Chapter 5 Discussion and Conclusion
5.4 Conclusion
In this pilot study, we used a complex statistical method, albeit standard in many non-medical disciplines, to test a hypothesis regarding the
relationship between ALS and the associated diseases. We screened over than 1,000 prior diseases associated with ALS and found 28 significant associations (17 positive and 11 negative). These positively associated diseases were symptoms concerning nutrition and metabolism and the comorbidities (the hypermetabolism group), and the negatively associated diseases were diabetes and the comorbidities (the hypometabolism group).
Hence, our results using different screened time windows and multivariate analysis to find that diseases associated with ALS support the evidence that hypermetabolism in the long term may be one of the causes of ALS.
Our findings are consistent with the known hypotheses regarding ALS and prior diseases and provide a more comprehensive explanation for the relationship between ALS and associated diseases.
Table 18 Summary of current epidemiological evidence on ALS, along with our preliminary results: case–control studies
Research Main association Our univariate analysis result
(screen period) Sutedja et al.
(2011)9
Patients used cholesterol-lowering agents OR=0.6 (95% CI:
0.4-0.9)
lower BMI OR=0.9 (95% CI:0.9- 1.0)
Lower in LDL/HDL ratio in women OR=0.4 (95% CI: 0.3-0.6);
in men OR=0.5 (95% CI: 0.4- 0.6)
Lower homocysteine levels in women OR=0.9 (95% CI:
0.9-1.0);
in men OR=0.9 (95% CI: 0.8-0.9)
Diabetes mellitus (ICD-9:250)N/A
Overweight, obesity and other hyperalimentation (ICD-9:278)N/A Ischemic heart disease (ICD-9:410~414)N/A
Occlusion of cerebral arteries (stroke) (ICD-9:434), OR=1.7 (before 1 year)
Phukan et al.(2012)44
13.8% of patients fulfilled the neary criteria for frontotemporal dementia;
34.1% of ALS patients without evidence of dementia fulfilled the recently published consensus criteria for cognitive impairment;
14% of ALS patients had evidence of cognitive impairment without executive dysfunction, and no cognitive abnormality was detected in almost half the cohort (46.9%)
Other cerebral degenerations(ICD-9:331)N/A
Fang et al.(2013)50
A previous cancer diagnosis was not associated with subsequent risk of ALS (OR=1.00; 95% CI:0.91-1.10),
An increased risk of ALS was observed during the first year after cancer diagnosis (OR=1.50; 95% CI:1.17-1.92),
A lower risk of cancer was observed in ALS patients after diagnosis compared with ALS-free individuals (IRR=0.84; 95%
CI:0.69-1.02),
A risk reduction was seen primarily two or more years after ALS diagnosis (IRR=0.64; 95% CI:0.45-0.88)
Neoplasm (ICD-9: 140-239)N/A
Research Main association Our univariate analysis result (screen period)
Seelen et al.(2014)41
Hypercholesterolemia (OR=0.76, 95%CI: 0.63-0.92, P=0.006) the use of statins (OR=0.45, 95%CI 0.35-0.59, P = 1.86×10-9) Immunosuppressive drugs (OR=0.26, 95%CI:0.08-0.86, P = 0.03)
Head trauma (OR=1.95, 95%CI:1.11-3.43, P=0.02)
No association was found with autoimmune diseases, cancer, psychiatric disorders or cardiovascular diseases, or survival.
