERS AND ADM...HEPATOBILIARY DISORDERSIMMUNE SYSTEM DISORDERSINFECTIONS AND INFESTATIO...INJURY, POISONING AND PRO...INVESTIGATIONSMETABOLISM AND NUTRITION ...MUSCULOSKELETAL AND CONNE...NEOPLASMS BENIGN, MALIGNA...NERVOUS SYSTEM DISORDERSPSYCHIATRIC DISORDERSRENAL AND URINARY DISORDE...REPRODUCTIVE SYSTEM AND B...RESPIRATORY, THORACIC AND...SKIN AND SUBCUTANEOUS TIS...SURGICAL AND MEDICAL PROC...VASCULAR DISORDERS
log-OR posterior means
P(O
R >
1|D
ata)
-3 -2 -1 0 1 2
0.0
0.2
0.4
0.6
0.8
1.0
ARRHYTHMIA ARTERIOSCLEROSIS CORONARY ARTERY BUNDLE BRANCH BLOCK LEFT EAR DISCOMFORT TINNITUS VERTIGO VERTIGO POSITIONAL CATARACT CONJUNCTIVAL HAEMORRHAGE
CONJUNCTIVITIS DIPLOPIA
DRY EYE EYE INFLAMMATION EYE PRURITUS EYELID OEDEMA ABDOMINAL DISTENSION ABDOMINAL PAIN ABDOMINAL PAIN UPPER ABDOMINAL TENDERNESS DIARRHOEA DRY MOUTH
DYSPEPSIA
FLATULENCE FOOD POISONING GASTROINTESTINAL HYPERMOTILITY GASTROINTESTINAL INFLAMMATION GASTROOESOPHAGEAL REFLUX DISEASE GINGIVAL BLEEDING NAUSEA STOMACH DISCOMFORT TOOTH DISORDER TOOTHACHE
FATIGUE
INJECTION SITE BRUISING INJECTION SITE HAEMATOMA IRRITABILITY MALAISE
LIVER DISORDER HYPERSENSITIVITY
SEASONAL ALLERGY ABDOMINAL INFECTION ACUTE SINUSITIS APPENDICITIS BRONCHITIS BRONCHITIS CHRONIC
CANDIDIASIS CAT SCRATCH DISEASE CELLULITIS STAPHYLOCOCCAL CERVICITIS CONDYLOMA ACUMINATUM
CYSTITIS DIVERTICULITIS EAR INFECTION ERYSIPELAS EYELID INFECTION
FOLLICULITIS
FUNGAL INFECTION FURUNCLE GASTROENTERITIS VIRAL
GENITAL INFECTION FEMALE GINGIVAL INFECTION
HERPES SIMPLEX
HERPES VIRUS INFECTION INFECTED INSECT BITE INFECTED SEBACEOUS CYST INFECTIOUS MONONUCLEOSIS INFLUENZA LABYRINTHITIS LARYNGITIS LOWER RESPIRATORY TRACT INFECTION MASTITIS NASOPHARYNGITIS ONYCHOMYCOSIS
ORAL PUSTULE OTITIS EXTERNA OTITIS MEDIA
PHARYNGITIS
PNEUMONIA POSTOPERATIVE WOUND INFECTION PULPITIS DENTAL PUNCTURE SITE INFECTION RASH PUSTULAR RHINITIS SIALOADENITIS
SINUSITIS
SKIN INFECTION SUBCUTANEOUS ABSCESS TINEA CRURIS TINEA INFECTION TINEA VERSICOLOUR TONSILLITIS TOOTH ABSCESS TOOTH INFECTION VAGINAL CANDIDIASIS
VAGINAL INFECTION VIRAL INFECTION VIRAL UPPER RESPIRATORY TRACT INFECTION
ANIMAL BITE CONTUSION
EXCORIATION FALL FOOT FRACTURE HAND FRACTURE HEAT STROKE POST-TRAUMATIC PAIN ROAD TRAFFIC ACCIDENT SCAPULA FRACTURE TENDON INJURY THERMAL BURN TOOTH FRACTURE TOOTH INJURY WOUND
BLOOD CHOLESTEROL INCREASED
BLOOD GLUCOSE INCREASED
BLOOD PRESSURE INCREASED
BODY TEMPERATURE INCREASED WEIGHT DECREASED WEIGHT INCREASED HYPERCHOLESTEROLAEMIA BACK PAIN INTERVERTEBRAL DISC DEGENERATION JOINT EFFUSION MYALGIA SHOULDER PAIN TENDONITIS
BASAL CELL CARCINOMA
FIBROUS HISTIOCYTOMA LIPOMA PROSTATE CANCER SEBORRHOEIC KERATOSIS SKIN PAPILLOMA
SQUAMOUS CELL CARCINOMA OF SKIN BURNING SENSATION