Overweight, obesity and other hyperalimentation (ICD-9:278)N/A Disorders of lipoid metabolism (ICD-9:272)N/A
Open wound of head (ICD-9:873), OR=1.7 (before 1 year) Contusion of eye and adnexa (ICD-9:921), OR=5.2 (before 7 year)
Overweight, obesity and other hyperalimentation (ICD-9:278)N/A Mariosa et
al.(2015)5
Diabetes OR=0.79, (95%CI:0.68–0.91)
Non-insulin-dependent diabetes OR=0.66, (95%CI:0.53–0.81) Insulin-dependent diabetes OR=0.83, (95%CI:0.60–1.15)
<50 years individuals insulin-dependent diabetes OR=5.38, (95%CI:1.87–15.51)
Diabetes mellitus (ICD-9:250)N/A
Mitchell et al. (2015)47
Association of ALS with odds of arthritis (OR=0.14, 95%CI:
0.11- 0.18);
Non-ALS neurological disease (OR=0.14, 95%CI: 0.07-0.27));
Liver disease (OR=0.19, 95%CI: 0.10-0.35);
Chronic obstructive pulmonary disorder or COPD (OR=0.23, 95%CI: 0.16-0.32);
Kidney disease (OR=0.32, 95%CI: 0.18-0.57);
adult asthma (OR=0.39, 95%CI: 0.30-0.51);
Diabetes (OR=0.47, 95%CI: 0.38-0.58);
Hypertension (OR=0.56, 95%CI: 0.49-0.64);
Mononeuritis of lower limb (ICD-9:355), OR=2.6 (before 1 year) Osteoarthrosis and allied disorders (ICD-9:715), OR=1.5 (before 9 year)
Other and unspecified arthropathies (ICD-9:716), OR=1.6 (before 9 year)
Other diseases of digestive system-liver(ICD-9:570~573)N/A Anxiety, dissociative and somatoform disorders (ICD-9:300), OR=1.6 (before 9 year)
Parkinson's disease(ICD-9:332), OR=4 (before 1 year)
Other extrapyramidal disease and abnormal movement disorders (ICD-9:333), OR=2.6 (before 1 year)
Nephritis, nephrotic syndrome, and nephrosis (ICD-9:580~589)N/A
Research Main association Our univariate analysis result (screen period)
Mitchell et al. (2015)47 (continued)
Obesity (OR=0.6, 95%CI: 0.49-0.74);
Hyperlipidemia or hypercholesterolemia (OR=0.62, 95%CI:
0.54-0.71);
Thyroid disease (OR=0.78, 95%CI: 0.60-1.02).
Spinocerebellar disease (ICD-9:334), OR=24 (before 1 year) Other diseases of spinal cord (ICD-9:336), OR=10.4 (before 1 year)
Trigeminal nerve disorders (ICD-9:350), OR=9.2 (before 5 year) Nerve root and plexus disorders (ICD-9:353), OR=2.4 (before 7 year)
Mononeuritis of upper limb and mononeuritis multiplex (ICD-9:354), OR=2.2 (before 1 year)
Nephritis, nepherotic syndrome, and nephrosis(ICD-9:580~589)N/A
Disorders of lipoid metabolism (ICD-9:272)N/A Disorders of thyroid gland(ICD-9:240~246)N/A Pupillo et
al.(2016)48
Disabling traumatic events OR=1.54 (95% CI: 1.24-1.92) Open wound of head (ICD-9:873), OR=1.7 (before 1 year) Contusion of eye and adnexa (ICD-9:921), OR=5.2 (before 7 year)
Harwood et al.(2016)20
An extra 10kJ/kg/day of PA (OR=1.47, 95% CI:1.10-1.97) An extra 10mins/day of vigorous PA (OR=1.03, 95%
CI:1.01-1.05)
Physical active N/A
Hollinger et al.(2016)42
Associate with age of ALS onset
BMI >30 (OR=1.994; 95%CI: 1.335-2.978) Hypertension (OR=0.499; 95%CI: 0.391-0.637) Hyperlipidemia (OR=0.416; 95%CI:0.316-0.547) Neurological (OR=0.097; 95%CI: 0.012-0.813)
Race (African-American) (OR=1.521; 95%CI: 1.07-2.162) Race (other) (OR=0.71; 95%CI: 0.553-0.91)
Gender (female) (OR=0.64; 95%CI:0.508-0.805) Associate with ALS duration
Liver disease (OR=0.389; 95%CI: 0.093-1.629)
Overweight, obesity and other hyperalimentation (ICD-9:278)N/A Hypertensive disease (ICD-9:401~405)N/A