CAROTID ARTERY STENOSIS CARPAL TUNNEL SYNDROME CEREBROVASCULAR ACCIDENT CEREBROVASCULAR INSUFFICIENCY DISTURBANCE IN ATTENTION
DIZZINESS
DIZZINESS POSTURAL DYSGEUSIA FACIAL PALSY HEADACHE HYPERSOMNIA HYPERTONIA HYPOAESTHESIA LETHARGY MEMORY IMPAIRMENT MIGRAINE NERVE COMPRESSION NEURALGIA PARAESTHESIA RESTLESS LEGS SYNDROME SCIATICA SENSORY DISTURBANCE
SINUS HEADACHE SOMNOLENCE SYNCOPE SYNCOPE VASOVAGAL
TENSION HEADACHE
AGITATION ALCOHOLISM
ANXIETY
ATTENTION DEFICIT/HYPERACTIVITY DISORDER BIPOLAR I DISORDER DEPRESSION DYSPHORIA
INSOMNIA LIBIDO DECREASED NERVOUSNESS PREMATURE EJACULATION STRESS CALCULUS BLADDER HAEMATURIA NEPHROLITHIASIS POLLAKIURIA STRESS INCONTINENCE TRIGONITIS URINARY INCONTINENCE URINARY RETENTION BENIGN PROSTATIC HYPERPLASIA CERVICAL DYSPLASIA
ERECTILE DYSFUNCTION OVARIAN CYST RUPTURED VAGINAL LACERATION VULVOVAGINAL DRYNESS ALLERGIC COUGH DYSPHONIA DYSPNOEA DYSPNOEA EXERTIONAL EPISTAXIS HYPERVENTILATION
NASAL CONGESTION RHINITIS ALLERGIC RHINORRHOEA
RHONCHI SINUS CONGESTION SLEEP APNOEA SYNDROME SNEEZING SNORING
THROAT IRRITATION ACNE ACTINIC KERATOSIS
DERMAL CYST
DERMATITIS CONTACT
ECCHYMOSIS
ECZEMA GUTTATE PSORIASIS INGROWING NAIL INTERTRIGO NIGHT SWEATS ONYCHOMADESIS SKIN HAEMORRHAGE SKIN LESION
URTICARIA
ENDODONTIC PROCEDURE FLUSHING
HOT FLUSH HYPERTENSION LYMPHOEDEMA
BLOOD AND LYMPHATIC SYSTE...CARDIAC DISORDERSEAR AND LABYRINTH DISORDE...ENDOCRINE DISORDERSEYE DISORDERSGASTROINTESTINAL DISORDER...GENERAL DISORDERS AND ADM...HEPATOBILIARY DISORDERSIMMUNE SYSTEM DISORDERSINFECTIONS AND INFESTATIO...INJURY, POISONING AND PRO...INVESTIGATIONSMETABOLISM AND NUTRITION ...MUSCULOSKELETAL AND CONNE...NEOPLASMS BENIGN, MALIGNA...NERVOUS SYSTEM DISORDERSPSYCHIATRIC DISORDERSRENAL AND URINARY DISORDE...REPRODUCTIVE SYSTEM AND B...RESPIRATORY, THORACIC AND...SKIN AND SUBCUTANEOUS TIS...SURGICAL AND MEDICAL PROC...VASCULAR DISORDERS
Posterior Summary of Bayesian Hierarchical Meta-Analysis Model
log-OR posterior means
P(O
R >
1|D
ata)
-3 -2 -1 0 1 2
0.0
0.2
0.4
0.6
0.8
1.0
ARRHYTHMIA ARTERIOSCLEROSIS CORONARY ARTERY BUNDLE BRANCH BLOCK LEFT EAR DISCOMFORT TINNITUS VERTIGO VERTIGO POSITIONAL CATARACT CONJUNCTIVAL HAEMORRHAGE
CONJUNCTIVITIS DIPLOPIA
DRY EYE EYE INFLAMMATION EYE PRURITUS EYELID OEDEMA ABDOMINAL DISTENSION ABDOMINAL PAIN ABDOMINAL PAIN UPPER ABDOMINAL TENDERNESS DIARRHOEA DRY MOUTH
DYSPEPSIA
FLATULENCE FOOD POISONING GASTROINTESTINAL HYPERMOTILITY GASTROINTESTINAL INFLAMMATION GASTROOESOPHAGEAL REFLUX DISEASE GINGIVAL BLEEDING NAUSEA STOMACH DISCOMFORT TOOTH DISORDER TOOTHACHE
FATIGUE
INJECTION SITE BRUISING INJECTION SITE HAEMATOMA IRRITABILITY MALAISE
LIVER DISORDER HYPERSENSITIVITY
SEASONAL ALLERGY ABDOMINAL INFECTION ACUTE SINUSITIS APPENDICITIS BRONCHITIS BRONCHITIS CHRONIC
CANDIDIASIS CAT SCRATCH DISEASE CELLULITIS STAPHYLOCOCCAL CERVICITIS CONDYLOMA ACUMINATUM
CYSTITIS DIVERTICULITIS EAR INFECTION ERYSIPELAS EYELID INFECTION
FOLLICULITIS
FUNGAL INFECTION FURUNCLE GASTROENTERITIS VIRAL
GENITAL INFECTION FEMALE GINGIVAL INFECTION
HERPES SIMPLEX
HERPES VIRUS INFECTION INFECTED INSECT BITE INFECTED SEBACEOUS CYST INFECTIOUS MONONUCLEOSIS INFLUENZA LABYRINTHITIS LARYNGITIS LOWER RESPIRATORY TRACT INFECTION MASTITIS NASOPHARYNGITIS ONYCHOMYCOSIS
ORAL PUSTULE OTITIS EXTERNA OTITIS MEDIA
PHARYNGITIS
PNEUMONIA POSTOPERATIVE WOUND INFECTION PULPITIS DENTAL PUNCTURE SITE INFECTION RASH PUSTULAR RHINITIS SIALOADENITIS
SINUSITIS
SKIN INFECTION SUBCUTANEOUS ABSCESS TINEA CRURIS TINEA INFECTION TINEA VERSICOLOUR TONSILLITIS TOOTH ABSCESS TOOTH INFECTION VAGINAL CANDIDIASIS
VAGINAL INFECTION VIRAL INFECTION VIRAL UPPER RESPIRATORY TRACT INFECTION
ANIMAL BITE CONTUSION
EXCORIATION FALL FOOT FRACTURE HAND FRACTURE HEAT STROKE POST-TRAUMATIC PAIN ROAD TRAFFIC ACCIDENT SCAPULA FRACTURE TENDON INJURY THERMAL BURN TOOTH FRACTURE TOOTH INJURY WOUND
BLOOD CHOLESTEROL INCREASED
BLOOD GLUCOSE INCREASED
BLOOD PRESSURE INCREASED
BODY TEMPERATURE INCREASED WEIGHT DECREASED WEIGHT INCREASED HYPERCHOLESTEROLAEMIA BACK PAIN INTERVERTEBRAL DISC DEGENERATION JOINT EFFUSION MYALGIA SHOULDER PAIN TENDONITIS
BASAL CELL CARCINOMA
FIBROUS HISTIOCYTOMA LIPOMA PROSTATE CANCER SEBORRHOEIC KERATOSIS SKIN PAPILLOMA
SQUAMOUS CELL CARCINOMA OF SKIN BURNING SENSATION
CAROTID ARTERY STENOSIS CARPAL TUNNEL SYNDROME CEREBROVASCULAR ACCIDENT CEREBROVASCULAR INSUFFICIENCY DISTURBANCE IN ATTENTION
DIZZINESS
DIZZINESS POSTURAL DYSGEUSIA FACIAL PALSY HEADACHE HYPERSOMNIA HYPERTONIA HYPOAESTHESIA LETHARGY MEMORY IMPAIRMENT MIGRAINE NERVE COMPRESSION NEURALGIA PARAESTHESIA RESTLESS LEGS SYNDROME SCIATICA SENSORY DISTURBANCE
SINUS HEADACHE SOMNOLENCE SYNCOPE SYNCOPE VASOVAGAL
TENSION HEADACHE
AGITATION ALCOHOLISM
ANXIETY
ATTENTION DEFICIT/HYPERACTIVITY DISORDER BIPOLAR I DISORDER DEPRESSION DYSPHORIA
INSOMNIA LIBIDO DECREASED NERVOUSNESS PREMATURE EJACULATION STRESS CALCULUS BLADDER HAEMATURIA NEPHROLITHIASIS POLLAKIURIA STRESS INCONTINENCE TRIGONITIS URINARY INCONTINENCE URINARY RETENTION BENIGN PROSTATIC HYPERPLASIA CERVICAL DYSPLASIA
ERECTILE DYSFUNCTION OVARIAN CYST RUPTURED VAGINAL LACERATION VULVOVAGINAL DRYNESS ALLERGIC COUGH DYSPHONIA DYSPNOEA DYSPNOEA EXERTIONAL EPISTAXIS HYPERVENTILATION
NASAL CONGESTION RHINITIS ALLERGIC RHINORRHOEA
RHONCHI SINUS CONGESTION SLEEP APNOEA SYNDROME SNEEZING SNORING
THROAT IRRITATION ACNE ACTINIC KERATOSIS
DERMAL CYST
DERMATITIS CONTACT
ECCHYMOSIS
ECZEMA GUTTATE PSORIASIS INGROWING NAIL INTERTRIGO NIGHT SWEATS ONYCHOMADESIS SKIN HAEMORRHAGE SKIN LESION
URTICARIA
ENDODONTIC PROCEDURE FLUSHING
HOT FLUSH HYPERTENSION LYMPHOEDEMA