Ischemic heart disease (ICD-9:410~414)N/A
Anxiety, dissociative and somatoform disorders (ICD-9:300), OR=1.6 (post 9 year)
Parkinson's disease(ICD-9:332), OR=4 (before 1 year)
Other extrapyramidal disease and abnormal movement disorders (ICD-9:333), OR=2.6 (before 1 year)
Spinocerebellar disease (ICD-9:334), OR=24 (before 1 year) Other diseases of spinal cord (ICD-9:336), OR=10.4 (before 1
year)
Research Main association Our univariate analysis result
(screen period) Hollinger et
al.(2016)42 (continued)
Race (African-American) (OR=0.691; 95%CI: 0.441-1.082) Race (other) (OR= 2.016; 95%CI: 1.479-2.748)
Gender (female) (OR=1.186 ; 95%CI: 0.894-1.575)
Trigeminal nerve disorders (ICD-9:350), OR=9.2 (before 5 year) Nerve root and plexus disorders (ICD-9:353), OR=2.4 (before 7 year)
Mononeuritis of upper limb and mononeuritis multiplex (ICD-9:354), OR=2.2 (before 1 year)
Other diseases of digestive system-liver(ICD-9:570~573)N/A Seals et
al.(2016)22
Trauma OR=1.09, 95% CI:0.99-1.19;
First trauma before age 55 y OR=1.22, 95% CI: 1.08-1.37;
First traumas at older ages OR= 0.97, 95% CI: 0.85-1.10
Open wound of head (ICD-9:873), OR=1.7 (before 1 year) Contusion of eye and adnexa (ICD-9:921), OR=5.2 (before 7 year)
Kioumourtz oglou et al.(2016)45
CVD admission at least three years prior to the date of ALS diagnosis was OR=1.15 (95% CI: 1.04-1.27); Atherosclerosis OR=1.36 (95% CI: 1.02-1.80);
Ischemic heart disease OR=1.14 (95% CI:0.99–1.31);
no COPD OR=1.15 (95% CI:1.04-1.28);
COPD OR=1.18 (95% CI: 0.80-1.73)
Ischemic heart disease (ICD-9:410~414)N/A
Occlusion of cerebral arteries (stroke) (ICD-9:434), OR=1.7 (before 1 year)
COPD (ICD-9:490-496)N/A
Timmins et al.(2016)51
ALS patients had good cardiac fitness and no reported cardiovascular events.
Fewer obese women in ALS (13.6%, P<0.05); men with a normal BMI (47.2%, P<0.001); the prevalence of dyslipidemia was lower (38.7%) compared with the general population.
Overweight, obesity and other hyperalimentation (ICD-9:278)N/A
Visser et al.(2017)46
Parents of patients died less from cardiovascular disease was OR=0.78 (95% CI:0.64-0.94)
Death for severe trauma OR=2.30 (95% CI:1.17-4.46); others includes mainly diseases of kidney, liver or lung OR=2.09 (95%
CI:1.27-3.40)
Ischemic heart disease (ICD-9:410~414)N/A
Other diseases of digestive system-liver(ICD-9:570~573)N/A Nephritis, nephrotic syndrome, and nephrosis
(ICD-9:580~589)N/A
Asthma(ICD-9:493), OR=1.5 (before 1 year)
Table 19 Summary of current epidemiological evidence on ALS along with our preliminary results: cohort studies
Research Main association Our univariate analysis result
(screen period) Turner et al.
(2012)43
the rate ratio for ALS in the non-CHD cohort, compared with the CHD cohort, was RR=1.14 (95% CI:1.05-1.22); for PD it was RR=0.95 (95% CI: 0.93-0.98); and for MS RR=0.95(95%CI:0.88 -1.04)
Ischemic heart disease (ICD-9:410~414)N/A
Parkinson's disease(ICD-9:332), OR=4 (before 1 year) Multiple sclerosis(ICD-9:340)N/A
Fondell et al.(2013)52
42 men were diagnosed with ALS.
Of those, 13 had reported no alopecia, 18 had reported moderate alopecia, and 11 had reported extensive alopecia at age 45 years.