BLOOD AND LYMPHATIC SYSTE...CARDIAC DISORDERSEAR AND LABYRINTH DISORDE...ENDOCRINE DISORDERSEYE DISORDERSGASTROINTESTINAL DISORDER...GENERAL DISORDERS AND ADM...HEPATOBILIARY DISORDERSIMMUNE SYSTEM DISORDERSINFECTIONS AND INFESTATIO...INJURY, POISONING AND PRO...INVESTIGATIONSMETABOLISM AND NUTRITION ...MUSCULOSKELETAL AND CONNE...NEOPLASMS BENIGN, MALIGNA...NERVOUS SYSTEM DISORDERSPSYCHIATRIC DISORDERSRENAL AND URINARY DISORDE...REPRODUCTIVE SYSTEM AND B...RESPIRATORY, THORACIC AND...SKIN AND SUBCUTANEOUS TIS...SURGICAL AND MEDICAL PROC...VASCULAR DISORDERS
Inferences of Binomial Hierarchical Model with Mixture Prior
SOC PT
Two sided Fisher's Exact
Post Prob OR=1
Post Prob OR>1
Post Prob OR>1.1
Post Prob OR>1.2
Post Prob OR>2
GENERAL DISORDERS AND ADMINISTRATION SITE FATIGUE 0.019 0.82 0.18 0.18 0.18 0.10INFECTIONS AND INFESTATIONS
HERPES SIMPLEX 0.039 0.75 0.25 0.25 0.25 0.21
INFECTIONS AND INFESTATIONS SINUSITIS 0.012 0.72 0.27 0.27 0.27 0.19SKIN AND SUBCUTANEOUS TISSUE DISORDERS ECCHYMOSIS 0.005 0.11 0.89 0.89 0.89 0.89
Bayesian Patient Level Models
• IPD models to include within patient correlation and patient level factors while incorporating MedDRA coding hierarchy
• Data from one study is used:618 subject, 207 unique AEs, N = 127926
),0(~ I), ,0MVN(~
ksubject for covariates ofset theis Z where
Z )logit(t ,Z)logit(c
),(~X),(~Y
2k
2b
k
kkbjbjkbjkkbj kbj
kbjkbj
Normal
cBernoullitBernoulli kbjkbj
Simulation Study• Simulation scheme:
– Randomly assign subjects to treatment or placebo to create a “null” scenario
– Adverse events within subject remain unchanged to maintain the SOC/PT hierarchy
– 1000 simulated datasets• Family-wise error rates (also FDR in this case) of
Fisher’s exact text unadjusted for multiplicity and Poisson regression with mixture prior are compared
• Percentage of simulated datasets yielding Y=0, 1, 2 or ≥3 incorrectly flagged adverse events out of 464 PTs are also compared
Distribution of Y (%)
FWER/ FDR
1 2 >=3
Non-adjusted 2-sided Fisher’s exact test
2-sided test, p-value <=0.05 99.1 2.7 5.4 91
Non-adjusted 1-sided Fisher’s exact test
p-value<=0.05 90.1 22.7 26.9 40.5
Bayes Hierarchical Poisson Model *
c=1, p=0.7 10.2 7.5 2.0 0.7
c=1, p=0.8 6.1 4.6 1.3 0.2
c=1, p=0.9 2.8 2.7 0.1 0.0
c=1.2, p=0.7 10.2 7.6 1.9 0.7
c=1.2, p=0.8 6.0 4.6 1.2 0.2
c=1.2, p=0.9 2.7 2.6 0.1 0.0
c=2, p=0.7 7.0 5.3 1.5 0.2
c=2, p=0.8 3.7 3.3 0.4 0.0
c=2, p=0.9 1.3 1.2 0.1 0.0
RR≠1, p=0.7 13.8 10.3 2.5 1.0
RR≠1, p=0.8 7.9 6.3 1.4 0.2
RR≠1, p=0.9 3.6 3.5 0.1 0.0
* pDatacRRbj )|Pr(
Simulation Study• 464 independent tests with alpha=0.05 would
yield in average about 23 signals and have FDR=1 if no multiplicity is adjusted for.
• Correlation of the AE data reduced the error rate in our simulation study
• But the FDR is still as high as 99.1%. For 91% cases there are at least 3 falsely identified signals.
• The FWERs/FDRs for all Bayes model results are much lower and acceptable.
Closing Remarks• Current traditional approach of flagging
routinely collected AEs based on unadjusted p-values or CIs can result in excessive false positive signals– As a result, it can cause undue concern for
approval/labeling/post marketing commitment
• Commonly used meta-analysis methods for aggregated binary outcome (OR)– Peto’s method is not recommended for
severely unbalanced studies or common events unless treatment effects are small
– MH method: needs continuity correction
Closing Remarks (Cont.)• Bayesian meta-analysis hierarchical mixture modeling
provides a useful tool to analyze data from multiple studies and address multiplicity – Allows for explicitly modeling AEs with the existing MedDRA coding
structure– Use a mixture prior by allowing a point mass on equality of the treatment
and control rates– Study differences can be accounted for– No need to add continuity correction. Double zero studies are included.– For less common AEs and studies without a great amount of follow-up
variation between treatment groups, inferences from Poisson regression and logistic regression models are very similar
• Computation for signal detection using IPD is challenging• Graphics are effective in displaying flagged signals
Future Work• More sensitivity analysis on the performance of the
models• Further simulation study on type II error and operating
characteristics of Bayesian models• Zero-inflated Poisson model might be a good approach
for relatively healthy population• Incorporating severity information of AEs• Multi-axial structure of MedDRA coding system• The field of clinical trial signal detection is still in its
infancy– More research and practice are needed– Statisticians need to work with clinicians/safety scientists closely
to further advance this field
References• Bate A, Lindquist M, Edwards, IR, Olsson S, Orre R, Lansner A, and De
Freitas RM (1998). A Bayesian neural network method for adverse drug reaction signal detection. Eur J Clin Pharmacol 54:315-321
• Berry S and Berry D (2004) Accounting for multiplicities in assessing drug safety: a three-level hierarchical mixture model. Biometrics, 60: 418-426
• Chi G, Hung HMJ, and O’Neill R (2002). Some comments on “Adaptive Trials and Bayesian Statistics in Drug Development” by Don Berry. In Pharmaceutical Report, Vol 9, 1-11
• Crowe B, Xia A, Watson D, Shi H, Lin S, Kuebler J, Berlin J, et al. (2008). Recommendations for Safety Planning, Data Collection, Evaluation and Reporting During Drug, Biologic and Vaccine Development: A Report of the PhRMA Safety Planning, Evaluation and Reporting Team (SPERT). Manuscript in preparation.