ALS compared with those who reported no alopecia (RR= 2.74, 95%CI: 1.23-6.13)
increased risk of ALS with increasing level of balding at age 45 years (Ptrend = 0.02)
Diseases of hair and hair follicles(ICD-9:704)N/A
Freedman et al.(2013)40
ALS mortality was not significantly associated with the incidence of total cancers SMR=1.00 (95%CI:0.95-1.06)
A significantly elevated risk of ALS death among survivors of melanoma SMR=1.49 (95%CI:1.17-1.85)
Tongue cancer SMR=2.57 (95%CI:1.41-4.32),
Significantly reduced ALS death risk among prostate cancer survivors SMR=0.86 (95 %CI:0.76-0.96)
Malignant melanoma of skin(ICD-9:172)N/A Other malignant neoplasm of skin(ICD-9:173)N/A Malignant neoplasm of tongue(ICD-9:141)N/A
Turner et al.(2013)14
5–54y Asthma RR:1.60, (95%CI:1.34-1.91)
<30y Insulin-dependent diabetes RR:3.94, (95%CI: 1.84-7.50) Multiple sclerosis RR:4.25, (95%CI:3.57-5.02)
Myasthenia gravis RR:5.02, (95%CI: 3.51-6.96) Myxedema RR:1.20 (95%CI: 1.10-1.31)
Polymyositis RR:6.05 (95%CI: 3.12-10.57)
Asthma(ICD-9:493), OR=1.5 (before 1 year) Diabetes mellitus (ICD-9:250)N/A
Myoneural disorders(ICD-9:358), OR=4.2 (before 1 year) Acquired hypothyroidism(ICD-9:244)N/A
Diffuse diseases of connective tissue(ICD-9:710)N/A
Research Main association Our univariate analysis result (screen period)
Freedman et al. (2014)17
ALS after all cancers combined in the 10-year follow-up period (HR=0.99; 95%CI:0.81-1.22)
ALS after all cancers combined after 1-year follow-up period (HR=1.98; 95%CI:1.10-3.57)
Neoplasm (ICD-9: 140-239)N/A
Sun et al.(2014)6
Diabetes HR=1.35 (95%CI: 1.10-1.67); men (HR= 1.48; 95%
CI:1.13-1.94); women (HR= 1.17; 95% CI:0.84-1.64),
while men aged ≤65 years showed the most increased HR=1.67 (95% CI:1.18-2.36).
Diabetes mellitus (ICD-9:250)N/A
Turner et al.
(2015)11
An increased rate ratio for ALS was found in
relation to prior AVM (RR:2.69, 95% CI: 1.23-5.12, p=0.005), all strokes (RR:1.38, 95% CI: 1.27-1.51, p<0.001, and TIA (RR:1.47, 95% CI: 1.29-1.68, p<0.001).
Other congenital anomalies of circulatory system(ICD-9:747)N/A Occlusion of cerebral arteries (stroke) (ICD-9:434), OR=1.7 (before 1 year)
Transient cerebral ischemia(ICD-9:435)N/A Ji et
al.(2016)7
ALS with AUD compared ALS without AUD (SIR=0.54; 95% CI:
0.45-0.63)
the results of a family history of ALS were excluded were not changed (N = 134, SIR=0.53, 95% CI:0.45-0.63)
Alcohol dependence syndrome(ICD-9:303)N/A
HR=5.27, 95%CI: 1.09-15.40, p=0.041 testicular cancer
HR=3.82, 95%CI: 1.06-9.62, p=0.042
cutaneous malignant melanoma HR=1.62, 95%CI: 0.88-2.71, p=0.12
Neoplasm (ICD-9: 140-239)N/A
Research Main association Our univariate analysis result (screen period)
Fang et al.(2016)19
the fastest skiers had a higher risk (HR=2.08, 95%CI:1.12-3.84);
skiers who had 4 races (HR=1.88, 95%CI: 1.05-3.35),
finishing at 180% of winner time had a lower risk (HR= 0.46, 95%CI: 0.24-0.87)
Physical active N/A
Turner et al.(2016)8
People with psychiatric disorders who had a subsequent hospital diagnosis of ALS
<1 year:
Schizophrenia (narrow) RR=2.69(1.74-3.97);
Schizophrenia (broad) RR=2.95(2.13-4.00);
Bipolar (narrow) RR=3.20(1.94-4.97);
Bipolar (broad) RR=3.54(2.23-5.35);
Depression RR=4.37(3.81-5.01);
Anxiety RR=3.59(2.93-4.36);
1–4 years:
Bipolar (narrow) RR=1.91(1.32-2.67);
Bipolar (broad) RR=2.01(1.41-2.78);
Depression RR=2.24(2.00-2.51);
Anxiety, dissociative and somatoform disorders(ICD-9:300), OR=1.6 (before 9 year)
76