• DuMouchel W (1999). Bayesian data mining in large frequency tables, with an application to the FDA Spontaneous Reporting System (with discussion). The American Statistician 53:177-202
• Gould AL. Drug safety evaluation in and after clinical trials. Deming Conference, Atlantic City, 3 December 2002
• Mehrotra, DV and Heyse, JF (2004). Multiplicity considerations in clinical safety analysis. Statistical Methods in Medical Research 13, 227-238
• Spiegelhalter DJ, Best NG, Carlin BP and van der Linde A (2002) Bayesian measures of model complexity and fit (with discussion). J. Roy. Statist. Soc. B. 64, 583-640.
Incidence Rate of Treatment Arm
0.00 0.10 0.20 0.30
010
2030
4050
Min. 0 1st Qu. 0 Median 0 Mean 0.003 3rd Qu. 0.003 Max. 0.333
Incidence Rate of Placebo Arm
0.00 0.05 0.10 0.15
020
4060
80 Min. 0 1st Qu. 0 Median 0 Mean 0.003 3rd Qu. 0 Max. 0.164
Bayesian Hierarchical Model for AE (Berry & Berry 2004)
• PT level assumptions:
• SOC level assumptions:
),()1(]0[~),(~
2
2
iiiij
iij
NIN
• Global assumptions:
),(~),(~),(~
20
20
BetaTNTN
i
i
i
)1()(~)1()(~),(~),(~),(~),(~),(~),(~
2
2
2
2
200000
200000
IExpIExp
IGIGIGTIGT
TNTN
TT
TT
SOC: Injury, Poisoning and Procedural Complications
Preferred TermCtrl r(%)
Trt r(%)
diff (Trt-Ctrl ) Preferred Term
Ctrl r(%)
Trt r(%)
diff (Trt-Ctrl )
1 Alcohol Poisoning 0.00 0.08 0.080 26 Limb Injury 0.14 0.16 0.0222 Animal Bite 0.14 0.24 0.102 27 Mouth Injury 0.00 0.08 0.0803 Arthropod Bite 0.56 0.24 -0.315 28 Muscle Injury 0.00 0.08 0.0804 Back Injury 0.69 0.24 -0.453 29 Muscle Strain 0.69 0.72 0.0285 Cartilage Injury 0.14 0.00 -0.139 30 Neck Injury 0.14 0.08 -0.0596 Chemical Eye Injury 0.14 0.00 -0.139 31 Pain Trauma Activated 0.14 0.40 0.2637 Closed Head Injury 0.00 0.08 0.080 32 Pneumothorax Traumatic 0.00 0.08 0.0808 Concussion 0.28 0.00 -0.278 33 Post Procedural Complication 0.14 0.00 -0.1399 Contrast Media Reaction 0.14 0.00 -0.139 34 Post Procedural Pain 0.00 0.08 0.080
10 Contusion 0.83 0.80 -0.030 35 Procedural Pain 0.28 0.08 -0.19711 Epicondylitis 0.14 0.08 -0.059 36 Rib Fracture 0.14 0.08 -0.05912 Excoriation 0.00 0.64 0.643 37 Road Traffic Accident 0.00 0.16 0.16113 Eye Injury 0.14 0.08 -0.059 38 Scapula Fracture 0.00 0.08 0.08014 Fall 0.00 0.32 0.321 39 Skeletal Injury 0.42 0.00 -0.41715 Foot Fracture 0.00 0.32 0.321 40 Skin Laceration 1.11 0.72 -0.38816 Foreign Body in Eye 0.14 0.00 -0.139 41 Splinter 0.14 0.08 -0.05917 Hand Fracture 0.00 0.24 0.241 42 Sunburn 0.28 0.24 -0.03718 Heat Exhaustion 0.14 0.00 -0.139 43 Tendon Injury 0.00 0.08 0.08019 Heat Stroke 0.00 0.08 0.080 44 Thermal Burn 0.00 0.16 0.16120 Hip Fracture 0.00 0.08 0.080 45 Tooth Fracture 0.00 0.08 0.08021 Injury Corneal 0.14 0.00 -0.139 46 Tooth Injury 0.00 0.16 0.16122 Jaw Fracture 0.14 0.08 -0.059 47 Traumatic Haematoma 0.28 0.08 -0.19723 Joint Injury 0.00 0.08 0.080 48 Wound 0.14 0.24 0.10224 Joint Sprain 0.28 0.16 -0.117 49 Wrist Fracture 0.14 0.00 -0.13925 Ligament Injury 0.14 0.08 -0.059